Respiratory Emergencies (Monograph of the European Respiratory Society)

Preface Access to free airways is the first consideration in emergency situations, such as at the scene of an accident,...

Author: European Respiratory Society

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Preface Access to free airways is the first consideration in emergency situations, such as at the scene of an accident, and respiratory emergencies represent an important part of acute medicine in general. Respiratory problems also play a crucial part in critical care medicine and constitute an important share of the numerous problems in an intensive care unit. As breathing difficulties are experienced with anguish, these symptoms can generally be very frightening, particularly to those suffering from them. It seems reasonable to assume that respiratory emergencies are mostly handled by physicians specialised in respiratory diseases. However, this is far from the case and the tradition in this regard varies from country to country. In some countries, there is close collaboration between respiratory and intensive care units, whereas in other countries this collaboration is occurs less frequently. It may also be problematic finding novel scientific achievements within the field of respiratory emergencies since there is no clear forum for these kinds of publications. The number of scientific papers emphasising respiratory emergencies finding their way into respiratory journals is not overwhelming, which is a pity and is something that we could, and should, try to change in the future. As a result, those interested in respiratory emergencies who are searching for compiled information focused in this field have to put in a great deal of work seeking information from various sources. Therefore, it is very satisfying and a great pleasure to announce this issue of European Respiratory Monograph on respiratory emergencies. In this issue of the monograph, different aspects of respiratory emergencies have been covered by the best specialists in the field. The Monograph gives insights into acute respiratory events due to exacerbations of obstructive pulmonary diseases, infections, accidents, neuromuscular disorders, acute respiratory distress syndrome, and much else. It is my hope that it will reach many readers and that it may help to throw a bridge across between specialists in respiratory and intensive care medicine. K. Larsson Editor in Chief

Eur Respir Mon, 2006, 36, viii. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

viii

INTRODUCTION

S. Nava*, T. Welte# *Respiratory Intensive Care Unit, S. Maugeri Foundation, Scientific Institute for Research and Care, Pavia, Italy. Fax: 39 0382592075; E-mail: [email protected]; #Dept of Respiratory Medicine, Hannover Medical School, Hannover, Germany. Fax: 49 5115328532; E-mail: [email protected]

Emergency medical admissions constitute a substantial proportion of the workload of the respiratory and cardiology wards, and of the emergency departments. Mortality among these patients is significant and may be determined by the quality of care provided. According to the risk stratification of the patients, the mortality rate may vary from 1% to w30%. Interestingly enough, among the numerous variables associated with in-hospital mortality, two of the most powerful independent predictors are respiratory rate and oxygen saturation, suggesting that the respiratory system is very often involved either as a primary trigger of the emergency or as a secondary target of another organ’s acute dysfunction. Most pulmonologists or intensivists, when asked about what they consider to be a respiratory emergency, are likely to suggest the occurrence of acute respiratory failure, either "purely hypoxic" or hypercapnic. It follows that the main causes of acute respiratory problems are considered to be an exacerbation of chronic obstructive pulmonary disease or a restrictive disease, pulmonary infections, acute respiratory distress syndrome and cardiogenic pulmonary oedema. Consequently, the larger part of books, monographs and reviews on acute respiratory problems deal with these specific topics. However, in our daily practice, we have to face other important, although less frequent, respiratory emergencies, such as haemoptysis, ingestion of foreign bodies, pneumothorax, drowning and inhalation injury. Indeed, some peculiar aspects, such as paediatric respiratory emergencies and the occurrence of respiratory failure during pregnancy, are very seldom assessed if they are not covered in specific publications. The idea of this Monograph, published by the European Respiratory Society, was to fill this gap, giving the readers the opportunity to have a complete overview of the respiratory emergencies that account for y20–30% of all the emergency admissions to hospital. The guest editors have asked international experts to not only write an up-to-date review of their specialist subject, but also, when feasible, to give some personal insights based on their long experience in the field. A great amount of effort has been put in by everyone involved in the project, from the publishers to the authors. Have we succeeded? The answer is down to the readers!

Eur Respir Mon, 2006, 36, ix. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

ix

CHAPTER 1

Hypoxic and hypercapnic respiratory failure P. Ceriana, S. Nava Respiratory Intensive Care Unit, S. Maugeri Foundation, Scientific Institute for Research and Care, Pavia, Italy. Correspondence: P. Ceriana, Respiratory Intensive Care Unit, Fondazione "S.Maugeri", Via Ferrata 8, 27100 Pavia, Italy. Fax: 39 382592075; E-mail: [email protected]

Maintenance of normal arterial blood pH and adequate oxygen supply are essential prerequisites for normal cellular function, body homeostasis and mitochondrial energy production. This results from complex interactions between the respiratory and cardiovascular systems, blood and cellular metabolism; problems arising at any of these steps may result in failure to maintain normal arterial blood pH and adequate oxygen supply. The respiratory system is the first link in this complex chain (table 1), and can be considered to consist of two parts: the lungs, which are the gas-exchanging organ, and the pump, whose task is to ventilate the lungs [1]. The pump includes the respiratory controllers in the central nervous system, the connecting pathways with the respiratory muscles (spinal and peripheral nerves) and the chest wall and the respiratory muscles. Respiratory failure is a condition in which the respiratory system fails in one or both of its gas exchange functions, i.e. oxygenation and clearance of carbon dioxide. Therefore, failure of an individual part of the respiratory system can lead to a distinct clinical entity; diseases affecting the lung (i.e. pneumonia, interstitial lung disease, acute cardiogenic pulmonary oedema (ACPO), acute lung injury (ALI) and acute respiratory distress syndrome(ARDS)) mainly compromise oxygen transport, whereas problems with the ventilatory pump (opiate overdose, chronic obstructive lung disease, kyphoscoliosis, neuromuscular disease, etc.) cause alveolar hypoventilation and decreased carbon dioxide elimination. Any condition in which the arterial oxygen tension (Pa,O2) is v7.3–8.0 kPa breathing room air is generally called hypoxic (or type I) respiratory failure, whereas hypercapnic respiratory failure is a condition in which arterial carbon dioxide tension (Pa,CO2) isw6.5–6.6 kPa, with or without acidosis (arterial blood pHv7.36). Hypoxaemia and hypercapnia can coexist in the same patient, since both functions of the lung can fail simultaneously or at different stages of the same disease. When Pa,O2 is measured in an arterial blood sample, the tension of the aliquot of oxygen in physical solution rather than the arterial oxygen content is measured; the majority of the oxygen is bound to haemoglobin and in equilibrium with the much smaller pool in physical solution [2]. At usual Pa,O2, this is y0.3 mL?dL-1, making a negligible contribution to total oxygen delivery; it can rise to 2 mL?dL-1 breathing 100% oxygen and to 6 mL?dL-1 breathing 100% hyperbaric oxygen (three atmospheres). The relationship between these two pools is nonlinear, being described by the haemoglobin dissociation curve; haemoglobin saturation does not significantly decrease in cases of moderate falls in Pa,O2 (up to 10 kPa) and the oxygen content can remain high even under conditions of moderate hypoxaemia; hence Pa,O2 influences blood oxygen content only indirectly, through its effect on haemoglobin–oxygen binding. Eur Respir Mon, 2006, 36, 1–15. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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P. CERIANA, S. NAVA

Table 1. – Steps in gas transport from the environment to peripheral tissue Step

System involved

Movement of gases between the environment and the lungs Intrapulmonary gas exchange with mixed venous blood Gas transport to and from peripheral tissues Tissue gas exchange and oxygen utilisation

Respiratory system Respiratory system, cardiovascular system Cardiovascular system, blood Blood, cellular metabolism

Hypoxaemia, which refers to decreased delivery of oxygen from the atmosphere to the blood, must also be distinguished from hypoxia, which refers to reduced delivery of oxygen to the tissues; it is possible to have hypoxaemia without hypoxia and vice versa. From the above, it is clear that laboratory data are essential to the diagnosis of respiratory failure, but it must be borne in mind that the threshold values must not be considered absolute, since they must be evaluated together with patient history and clinical assessment. From a clinical point of view, it can be useful to distinguish acute respiratory failure, a clinical state of sudden appearance in a previously healthy organ, from chronic respiratory failure, whose onset is usually slow and insidious. The most indicative examples of the first group are ACPO, ARDS and pneumonia for parenchyal disorders and opiate overdose and Guillain–Barre´ syndrome for ventilatory pump diseases. Generally, chronic respiratory failure is characterised by phases of relative stability interrupted by phases of exacerbation (acute-on-chronic respiratory failure); an example of a chronic parenchymal disease is idiopathic pulmonary fibrosis, whereas chronic pump failure is typical of all neuromuscular and chest wall disorders and of the advanced stage of chronic obstructive pulmonary disease (COPD). In the following paragraphs, the main pathophysiological hallmarks of hypoxic and hypercapnic respiratory failure are briefly summarised.

Hypoxic respiratory failure Oxygen stores in human lungs are extremely poor, being limited to the small amount present in the functional residual capacity (FRC), which functions as a sort of oxygen reservoir. In the case of apnoea, such as after loss of consciousness, the amount of oxygen present at FRC continues to diffuse into the blood and is sufficient to maintain arterial oxygen saturation for no more than 1 min, unless the patient has previously completed a full exhalation, in which case, with no air left in the lung, desaturation would occur even earlier [3]. Pathological changes of FRC, such as those that occur in restrictive or obstructive diseases, may also explain why patients can develop hypoxaemia slowly (obstructive, with increased FRC) or quickly (restrictive, with decreased FRC) upon interruption of oxygen therapy. This concept is not devoid of clinical relevance. The onset and the course of hypoxaemia can be rapid and stormy, especially when shunt is the underlying mechanism; prompt and sometimes aggressive therapeutic measures must be put in place in order to prevent possible injuries to vital organs. The hallmark of lung failure is, as previously stated, hypoxaemia. The Pa,O2 alone, however, gives very little information about the state of the lung, since the same Pa,O2 can underlie both severe lung disease and an intact lung parenchyma. In the presence of a low Pa,O2, the ratio between Pa,O2 and the inspiratory oxygen fraction (FI,O2) (Pa,O2/FI,O2), which isw53–60 kPa in a normal subject and bears witness to severe hypoxic respiratory failure when v40 kPa, must first be calculated. The importance of this ratio becomes apparent with the following example: a Pa,O2 of 10 kPa when a subject breathes an FI,O2 2

HYPOXIC AND HYPERCAPNIC RESPIRATORY FAILURE

of 100% may be adequate as an absolute value, for avoiding cellular hypoxia, but indicates severe pulmonary dysfunction, since the Pa,O2/FI,O2 is only 10. Since hypoxaemia does not necessarily mean lung disease, the second diagnostic step in the case of a low Pa,O2 is calculation of the alveolar–arterial oxygen tension difference (PA,O2–Pa,O2, or PA–a,O2), where PA,O2 is alveolar oxygen tension. Although Pa,O2 can easily be measured using an arterial blood sample, PA,O2 must be derived from the alveolar gas equation, which can help to discriminate pulmonary from extrapulmonary causes of hypoxaemia:

PA,O2 ~EBPF I,O2 Pa,CO2 =RQ,

ð1Þ

where EBP is the effective barometric pressure, i.e. the difference between barometric pressure and water vapour pressure at body temperature (6.2 kPa at 37uC), and RQ the respiratory quotient (y0.8 on a standard diet) (table 2) [4]. This simple measurement permits discrimination between, for example, conditions in which the lung parenchyma is substantially intact and the gradient is narrow (v1.3– 2.0 kPa) and true lung diseases in which the gas exchange problem causes a widening of the gradient (w2.6 kPa). There are six pathophysiological mechanisms underlying hypoxaemia, and its origin can be found within or outside the lung (table 2) [5]. Only hypoxaemic states of pulmonary origin are taken into account in the following paragraphs.

Impaired diffusion In the presence of diffusion defects, full equilibration of alveolar gas with pulmonary capillary blood is prevented; factors that can be an obstacle to oxygen diffusion are an increased distance between alveolus and erythrocyte, a decreased oxygen gradient for diffusion and a shortened transit time of the red cell through the capillary. In this case, arterial oxygen saturation at rest can be within the normal range, and desaturation is manifest only in the presence of a high cardiac output, in which there is insufficient time for haemoglobin to combine with oxygen through a thickened alveolar capillary membrane. Diffusion defects are less important clinically and may produce hypoxaemia only during exercise, easily corrected with supplemental oxygen [6]. Table 2. – Mechanism, site and possible causes of hypoxaemia PA-a,O2 Mechanism

Site

Possible causes

Room air

100% O2

Hypoventilation Impaired alveolar oxygen diffusion

Extrapulmonary Pulmonary

Respiratory centre depression Pulmonary fibrosis, pulmonary resection

Normal Normal

Ventilation/perfusion mismatch

Pulmonary

Shunt of systemic venous blood

Pulmonary, extrapulmonary (cardiac) Extrapulmonary

Emphysema, pulmonary embolism Pneumonia, cardiac septal defect

Normal Normal at rest, reduced under effort Increased Increased

Increased

Normal

Normal

Normal

Normal

Inhalation of hypoxic gas mixture Abnormal desaturation of systemic venous blood

Extrapulmonary

Toxic fume inhalation, high altitude Fever, low cardiac output

Normal

The only mechanism not responsive to supplemental oxygen is shunt. PA–a,O2: alveolar–arterial oxygen tension difference. 3

P. CERIANA, S. NAVA

Ventilation/perfusion mismatching This is the most frequent contributor to clinically relevant oxygen desaturation, and the basic mechanism responsible for hypoxaemia in the majority of airway diseases, such as emphysema, chronic bronchitis, cystic fibrosis and asthma. In healthy subjects, most alveolar capillary units have ventilation/perfusion (V9/Q9) ratios ranging 0.5–2.0, depending on regional differences in ventilation and perfusion; under these conditions, full gas exchange efficiency is maintained, since the capillary blood that leaves these alveoli displays very similar gas levels to alveolar ones. A relevant contribution to the maintenance of this homeostasis is provided by an autoregulatory mechanism called hypoxic pulmonary vasoconstriction; when the reduced ventilation to a lung region causes a decrease in PA,O2, blood flow is diverted towards the nearest better ventilated areas through constriction of local pulmonary vessels [7]. Lung units that are better perfused than ventilated cause oxygen desaturation, whereas those with a high V9/Q9 ratio contribute to dead space but not to hypoxaemia. In order to understand why V9/Q9 mismatch causes hypoxaemia, it must first be remembered that the relationship between oxygen content and Pa,O2 is curvilinear; at normal barometric pressure, when haemoglobin is already fully saturated, little additional oxygen can be carried into the blood, despite a maximal rise in oxygen tension in the overventilated alveolus. When aliquots of blood coming from lung units with different V9/Q9 ratios combine, they mix their individual gas contents (not their oxygen tensions). Hence, when equal volumes of blood mix after passage through well- and poorly ventilated lung units, the resultant oxygen content is halfway between the two, but the mixed Pa,O2 is markedly shifted towards that of the poorly ventilated areas [6]. In this case, attempts to compensate for the underventilation of low V9/Q9 units with hyperventilation of high V9/ Q9 ones cannot maintain Pa,O2 at normal levels. This explains why, even with normal total ventilation and perfusion values, regional V9/Q9 mismatching can be sufficient to cause hypoxaemia. As in the case of impaired diffusion, supplemental oxygen enables the correction of low Pa,O2 when V9/Q9 mismatch is the main problem; the lower the V9/Q9 ratio of poorly ventilated areas, the longer the duration of oxygen inhalation required to reverse hypoxaemia.

Shunt Shunt refers to systemic venous blood that either bypasses the lungs or crosses nonventilated alveoli without being oxygenated. This may happen in extrapulmonary diseases, such as right-to-left congenital heart diseases, after opening of the foramen ovale (even in adulthood) due to increased right ventricular afterload or when venous blood passes through arteriovenous communications. However, in the majority of cases, shunt is caused by pulmonary disease, being the most common cause of hypoxaemia in critically ill patients affected by pneumonia, ALI or ARDS. In the normal subject, there is a negligible right-to-left shunt,y2–5% of cardiac output; this is derived from the systemic venous blood that returns to the left heart through the thebesian and bronchial veins and is called anatomical shunt. A true shunt, conversely, is created in the presence of atelectasis, pulmonary oedema and pneumonia, in which venous blood perfuses nonventilated alveoli (V9/Q9=0), and no gas exchange takes place. Total cardiac output (Q9tot) is the sum of pulmonary capillary blood flow (Q9c) plus the shunted aliquot (Q9sh), also called venous admixture:

Q0 tot~Q0 czQ0 sh:

ð2Þ

The shunt fraction (Q9sh/Q9tot) provides a reliable estimate of the degree of oxygenation failure; it is normallyy2–5%, and values ofw15–20% are found in cases 4


of relevant respiratory failure. It can be calculated using the shunt equation (equation 3), after breathing 100% oxygen for i20 min: Q0 sh Cc,O2 Ca,O2 ~ ð3Þ Q0 tot Cc,O2 Cv,O2 where Ca,O2, Cv,O2 and Cc,O2 are the arterial, mixed venous and end-capillary oxygen content, respectively. In clinical practice, pulmonary Cc,O2 cannot be directly measured and is assumed to be equal to the alveolar content. Venous admixture can be divided into: 1) blood which has passed from the right to the left side of the circulation and picked up no oxygen in the lung (true shunt); and 2) blood which has picked up some oxygen in the lungs but is still incompletely oxygenated, having passed through zones of low V9/Q9 ratio [8]. This is the reason why venous admixture is variably responsive to the administration of supplemental oxygen, whereas changes in FI,O2, in either direction, have very little effect on Pa,O2 in the case of true shunt.

Hypoxaemic states Many pathological states, whose aetiology, clinical course and prognosis can be very different, are included under the definition hypoxic respiratory failure. Despite their heterogeneity, however, the pathological mechanisms underlying hypoxaemia lead back, in the majority of cases, to alveolar collapse, alveolar flooding or impaired hypoxic pulmonary vasoconstriction. Alveolar collapse develops as a consequence of: 1) reduced alveolar stretching, as in the case of reduced diaphragmatic excursions; 2) after reabsorption of alveolar gas, as in the case of bronchial obstruction; and 3) external compression that limits tidal opening and distension, as in the case of pleural effusion. Hypoxic pulmonary vasoconstriction is impaired in some disease states (pneumonia, sepsis and liver failure), mainly as a consequence of local cytokine production. Alveolar flooding is generally the most important mechanism underlying complex and clinically relevant hypoxaemic states, such as ACPO, ALI and ARDS. In most cases of respiratory failure, hypoxaemia results from a combination of these three mechanisms, and the magnitude of the contribution of each can vary over the course of a particular disease. For schematic purposes, alveolar flooding is divided into two types in the following two sections, the hydrostatic type (best represented by ACPO) and the inflammatory type (ALI and ARDS). As explained, however, this distinction is not strict, since both mechanisms frequently coexist and overlap in the same disease.

Hydrostatic pulmonary oedema Pulmonary oedema results when the quantity of fluid that crosses the pulmonary endothelium into the interstitial space and alveolar cavities overwhelms the lung’s capacity to clear and drain fluids. In the normal lung, pulmonary capillary blood is separated from the interstitium by a single layer of endothelial cells which facilitates the easy passage of water and small solutes; this endothelial membrane has a system of pores that regulates the passage of larger molecules. The alveolar epithelium, conversely, is much less permeable to fluid and protein, having much smaller pores and tighter intercellular junctions [9]. Between the microvascular endothelium and the alveolar epithelium, there is a very thin interstitial space, the main route through which gas exchange take place. Besides this thin perialveolar interstitial space, there is also an extra-alveolar thick space, which includes 5

P. CERIANA, S. NAVA

airways, lymphatics and microvessels and takes part in protein exchange and fluid resorption. Under physiological conditions, fluids and proteins moving out from the pulmonary microvessels collect in the extra-alveolar interstitial space, and are then drained through the lymphatic vessels and eventually into the venous system; when interstitial fluid is collected in excess, it forms a type of cuff around airways and blood vessels [10]. Therefore, pulmonary lymph flow rate and composition are reliable indicators of transvascular fluid and solute filtration rate. The quantity of fluid that can be collected into the interstitial space depends upon the endothelial filtration rate, interstitial capacity and lymph drainage capability. Alveolar flooding occurs when the interstitium has reached its maximum fluid capacity and the net flow out from the pulmonary vessels exceeds lymphatic drainage. Penetration of fluid into the alveoli can occur through the interepithelial junctions of the alveolar walls or through the epithelium of the terminal bronchioles, thus filling the alveolus from the top [11]. However this penetration occurs, the fluid first accumulates close to the alveolar junctions, and then the whole alveolus and bronchial tree become filled with fluid. Resolution of oedema takes place through active transport of sodium across the alveolar epithelium into the interstitium and pulmonary circulation; this generates an osmotic gradient that clears fluid from the air spaces [12]. Sodium is transported through specific channels at the apex of the alveolar cell and then is actively pumped out by a sodium/potassium adenosine triphosphatase [13]. The main determinant of filtration across the endothelial layer is the microvascular hydrostatic pressure (MVHP), which reflects downstream variations in pulmonary venous and left atrial pressure; it cannot be directly measured in the clinical setting, but an estimate can be obtained using pulmonary capillary wedge pressure. However, this is not the only force governing movements of fluid through the endothelial membrane; interstitial hydrostatic pressure, which becomes more negative from the periphery towards the hilum, probably cooperates in the mobilisation of fluid to the central collecting sites. Opposite forces are generated by protein oncotic pressures, intravascular and interstitial, respectively. The normal ratio of lymph to plasma protein concentration is y0.6; hence the net force tends to draw water into the microvessel. Hypoproteinaemia per se is not sufficient to cause pulmonary oedema, but, in the presence of elevated MVHP, makes the lung more susceptible to it. Hydrostatic pulmonary oedema with elevated MVHP is generally precipitated by an increase in left atrial pressure due to cardiac diseases (ACPO), as occurs in left ventricular failure, myocardial ischaemia, mitral regurgitation, volume overload in a poorly compliant left ventricle or renal failure, etc. To explain pulmonary oedema simply as a balance between opposing hydrostatic forces is, however, reductive, since the role played by neurohormonal and inflammatory activation in the pathogenesis and outcome of this syndrome is now well established. Laboratory and clinical studies conducted since the mid-1990s have, indeed, added new pieces of information to what has already been established from classical studies [14]. ACPO is associated with injury and increased permeability of the alveolocapillary barrier; if hydrostatic pressure alone were responsible for the oedema, the protein concentration in the alveolar fluid would decrease from the normal level ofy20 g?L-1 due to dilution by plasma ultrafiltrate [15]. On the contrary, some studies found this concentration to be almost doubled, signifying massive flux of protein-rich fluid. Further evidence of alveolocapillary damage was the detection, in some patients’ blood, of high levels of surfactant proteins A and B, which remained elevated forw24 h, well beyond the restoration of the normal haemodynamic state, despite their short half-lives [16]. All of these data, together with the elevated levels of some inflammatory mediators (interleukin 6 and tumour necrosis factor-a), support the hypothesis that inflammation plays a significant role in the alveolocapillary damage seen in ACPO [17]. It is generally 6


short-lived with proper and prompt treatment, but, in the first few days after the acute episode, patients are particularly vulnerable to relapses, due to the instability of the capillary membrane. ACPO can develop even with a well-compensated left heart in the case of transient episodes of diastolic dysfunction, such as during arrhythmias, hypertensive crises and ischaemia; sudden increases in MVHP can cause transient alveolar flooding known as flash pulmonary oedema, whose clinical and radiographic appearance and resolution can be impressively rapid [18].

Inflammatory pulmonary oedema This generic term refers to all of the hypoxaemic states in which alveoli are flooded with a protein-rich exudate that crosses leaky capillaries in the presence of a normal MVHP; although the initial insult can belong to a wide range of disease states, the final common pathway is the activation of a systemic inflammatory response that damages the alveolar–capillary membrane from either the gas side (smoke inhalation and aspiration of gastric acid) or the capillary side (sepsis). Increased membrane permeability permits the passage of protein-rich fluid into the interstitium and alveoli, with consequent inhibition of surfactant and diffuse atelectasis [19]. This kind of noncardiogenic pulmonary oedema can even be short-lived if the inciting event causes disruption of the pulmonary capillary membrane but without major endothelial damage, as in the case of heroin-induced and neurogenic (after major head trauma) pulmonary oedema [20]. In these cases, resolution of oedema occurs promptly, without widespread endothelial damage or a protracted inflammatory response, and the patient usually displays a favourable clinical outcome. In the majority of cases, however, the injury to the alveolocapillary membrane is protracted over a longer period of time, with a cascade pattern, and the functional impairment of the lung can, in some cases, be permanent. The majority of severe hypoxaemic states, independent of aetiology, are currently grouped under the definition of ALI or ARDS [21], according to the criteria listed in table 3. These diseases probably represent the ends of a broader spectrum of lung injury, and it is not quite clear whether they should be considered separate clinical entities or different phases of the same disease, since most cases of ALI do not necessarily progress towards full-blown ARDS. The precipitating causes of ARDS can cause a direct insult to the lung (ARDS of pulmonary origin) or can affect the lung indirectly as a complication of a remote disease process (ARDS of extrapulmonary origin). Thus despite the presence of different pathogenetic pathways, the histopathological response of the lung to injury can be the same. The role played by circulating inflammatory mediators is pivotal, especially in extrapulmonary ARDS; cytokines released by neutrophils and macrophages induce an inflammatory response in the pulmonary microvasculature and activation of the complement and clotting systems. Vasoactive mediators of endothelial origin (nitric oxide, endothelin and cyclooxygenase derivatives) cause alterations in vascular tone and Table 3. – Criteria used to define acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) Disease ALI ARDS

Onset Acute Acute

Chest radiograph

Pulmonary capillary wedge pressure mmHg #

Bilateral infiltrates Bilateral infiltrates

ƒ18 ƒ18#

Pa,O2/FI,O2 kPa v40 v27

Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction. #: or, if not measured, no evidence of left atrial hypertension. 1 mmHg=0.133 kPa. 7

P. CERIANA, S. NAVA

loss of hypoxic pulmonary vasoconstriction, whereas problems in the coagulative system lead to the formation of microthrombi. The result is an inflammatory cascade with endothelial and epithelial cell damage and ultrastructural changes that cause increased permeability of the alveolar capillary membrane [22]. The histological aspect of ARDS is stereotypical, and follows three partially overlapping phases, exudative, proliferative and fibrotic, the common aspect being disruption of the alveolar capillary unit, also described as diffuse alveolar damage [23]. The first (exudative) stage is manifest within 48 h following the insult and consists of nonspecific alveolar proteinaceous oedema; plasma proteins condense with cell debris and form typical hyaline membranes, which, together with fibrin thrombi, line the wall of alveoli and alveolar ducts. The second, or proliferative, stage occurs y1 week after the insult and may lead to the resorption or consolidation of oedema, with progression towards healing or formation of intra-alveolar and interstitial organisative tissue. In the third stage, deposition of collagen occurs, with diffuse fibrosis and vascular remodelling with the formation of scarry and cystic areas [19]. Despite the presence of common pathogenetic mechanisms, the pulmonary and extrapulmonary forms of ARDS differ in as far as the mechanical properties of the respiratory system and the response to ventilatory treatment are concerned. Indeed, in the first, lung elastance is higher, whereas, in the second, the increased abdominal pressure causes an increase in chest wall elastance, probably responsible for the prevalence of lung consolidation in the first and alveolar collapse in the second [24]. The lung appears to be stiffer in pulmonary ARDS and more compliant in the extrapulmonary form, with, respectively, worse and better responses to the application of positive end-expiratory pressure. The clinical consequence during mechanical ventilation can be a greater risk of barotrauma in pulmonary ARDS and haemodynamic impairment in the extrapulmonary form.

Hypercapnic respiratory failure Carbon dioxide delivered to the lung by venous blood diffuses into the alveoli and is eliminated breath by breath by means of the ventilatory pump. Alveolar carbon dioxide concentration (the main determinant of Pa,CO2) is directly proportional to carbon dioxide production (V’CO2) and inversely proportional to alveolar ventilation (V’A):

Pa,CO2 ~

V 0 CO2 K V 0A

ð4Þ

where K is the proportionality constant. From the above equation, it can be seen that hypercapnia can result from increased production or inadequate clearance. The first case refers to all clinical situations with increased metabolic activity (fever, excessive carbohydrate intake, malignant hyperthermia, strenuous physical exercise, etc.); in the presence of an efficient ventilatory pump, however, the extra carbon dioxide load can be afforded without the development of clinically relevant or long-lasting hypercapnia. Most clinically relevant hypercapnic states, conversely, result from inadequate clearance as a consequence of alveolar hypoventilation. V’A is the product of respiratory frequency (fR) and alveolar tidal volume (VT), the difference between VT and dead space (VD), the latter being the volume of inspired air that does not participate in gas exchange, V 0 A~f R(V TV D): 8

ð5Þ


VD, also called physiological dead space, is the sum of anatomical dead space (y150 mL in adults) and alveolar dead space, the volume of alveoli with a high or infinite V9/Q9 ratio. Physiological dead space is expressed not as an absolute value but as a ratio (VD/VT) since, although variable with VT, it remains a constant proportion thereof (normally y0.3). Most frequent causes of increased VD/VT are parenchymal diseases such as emphysema or ARDS and circulatory problems such as low output states and pulmonary embolism. Since V’A is the difference between minute ventilation (V’E) and VD, it can be assumed that a reduced V’A develops when VD/VT increases at constant V’E and V’CO2, or when V’E decreases but VD/VT and V’CO2 remain constant [25]. Normally, the ventilatory drive adjusts the output of the muscular pump in proportion to metabolic activity in order to maintain arterial blood pH within narrow limits (7.38– 7.42); hence, efficiency of the ventilatory pump requires both integrity of the output pathway from the brain to the respiratory muscles and adequate force and coordination of the chest wall and respiratory muscles. At rest, the normal Pa,CO2 isy5.3 kPa, whereas values of w6 kPa are considered abnormal. Owing to the very large volume of carbon dioxide stored buffered in the body (y120 L), every change in V’A requires i20 min for the achievement of a new steady state; this turns to be useful in some clinical contexts, since, even in the case of total respiratory arrest, the rise in Pa,CO2 is slow (y0.4– 0.8 kPa?min-1) [26]. This slower progression of hypercapnia gives the physician less stringent time limits for the management of the hypercapnic patient, giving more chances of success even with a less aggressive treatment (i.e. noninvasive ventilation), and hence with an approach different to that required in the case of a rapidly evolving hypoxaemic crisis. Causes of pump failure can be grouped into three major categories: central depression, mechanical defect of the ventilatory pump, and muscle fatigue (table 4). These three mechanisms often coexist in the same disease and bring their own contribution to the development of reduced V’A and hypercapnia [27]. The disease state that best exemplifies the hallmark of pump failure with both components of muscle fatigue and mechanical defect, and that, at the same time, is the most frequent cause of clinically relevant hypercapnia that the physician has to cope with is exacerbation of COPD, which is discussed briefly in the following section.

Exacerbation of chronic obstructive pulmonary disease Pathophysiological background. The classic distinction of COPD patients into pink puffers (predominance of emphysema) and blue bloaters (predominance of chronic bronchitis) is seldom applicable in the clinical context, the two components being almost Table 4. – Main causes of ventilatory pump failure

Central depression Mechanical defect

Muscle fatigue

Disease

Mechanism

Anaesthesia, disease of the medulla, central sleep apnoea (encephalitis) Kyphoscoliosis, flail chest, diaphragmatic paralysis, nerve (Guillain–Barre`) or muscle diseases (myopathies)

Inadequate output from the controlling centres with reduced respiratory drive Interrupted output pathway, altered geometry of the chest wall or deficit of the peripheral effector with failure of proper pumping mechanism Increased energy demand (hyperinflation, acute asthma) or reduced energy supply (low cardiac output, malnutrition)

COPD, heart failure, myasthenia gravis, extreme inanition, sepsis

COPD: chronic obstructive pulmonary disease. 9

P. CERIANA, S. NAVA

always overlapping. Emphysema destroys the alveolar surface membrane, blood vessels and interalveolar attachments, reducing diffusing capacity and elastic recoil, whereas chronic bronchitis causes damage to airways with chronic inflammation, bronchospasm and mucus production [28]. Airflow reduction and limitation, hallmarks of COPD, come from either an anatomical or a functional problem. The anatomical problem is the reduction of the bronchial lumen due to increased muscular tone, secretions and mucosal oedema. The functional problem is more complex; loss of alveolar attachments cause early collapse of the small airway during expiration and loss of elastic recoil makes the time available for expiration insufficient to completely deflate the lung to functional residual capacity (FRC) [29]. The result is air trapping with a shift of the FRC towards total lung capacity, pulmonary hyperinflation and alteration of chest wall geometry, with flattening of the diaphragm due to shortening of apposition zone fibres.

Pathophysiological implications. During tidal breathing, the pressure generated by the respiratory muscles (Pmus) must overcome the resistive component of the conducting airways (Pres) and the elastic component opposed by the thoracopulmonary system (Pel), being the negligible aliquot of force necessary to overcome tissue inertial resistance, as shown in the equation of motion:

Pmus~PreszPel:

ð6Þ

Pel is influenced by the volume (V) inhaled starting from FRC and the elastic properties (elastance) of the respiratory system (Ers) (Pel=ErsV), whereas Pres is influenced by airway resistance (Rrs) and flow (V’) (Pres=RrsV’). Therefore, equation 6 can also be expressed in the following way: Pmus~RrsV 0 zE rsV :

ð7Þ

During the first phase, the inspiratory effort in mainly influenced by the resistive component, whereas elastic work may be more important in the second phase, as the inhaled volume increases. In the COPD patient, the increase in end-expiratory lung volume in excess of the elastic equilibrium volume (FRC) makes the alveolar pressure positive at end-expiration (intrinsic positive end-expiratory pressure (PEEPi)) [30]. The presence of PEEPi at the beginning of every inspiration constitutes an extra burden for the respiratory muscles since inspiratory flow does not start until this threshold load is offset and a negative gradient between alveolar and mouth pressure created (fig. 1) [31]. In order to account for this additional component of the overall inspiratory load, the equation of motion in the COPD patient must be rewritten as follows: Pmus~PEEPizRrsV 0 zE rsV :

ð8Þ

The extra load imposed by PEEPi can account forw40% of the total respiratory load, with a significant increase in the work performed by the respiratory muscles per breath [32]. If the respiratory act is considered as a balance between a load and a force, then the normal subject is in a very favourable situation, having a force largely sufficient to face a normal tidal load without perception and a temporarily increased load with ease. This relationship can be expressed as the ratio between tidal inspiratory transdiaphragmatic pressure (Pdi) (expression of load) and the maximal transdiaphragmatic pressure developed by the subject (Pdi,max) (expression of force), which normally ranges 0.05–0.10 [33]. The COPD patient, conversely, is in a totally disadvantageous situation since their tidal load per breath is relevant; besides the threshold load of PEEPi and the resistive load of stenotic airways, they must carry out increased elastic work, since the overinflated lung is less distensible, being on the 10


Flow L·s-1

a)

Poes cmH2O

b) 30 15 0

-15

-30 -5

0

5

10

15

20 Time s

25

30

35

40

45

Fig. 1. – a) Airway flow; and b) oesophageal pressure (Poes) during the respiratory cycle. The pairs of vertical arrows indicate the beginning of pressure deflection (start of inspiratory effort) and inspiratory flow, respectively. The interval between these two arrows corresponds to a pressure gradient of 6 cmH2O (b), due to intrinsic positive end-expiratory pressure. This is the extra load that must be offset before every inspiration.

steeper portion of the pressure/volume curve. Furthermore, in the presence of severe hyperinflation, at the beginning of inspiration, the ribcage can be distended beyond its relaxing volume so that extra work must be carried out by the respiratory muscles to expand the chest [34]. With respect to force, the situation of the COPD patient is even worse, since hyperinflation flattens the diaphragm and shortens the apposition zone fibres. Every skeletal muscle has an optimum length at which maximal force is developed, and, for the respiratory muscles, this length corresponds to FRC or even lower lung volumes; hence, when the diaphragm must operate at lung volumes well above FRC and close to total lung capacity, the maximal force developed is greatly reduced [27]. Besides this geometric distortion, there are other factors linked to COPD that worsen muscle strength [35]: 1) the vicious cycle between dyspnoea and reduced physical activity leads to a sedentary lifestyle, with progressive muscle deconditioning and loss of lean body mass; 2) reduced dietary protein intake; 3) chronic use of steroids; 4) elevated circulating levels of cytokines; and 5) reduced levels of testosterone and growth hormone. This leads to a load/force ratio (Pdi/Pdi,max) that is markedly increased (0.2–0.3), with consequent narrowing of the respiratory muscle reserve and approaching the area of fatigue (fig. 2) [36]. Bellemare and Grassino [37] demonstrated that the occurrence of muscle fatigue is also influenced by the proportion of the total respiratory time (ttot) devoted to inspiration (tI) (tI/ttot), with a direct relationship between tI/ttot and respiratory muscle workload. The product of Pdi/Pdi,max and tI/ttot is the tension-time index, which indicates the endurance capacity of a muscle; a value of v0.15 for the diaphragm is almost entirely accurate in predicting the capacity of the subject to sustain spontaneous breathing indefinitely. In the presence of a clinical condition that further increases the mechanical load of breathing or when the energy demand cannot be met by 11

P. CERIANA, S. NAVA

Pdi cmH2O

a) 30 20 10 0

-10 Pga cmH2O

b)

Poes cmH2O

c) 10 0

-10 -20 -30 0

5

10

15

20

25 Time s

30

35

40

45

50

Fig. 2. – a) Transdiaphragmatic (Pdi); b) gastric (Pga); and c) oesophageal pressure (Poes) in a patient with advanced chronic obstructive pulmonary disease. After a maximal inspiratory effort (left deflection; maximal Pdi (Pdi,max) 24 cmH2O), the patient takes a few tidal breaths (right deflections; Pdi 9 cmH2O) with a Pdi/Pdi,max ratio of y0.37.

an adequate supply, respiratory muscle fatigue can develop. Independently of the nature of the precipitating event and the speed of the clinical course, the final common pathway leading to ventilatory pump failure is inability of the respiratory muscles to develop adequate Pdi during tidal breathing, with consequent reduced V’A and hypercapnia. Retention of carbon dioxide, however, often takes place in a more insidious way, especially in the stable COPD patient; the chronic burden on the respiratory muscles probably modifies the central drive via a feedback mechanism and the patient adopts a ventilatory pattern with increased fR and reduced VT (rapid shallow breathing) [38]. With this respiratory pattern, the patient develops a lower tidal Pdi, thus reducing the energetic cost of breathing; however, although total V’E is often unchanged, this respiratory pattern invariably increases VD/VT and reduces V’A, with development of hypercapnia. It is noteworthy that most COPD patients can voluntarily increase V’A, with achievement of normocapnia, but they wisely choose this pattern that, even if less efficient in terms of gas exchange, preserves the respiratory muscles from fatigue and the ventilatory pump from exaustion. Few hypotheses have been made to elucidate this change in ventilatory pattern, but one of the most intriguing relies on the generation of reactive oxygen species from stressed respiratory muscles, with consequent release of cytokines, mainly interleukin-6 [39]. This can, in turn, modulate the respiratory centres and the 12


hypothalamic-pituitary-adrenal axis, with release of adrenocorticotropic hormone and bendorphins; these endogenous opioids decrease the discharge rate of the respiratory centres [40] and the activity of the ventilatory pump and probably modulate the perception of dyspnoea.

Conclusions The respiratory system consists of two parts, the lungs and the ventilatory pump. Failure of these two components can generate hypoxia and hypercapnia. The onset and clinical course of hypoxaemia can be rapid and stormy, especially when shunt is the underlying mechanism; prompt and sometime aggressive therapeutic measures must be put in place in order to prevent possible injuries to vital organs. The slower progression of hypercapnia, conversely, affords the physician less stringent time limits for the management of the hypercapnic patient, giving more chances of success even with a less aggressive treatment, and hence with an approach different to that required in the case of a rapidly evolving hypoxaemic crisis.

Summary Respiratory failure is a condition in which the respiratory system fails in one or both of its gas exchange functions, i.e. oxygenation and clearance of carbon dioxide. Any condition in which the arterial oxygen tension is v7.3–8.0 kPa breathing room air is generally called hypoxic (or type I) respiratory failure, whereas hypercapnic respiratory failure is a condition in which arterial carbon dioxide tension is w6.5– 6.6 kPa, with or without acidosis (arterial blood pH v7.36). The most important causes of hypoxaemia are impaired diffusion, ventilation/perfusion mismatch and shunt, whereas alveolar collapse, alveolar flooding and impaired hypoxic pulmonary vasoconstriction are the main pathological mechanisms. Alveolar flooding is generally the most important mechanism underlying severe hypoxaemic states such as acute cardiogenic pulmonary oedema (ACPO), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The prevalence of hydrostatic (ACPO) or inflammatory (ALI, ARDS) mechanisms in pulmonary oedema deeply impacts upon clinical course and outcome. Most hypercapnic states result from inadequate clearance due to alveolar hypoventilation and increased dead space (dead space/tidal volume); this may happen in parenchymal diseases such as emphysema and in circulatory problems such as pulmonary embolism. Normally, the ventilatory drive adjusts the output of the muscular pump in proportion to metabolic activity, in order to maintain arterial blood pH within narrow limits (7.38–7.42). Causes of pump failure can be grouped into three major categories: central depression, mechanical defect of the ventilatory pump, and muscle fatigue. Exacerbation of chronic obstructive pulmonary disease is the most important cause of hypercapnic respiratory failure; the increased load of the respiratory system and reduced muscular force induce the patient to adopt a rapid shallow breathing pattern in order to preserve the ventilatory pump from fatigue and exhaustion. Keywords: Chronic obstructive pulmonary disease, hypercapnia, hypoxaemia, pulmonary oedema, shunt, ventilatory pump. 13

P. CERIANA, S. NAVA

References 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15. 16.

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Roussos C. Ventilatory failure and respiratory muscles. In: Roussos C, Macklem PT, eds. The Thorax. New York, NY, Marcel Dekker, 1985; pp. 884–888. Siggaard-Anderson O, Fogh-Andersen N, Gothgen IH, et al. Oxygen status of arterial and mixed venous blood. Crit Care Med 1995; 23: 1284–1293. Dakin J. Assessment of oxygenation. In: Dakin J, Kourteli E, Winter R, eds. Making Sense of Lung Function Tests. London, Arnold, 2002; pp 83–93. Boysen PG, Kirby RR. Practical application of blood gas measurements. In: Civetta JM, Taylor RW, Kirby RR, eds. Critical Care. Philadelphia, PA, Lippincott, 1988; pp. 311–314. Hall JB, Schmidt GA, Wood LD. Acute hypoxemic respiratory failure. In: Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. Philadelphia, PA, Saunders, 2000; pp. 2413–2442. West JB. Ventilation–perfusion relationships. Am Rev Respir Dis 1977; 116: 919–943. Marshall BE, Hanson CW, Frasch F. Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. 1. Physiologic concepts. Intensive Care Med 1994; 20: 291–297. Nunn JF. Distribution of pulmonary ventilation and perfusion. In: Nunn JF, ed. Nunn’s Applied Respiratory Physiology. 3rd Edn. Cambridge, Butterworths, 1987; pp. 167–176. Staub NC. Pulmonary edema. Physiol Rev 1974; 54: 678–811. Staub NC, Nagamo H, Pearce ML. Pulmonary edema in dogs, especially the sequence of fluid accumulation in lungs. J Appl Physiol 1967; 22: 227–240. Staub NC. Alveolar flooding and clearance. Am Rev Respir Dis 1983; 127: S44–S51. Effros RM, Mason GR, Hukkanen J. New evidence for active sodium transport from fluid-filled rat lungs. J Appl Physiol 1989; 66: 906–919. Matthay MA, Folkesson HG, Verkman AS. Salt and water transport across alveolar and distal airway epithelia in the adult lung. Am J Physiol 1996; 270: L487–L503. Crapo JD. New concepts in the formation of pulmonary edema. Am Rev Respir Dis 1993; 147: 790–792. Baldwin DR, Wise R, Andrews JM. Microlavage: a technique for determining the volume of epithelial lining fluid. Thorax 1991; 46: 658–662. Doyle IR, Hermans C, Bernard A. Clearance of Clara cell secretory protein (CC16) and surfactant proteins A and B from blood in acute respiratory failure. Am J Respir Crit Care Med 1998; 158: 1528–1535. Haupt MT. Cardiogenic pulmonary edema: an inflammatory disorder? Crit Care Med 2003; 31: 1282–1283. Kramer K, Kirkman P, Kitzman D, et al. Flash pulmonary edema: association with hypertension and reoccurrence despite coronary revascularization. Am Heart J 2000; 140: 451–455. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342: 1334– 1349. Colice GL, Matthay MA, Bass E. Neurogenic pulmonary edema. Am Rev Respir Dis 1984; 130: 941–948. Cheng IW, Matthay MA. Acute lung injury and the acute respiratory distress syndrome. Crit Care Clin 2003; 19: 693–712. Shimabukuro DW, Sawa T, Gropper MA. Injury and repair in lung and airways. Crit Care Med 2003; 31: S524–S531. Mendez JL, Hubmayr RD. New insights into the pathology of acute respiratory failure. Curr Opin Crit Care 2005; 11: 29–36. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes? Am J Respir Crit Care Med 1998; 158: 3–11. Roussos C. The failing ventilatory pump. Lung 1985; 160: 59–84.

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Dakin J. Assessment of ventilation. In: Dakin J, Kourteli E, Winter R, eds. Making Sense of Lung Function Tests. London, Arnold, 2002; pp. 75–81. Roussos C, Macklem PT. The respiratory muscles. N Engl J Med 1982; 307: 786–797. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152: S77–S120. Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease. Eur Respir J 1995; 8: 1398–1420. Kimball WR, Leith DE, Robins AG. Dynamic hyperinflation and ventilatory dependence in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126: 991–995. Ninane V, Yernault JC, De Tryer A. Intrinsic PEEP in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 147: 845–849. Appendini L, Purro A, Patessio A, et al. Partitioning of inspiratory muscle workload and pressure assistance in ventilator-dependent COPD patients. Am J Respir Crit Care Med 1996; 154: 1301– 1309. Roussos C, Fixley D, Gross D, Macklem PT. Fatigue of the respiratory muscles and their synergistic behavior. J Appl Physiol 1979; 46: 897–904. Ranieri VM, Giuliani R, Mascia L, et al. Chest wall and lung contribution to the elastic properties of the respiratory system in patients with chronic obstructive pulmonary disease. Eur Resp J 1996; 9: 1232–1239. Casaburi R. Skeletal muscle function in COPD. Chest 2000; 117: S267–S271. Begin P, Grassino A. Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 143: 905–912. Bellemare F, Grassino A. Effects of pressure and timing of contraction on human diaphragm fatigue. J Appl Physiol 1982; 53: 1190–1195. Tobin MJ, Perez W, Guenther SM, Semmes BJ. The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 1986; 143: 1111– 1118. Vasilakopoulos T, Katsaounou P, Karantza MH, Kollintza A, Zakyntinos S, Roussos C. Strenuous resistive breathing induces plasma cytokines. Am J Respir Crit Care Med 2002; 166: 1–7. Scardella AT, Parisi RA, Phair DK, Santiago TV, Edelman NA. The role of endogenous opioids in the ventilatory response to acute flow-resistive loads. Am Rev Respir Dis 1986; 133: 26–31.

15

CHAPTER 2

Exacerbation of obstructive lung diseases: therapy J.R. Hurst, J.A. Wedzicha Academic Unit of Respiratory Medicine, Royal Free & University College Medical School, London, UK. Correspondence: J.A. Wedzicha, Academic Unit of Respiratory Medicine, Royal Free & University College Medical School, Rowland Hill Street, London, NW3 2PF, UK. Fax: 44 2074726141; E-mail: [email protected]

Scope Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent diseases [1, 2]. Both are associated with periodic deteriorations in symptoms and lung function, termed exacerbations, which represent a major cause of morbidity, mortality, hospital admission and healthcare costs. Indeed, exacerbations of asthma and COPD are the commonest respiratory emergencies [3]. This review considers the emergency management of exacerbations of the principal obstructive lung diseases, asthma and COPD. The review discusses the similarities and differences between the approaches to current management, with reference to published studies and guidelines, and the underlying pathophysiology. It does not address the specialist management of paediatric asthma, nor the management of emergencies in other conditions such as cystic fibrosis and bronchiectasis, although these may also be associated with airflow obstruction. Where possible, evidence is presented from randomised controlled trials, or systematic reviews and meta-analyses of such data, in order to provide the most robust evidence supporting the therapies discussed.

Basic principles Asthma and COPD are chronic inflammatory conditions, and, although there are important differences in the nature of the inflammation between the two diseases, exacerbations generally arise as a result of an additional insult to the airway, resulting in a deterioration in symptoms and/or lung function. In asthma, this insult is most commonly a viral infection or allergen. In COPD, viral infections are also important, but bacterial pathogens are significant too. The Global Initiative for Asthma (GINA) guidelines [1] define an exacerbation of asthma as an episode of rapidly progressive increasing shortness of breath, cough, wheezing or chest tightness, or some combination of these symptoms, characterised by a decrease in expiratory airflow. It is now generally accepted that a COPD exacerbation may be defined as a sustained worsening of symptoms from the stable state, which is acute in onset and beyond the patient’s usual day-to-day variation. These symptoms typically include breathlessness, sputum volume and sputum purulence, perhaps accompanied by increased cough, wheeze, chest tightness, features of a cold, oedema, fatigue or confusion. There has been, however, considerable debate about the precise definition of exacerbation in COPD, and, although such differences may appear subtle, Eur Respir Mon, 2006, 36, 16–33. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

16

THERAPY FOR EXACERBATIONS OF ASTHMA AND COPD

they become important in the interpretation of clinical studies. Notwithstanding these differences in aetiology and definition, the management of exacerbations of both conditions follows two basic principles: exacerbation-modifying agents act directly on the cause of the exacerbation or the host inflammatory and immune responses, and other modalities act to support respiratory function until exacerbation-modifying agents are able to act. Furthermore, guidelines for both conditions recommend a stepwise approach, with escalation of therapy according to exacerbation severity and response to initial treatment. In the present chapter, it is assumed that the exacerbation is of at least sufficient severity to warrant hospital assessment, and treatment modalities that may be employed during the initial period during which the patient’s condition is stabilised are described.

Outline In the following sections, the specific therapies available for the treatment of exacerbations of COPD and asthma are considered, and the evidence base for their use described with reference to published guidelines and the underlying pathophysiology. Many such guidelines have been produced; the guidelines cited most commonly herein are the World Health Organization GINA [1] and Global Initiative for Chronic Obstructive Lung Disease (GOLD) [2] documents. The more recent British Thoracic Society/Scottish Intercollegiate Guidelines Network document on asthma [4] and the COPD guidelines of the UK National Institute for Health and Clinical Excellence [5] are also worthy of particular mention for their use of explicit evidence statements in the recommendations made. It has been reported that adherence to asthma management protocols is associated with improved patient outcomes and reduced costs [6]. Furthermore, in COPD, it was shown in 2004 that early treatment of an exacerbation is associated with a quicker recovery of symptoms, emphasising the importance of prompt therapy [7]. The GINA guidelines include a useful figure summarising the hospital management of an asthma exacerbation, reproduced here as figure 1 [1]. Table 1 represents a summary of the hospital management of a COPD exacerbation, as recommended in the GOLD document [2].

b2-Agonists and anticholinergic bronchodilators Exacerbations of both asthma and COPD are associated with increased bronchoconstriction mediated via a variety of complex, interacting, inflammatory and neural mechanisms. An increase in the dose and/or frequency of short-acting bronchodilators, therefore, remains the first-line treatment in all exacerbations of both asthma and COPD. Regarding specific dose schedules, neither the GINA guidelines [1] nor the GOLD document [2] make specific recommendations, advising instead that dosing regimens are tailored to the severity of the episode and clinical responses to initial treatment. The GOLD guidelines on COPD [2] recommend short-acting b2-agonists (SABAs) as first-line bronchodilator therapy on exacerbation of COPD, with the addition of anticholinergics in the absence of an appropriate clinical response. There is little highquality evidence comparing SABAs and anticholinergics in COPD. A meta-analysis has demonstrated equivalence between these classes of drug in the recovery of forced expiratory volume in one second (FEV1) at 90 min [8], but these studies did not include newer SABAs, such as salbutamol (USA name albuterol) or terbutaline. Also, any 17

J.R. HURST, J.A. WEDZICHA

Initial assessment History, physical examination (auscultation, use of accessory muscles, cardiac frequency, respiratory frequency, PEF or FEV1, Sa,O2, arterial blood gas levels of patient in extremis, other tests as indicated) Initial treatment Inhaled short-acting b2-agonist, usually by nebulisation, one dose every 20 min for 1 h Oxygen to achieve Sa,O2 ³ 90% (95% in children) Systemic glucocorticosteroids if no immediate response, if patient has recently taken an oral glucocorticosteroid, or if episode is severe Sedation is contraindicated in the treatment of exacerbations

Repeat assessment PE, PEF, Sa,O2, other tests as needed

Severe episode PEF 70% No distress Sa,O2 >90% (95% children)

Incomplete response within 12 h History: high-risk patient Physical examination: mild-to-moderate symptoms PEF 8 kPa Adjust O2 to Sa,O2 90% Hypercapnia? (Pa,CO2 >6.7 kPa) No No change in oxygen setting

Yes pH 8 kPa

Reassess ABG in 12 h Hypercapnia? Yes (Pa,CO2 >6.7 kPa) No Maintain O2 Sa,O2 90%

Yes

No Maintain O2 Sa,O2 90% Reassess ABG in 2 h

pH 8 kPa)

Yes

Consider mechanical ventilation, NPPV or intubation

No No change in oxygen setting Fig. 2. – Algorithm for an approach to controlled oxygen therapy on exacerbation of chronic obstructive pulmonary disease. ABG: arterial blood gas; Pa,O2: arterial oxygen tension; Sa,O2: arterial oxygen saturation; Pa,CO2: arterial carbon dioxide tension; NPPV: noninvasive positive pressure ventilation. Reproduced with permission from [56].

Although there are no specific criteria for intubation, other indications would include an inadequate response to maximal treatment and patient exhaustion. Therapy with bronchodilators, systemic corticosteroids and oxygen should continue. Bronchodilators may be administered via an inhaler and spacer inserted into the ventilator circuit. Given the considerable problems associated with invasive ventilation, NIV has been considered an alternative modality, but there is far less literature regarding this in asthma than in COPD. Only one randomised controlled trial (employing sham NIV versus bilevel positive airway pressure (BiPAP)), which enrolled 30 subjects and demonstrated a more rapid improvement in FEV1 and reduced need for hospitalisation with active treatment, has been published in acute asthma [57]. NIV in acute asthma is associated with a number of technical problems, including high respiratory frequency and airway pressures. Until further data are available, invasive ventilation remains the modality of choice for patients with acute asthma and respiratory failure requiring ventilatory support. 24


In contrast, in COPD, there is a large body of literature supporting the use of NIV as the treatment of choice for exacerbations associated with hypercapnic respiratory failure persisting after institution of optimal care. These data have recently been summarised in a Cochrane meta-analysis [58] highlighting the benefits of NIV in reducing mortality (relative risk 0.52; 95% CI 0.35–0.76), need for intubation, treatment failure, complications (primarily ventilator-associated pneumonia) and duration of hospital stay (weighted mean difference -3.24 days; 95% CI -4.42– -2.06), and its association with more rapid improvements in blood gas parameters. NIV is, therefore, also cost-effective [59]. Further benefits of NIV include the ability to use the treatment earlier and intermittently, thus facilitating normal communication, medication and nutritional input. NIV is likely to be beneficial through a number of mechanisms, including offloading fatigued respiratory muscles and improving ventilation/perfusion mismatch. In COPD, NIV is usually administered as BiPAP, but volume-cycled (and negative pressure) ventilators have also been employed. An appropriate flow rate of supplemental oxygen should be entrained into the ventilator tubing. NIV is not, however, an alternative to invasive ventilation when this is indicated, and the decision to start NIV should also involve the decision as to whether NIV would be the ceiling of treatment or a trial before progression, if necessary, to endotracheal intubation. The decision to institute invasive ventilation on exacerbation of COPD can be complex and should consider the wishes of the patient, their prior functional status, comorbid conditions and the degree of reversibility of the deterioration (but not, exclusively, either age or FEV1). That said, therapeutic nihilism surrounding invasive ventilation in COPD is generally exaggerated given that the mortality rate in the intensive care unit ofy20% is similar to that seen with respiratory failure of other causes [60]. Weaning from invasive ventilation following exacerbation of COPD can be challenging, and NIV may also have an important role in this setting [61]. The relative indications for NIV and invasive ventilation on exacerbation of COPD, as set out in the GOLD document [2], are presented in table 2.

Miscellaneous Methylxanthines Methylxanthine preparations, most commonly administered as intravenous aminophylline, have been used for exacerbations of both asthma and COPD since the 1930s. The putative mechanisms of action are many and varied, including effects on respiratory drive and muscle function in addition to their accepted role as bronchodilators. With the shift to evidence-based practice, use has declined as the absence of evidence of benefit has been more widely appreciated. In addition, it should be remembered that these drugs exhibit a low therapeutic index requiring serum monitoring, important interactions with other classes of drug used for exacerbation of airways disease, including the quinolone and macrolide antibiotics, and side-effects including, commonly, nausea and vomiting, and, more rarely but more seriously, cardiac tachyarrhythmias. The GINA guidelines continue to recommend consideration of intravenous methylxanthines in cases in which there is an inadequate response to combination bronchodilation with b2-agonist and anticholinergic agents [1]. Regarding improvement in spirometric indices, aminophylline is less effective than b2-agonists for acute asthma treated in the emergency department [62]. Furthermore, a review of 15 trials has concluded that there is no evidence of benefit when aminophylline is added to existing bronchodilatory regimens in the treatment of acute asthma, and use of aminophylline was associated with increased risk of both vomiting (OR 4.2; 95% CI 2.4–7.4) and 25


Table 2. – Indications and relative contraindications for assisted ventilation at exacerbation of chronic obstructive pulmonary disease Ventilation

Inclusion

Criteria

Noninvasive Selection

Invasive

Moderate-to-severe dyspnoea with use of accessory muscles and paradoxical abdominal motion Moderate-to-severe acidosis (pH v7.35) and hypercapnia (Pa,CO2 w6.0 kPa (w45 mmHg)) Respiratory frequency w25 breaths?min-1 Exclusion Respiratory arrest Cardiovascular instability (hypotension, arrhythmias, myocardial infarction) Somnolence, impaired mental status, uncooperative patient High aspiration risk, viscous or copious secretions Recent facial or gastro-oesophageal surgery Craniofacial trauma, fixed nasopharyngeal abnormalities Extreme obesity Selection Severe dyspnoea with use of accessory muscles and paradoxical abdominal motion Respiratory frequency w35 breaths?min-1 Life-threatening hypoxaemia (Pa,O2 v5.3 kPa (v40 mmHg) or Pa,O2/FI,O2 v200 mmHg) Severe acidosis (pH v7.25) and hypercapnia (Pa,CO2 w8.0 kPa (w60 mmHg)) Respiratory arrest Somnolence, impaired mental status Cardiovascular complications (hypotension, shock, cardiac failure) Other complications (metabolic abnormalities, sepsis, pneumonia, pulmonary embolism, barotrauma, massive pleural effusion) NIV failure or exclusion criteria

Pa,CO2: arterial carbon dioxide tension; Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction; NIV: noninvasive ventilation. 1 mmHg=0.133 kPa. Reproduced with permission from [2].

palpitation or arrhythmia (OR 2.9; 95% CI 1.5–5.7) [63]. However, a more recent paediatric study in 47 children admitted to an intensive care unit with status asthmaticus reported a significantly more rapid improvement in clinical asthma score with the addition of intravenous theophylline than seen in control subjects [64]. In COPD, a meta-analysis including 169 subjects from four studies also concluded that there is insufficient evidence to recommend theophyllines as standard treatment on exacerbation [65]. This is on the basis of an absence of effect on either pulmonary function or symptom parameters; however, these agents still appear as an option in many guidelines, including the GOLD document [2]. It should be noted that the debate concerns as much absence of evidence as good evidence to show absence of effect, and it may be that future studies with newer agents will necessitate revisiting the role of theophyllines in exacerbation of both COPD and asthma. This is especially relevant with the current development and trials of selective phosphodiesterase 4 inhibitors, including cilomilast and roflumilast.

Respiratory stimulants Centrally acting respiratory stimulants, most commonly administered on exacerbation of airways disease as intravenous doxapram, have fallen out of use with the widespread introduction of NIV for the acute treatment of exacerbation of COPD associated with hypercapnic respiratory failure. A small randomised trial of doxapram versus NIV in 17 patients concluded that any improvements seen in oxygenation from doxapram were not maintained, and not associated with the reduction in Pa,CO2 observed with NIV, thus indicating the superiority of NIV over doxapram [66]. Four trials including 176 patients in total were analysed in a Cochrane review [67]. There are a number of methodological problems with the included studies and the review concluded that, although doxapram may result in short-term improvements in blood gas tensions, NIV may well prove to be 26


more effective, although strong evidence of this is lacking. Use of doxapram is further limited by side-effects, including agitation. There may still be a role for the drug as a holding measure prior to the introduction of NIV, in cases in which NIV is inappropriate or unavailable, or as an adjunct to NIV. In asthma, it has generally been accepted, notwithstanding the points regarding NIV made above, that the presence of hypercapnia is an indication for immediate invasive ventilation, and there is, therefore, no accepted role for respiratory stimulants at exacerbation of asthma.

Magnesium sulphate Magnesium sulphate has recently been added to guidelines on asthma management, for patients with severe exacerbations or those not responding to standard therapies. Magnesium is a smooth muscle relaxant, resulting in bronchodilation. A systematic review examining 668 patients in seven trials found evidence of a benefit to pulmonary function favouring intravenous magnesium therapy only for those with the most severe exacerbations [68]. A subsequent multicentric blinded randomised controlled trial in 248 subjects confirmed this result, showing benefit only when FEV1 on admission was v25% of the predicted value [69]. The primary end-point was FEV1 at 240 min, with results demonstrating an effect size on predicted FEV1 of 9.7% (95% CI 4.0–15.3%; p=0.001). There were no reported side-effects. This study employed a dose of 2 g magnesium sulphate in 50 mL normal saline solution administered over 10–15 min. There are very few data on magnesium therapy on exacerbation of COPD, but one randomised and blinded study in 72 subjects has suggested an improvement in pulmonary function when used in addition to b2-agonists [70].

Mucolytics and associated therapies Data regarding mucolytics on exacerbation of COPD are lacking. Acetylcysteine, in addition to being mucolytic, is anti-inflammatory and may reduce exacerbation frequency in stable COPD. A randomised blinded trial that enrolled 50 patients recently reported no evidence of benefit with this drug in addition to standard therapy on exacerbation of COPD [71]. Iatrogenic bronchoconstriction with acetylcysteine during a trial in asthma resulted in the recommendation that mucolytics should not be used on exacerbation of asthma [72]. The GOLD document on COPD [2], however, recommends sputum clearance and suggests physical therapy for those patients producing w25 mL?day-1 sputum. However, there are few data to support physical therapy (or, indeed, saline nebulisation) on exacerbation of COPD. A systematic review of physical therapy (including patients with both COPD and bronchiectasis) highlights many of the methodological flaws in the published studies and is unable to recommend the routine use of such measures in COPD [73]. There is also no evidence to suggest a benefit with physical therapy on exacerbation of asthma. The important role of cough in clearing respiratory secretions suggests that antitussives are contraindicated. It is occasionally necessary to employ fibreoptic bronchoscopy in cases in which mucus plugging results in lobar collapse.

Leukotriene receptor antagonists Leukotriene antagonists have been investigated in asthma, with one randomised controlled trial in 194 subjects reporting a more rapid improvement in FEV1 and fewer treatment failures with the addition of intravenous montelukast to standard therapy [74]. Further data are awaited. 27


Helium–oxygen mixture (heliox) The use of heliox, a mixture of helium and oxygen (80:20 or 70:30), has been suggested at exacerbation of airways disease. It is of lower density than air (with or without supplemental oxygen) and may, therefore, decrease the work of breathing. A systematic review has concluded that heliox is not of benefit in either ventilated or nonventilated patients with exacerbation of COPD, but that further data regarding a possible reduction in the need for ventilation are required [75]. Heliox has also been investigated for the treatment of asthma with the similar conclusion that there is no evidence of improvement in pulmonary function parameters over standard care [76].

Other bronchodilators There is some evidence that halothane may improve bronchospasm and arterial blood gas tensions in ventilated patients with status asthmaticus [77]. There are also data on inhaled furosemide (acting as a bronchodilator), with one trial reporting no benefit in addition to therapy with b2-agonist [78] and a second showing improvement in pulmonary function only in the subgroup analysis of patients whose exacerbations were of the shortest duration [79].

General considerations The GOLD document emphasises the consideration of a variety of additional measures, including appropriate fluid balance, nutrition, and prophylaxis against venous thromboembolism (especially when patients are immobilised or polycythaemic) [2]. Comorbid conditions should be managed appropriately. In addition, outside the scope of the present review, maintenance therapy should be optimised following emergency admission to reduce the potential for future exacerbation. Finally, for patients not responding to maximal therapy or in whom escalation of treatment is considered inappropriate, a range of palliative measures may be instituted.

Future developments A number of future developments have been discussed in the above sections. To these should be added the potential of antiviral agents, given the importance of respiratory viruses in the aetiology of exacerbations of both COPD and asthma. Drugs active against rhinoviruses might be expected to be of particular benefit, including, for example, the picornaviral capsid-binding inhibitor pleconaril. Further data are awaited.

Conclusion Exacerbations of asthma and COPD cause considerable morbidity, mortality, hospital admission and healthcare cost. Exacerbations of both conditions are largely caused by infection, resulting in heightened airway inflammation with deterioration in symptoms and lung function. Although the nature of this inflammation is dissimilar, the principles of treatment in the two conditions, and many of the agents used, are the same. The aim of emergency treatment is to stabilise gas exchange and support respiratory function until disease-modifying agents are able to act. The main drugs used in both conditions are inhaled bronchodilators (SABAs, with or without anticholinergics), systemic corticosteroids and controlled oxygen therapy. An important distinction between asthma and COPD is the 28


benefit seen with antibiotics in those exacerbations of COPD associated with a change in the character of the sputum. For more severe exacerbations, a range of additional therapies are available. Many published guidelines exist to guide the management of these conditions. The development of newer and more specific therapies will no doubt result in the evolution of these guidelines over course of the coming years.

Keynote messages 1. Exacerbations of asthma and COPD cause considerable morbidity, mortality, hospital admission and healthcare cost. 2. Guidelines exist for the treatment of exacerbations of both conditions, and the adherence to published protocols has been associated with improved patient outcomes. 3. The main agents used in both conditions are inhaled bronchodilators, systemic corticosteroids and controlled oxygen therapy. Antibiotics are of benefit in those exacerbations of COPD associated with a change in the character of the sputum. 4. For more severe exacerbations, a range of additional therapies are available. 5. The development of newer and more specific therapies for exacerbations will require the development of the published guidelines over the coming years.

Summary Exacerbations of the major obstructive lung diseases, asthma and chronic obstructive pulmonary disease (COPD), cause considerable morbidity, mortality, hospital admission and healthcare cost. Exacerbations of both conditions are largely caused by infection, resulting in heightened airway inflammation in association with a deterioration in symptoms and lung function. Although the nature of the inflammation in the two conditions is dissimilar, the principles of treatment and many of the agents used are the same. This review outlines the evidence for the available treatment modalities in the emergency treatment of exacerbations of both asthma and COPD. The review focuses on hospital management in the emergency department and ward setting, and does not specifically cover issues relating to endotracheal intubation and mechanical ventilation, or paediatric disease. The aim of emergency treatment is to support gas exchange and respiratory function until disease-modifying agents are able to act. The major therapies used in both conditions are inhaled bronchodilators (short-acting b2-agonists, with or without anticholinergics), systemic corticosteroids and controlled oxygen therapy. An important distinction between asthma and COPD is the benefit seen with antibiotics in those exacerbations of COPD associated with a change in the character of the sputum. For more severe exacerbations, a range of additional therapies are available. Many published guidelines exist for reviewing the management of exacerbations in these conditions, and adherence to protocols has been associated with improved patient outcomes. The development of newer and more specific therapies will no doubt result in the development of these guidelines over the course of the coming years. Keywords: Asthma, chronic obstructive pulmonary disease, emergency, therapy.

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CHAPTER 3

Ventilation in obstructive lung disease T. Ko¨hnlein, T. Welte Dept of Respiratory Medicine, Hannover Medical School, Hannover, Germany. Correspondence: T. Welte, Dept of Respiratory Medicine, Hannover Medical School, Carl-NeubergStrasse 1, D-30625 Hannover, Germany. Fax: 49 5115328532; E-mail: [email protected]

Background The most frequent obstructive airway disease is chronic obstructive bronchitis (chronic obstructive pulmonary disease (COPD)). A number of other lung diseases might also result in small airway disease and bronchial obstruction. Important examples include bronchial asthma, acute bronchitis and overlapping forms of asthma, COPD and bronchial hyperreactivity. Less frequent, but also important diseases with peripheral bronchial obstruction include cystic fibrosis, bronchiectasis, pulmonary manifestations of collagen or vascular diseases, and others. Emergency patients with acute bronchial obstruction need immediate treatment, and decisions must be made before the exact diagnosis is known. Slowly progressive or acutely manifesting severe bronchial obstruction is a life-threatening emergency. In patients with subacute clinical forms of obstructive airway disease, all attempts should be made to improve the clinical situation with conservative treatment options to avoid further respiratory deterioration and the need for mechanical ventilation. Bronchodilating and anti-inflammatory drugs play an important role, in combination with oxygen application and instructions to the patient to perform improved and efficient techniques of breathing and coughing. Any fatality of respiratory insufficiency must be avoided by continuous monitoring and initiation of mechanical ventilation when appropriate.

Monitoring The clinical situation of the patient must be quickly assessed with simple means and techniques. Continuous control of vigilance, cooperation, heart rate, blood pressure, and breathing frequency is necessary. Pulse oximetry gives important and early information on the oxygenation of the arterial blood. Arterial or capillary blood gases and a red blood cell count should be determined without delay [1].

Oxygen therapy The aim of high-dose oxygen therapy is to augment the intrapulmonary oxygen partial pressure and to increase the oxygen gradient between the intra-alveolar space and haemoglobin. This accelerates oxygen transfer into the alveolo-capillary blood, despite pathological alterations of airway and/or lung tissue. In hypoxaemic patients, high doses of oxygen might be necessary until the peripheral oxygen saturation rises to w90%. Above this threshold, the inspiratory flow of oxygen should be down-titrated to maintain Eur Respir Mon, 2006, 36, 34–48. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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VENTILATION IN OBSTRUCTIVE LUNG DISEASE

oxygen saturations of 90–94%, and to avoid hyperoxic hypercapnia. The application of Venturi masks is helpful, since these masks allow a pre-selection of the inspiratory fraction of oxygen [2]. Treatment with oxygen is further discussed in chapter 2.

Drug therapy In patients with acute bronchial obstruction, immediate application of inhaled shortand long-acting bronchodilators is necessary. Combinations of b2-sympathicomimetics and anticholinergics are superior to the application of either drug class alone. The substances can be applied with pressurised metered-dose inhalers (pMDI) or with a conventional nebuliser. Other recommended drugs include intravenously applied theophylline and glucocorticoids, both limited to a treatment period of only a few days. The target of drug therapy is the relief of severe bronchial obstruction, thereby improving ventilation and gas exchange [3, 4]. A complete presentation of emergency drugs is provided in chapter 2.

Rationale and indication for mechanical ventilation Treatment with mechanical ventilation is performed in an attempt to correct the deteriorating gas exchange that is unresponsive to conservative measures. The aims of mechanical ventilation are as follows: 1) to improve hypoxaemia that has not been corrected with supplemental oxygen delivered by nasal cannula or face mask; 2) to reverse respiratory acidosis that has resulted from the underlying disease or from uncritical application of oxygen; and 3) to relieve respiratory distress until the primary disease process reverses or improves. Further targets are the improvement of clinical manifestations of respiratory failure e.g. dyspnoea, tachypnoea, accessory muscle recruitment, and paradoxic motion of the ribcage and abdomen [5, 6]. Alterations in lung mechanics, such as increased airways resistance and decreased lung compliance, result in increased work of breathing for the ventilatory muscles, particularly the diaphragm. Anaerobic metabolism may occur, resulting in lactic acidosis [7]. The initiation of mechanical ventilation ameliorates patient work to a considerable extent, resulting in a fall in plasma lactate and improvement in gas exchange [8]. The ventilatory muscles continue to perform some work, although the magnitude of this work tends not to be fatiguing when the majority of the minute ventilation is provided by the machine [9]. By reducing the patient’s work, mechanical ventilation decreases the demand of the diaphragm for excessive blood flow and creates an opportunity for reversing the circumstances producing diaphragmatic fatigue. Mechanical ventilation should reverse potentially life-threatening hypercapnia [10]. Although some authors have suggested physiological functions and thresholds to use when deciding whether mechanical ventilation is indicated, these criteria have never been subjected to any form of rigorous or systematic evaluation. Therefore, the decision to institute mechanical ventilation is currently based on clinical judgement rather than objective data [11]. In patients with severe obstructive lung disease, improvement of alveolar ventilation, reduction of work of breathing, and resting of the respiratory musculature can be obtained with endotracheal intubation or with noninvasive ventilation (NIV). Endotracheal intubation requires analgo-sedation of the patient and careful invasive monitoring in an intensive care unit (ICU). NIV can be performed in awake or only slightly sedated patients. The extent of invasive monitoring is less than in patients with 35

¨ HNLEIN, T. WELTE T. KO

invasive ventilation, allowing the procedure to be performed in ICUs or in specialised intermediate care units [12, 13]. As discussed below (Reasons for application of NIV section), there is no clear-cut border for when to ventilate a certain patient invasively or noninvasively, or when to switch from NIV to invasive ventilation [14]. The necessity for invasive ventilation is indicated by the following criteria: 1) severe acidosis (pH v7.25) and hypercapnia (arterial carbon dioxide tension w10 kPa (w74 mmHg)); 2) life-threatening hypoxaemia; 3) NIV failure, i.e. worsening of arterial blood gases and/or pH in 1–2 h after initiation of NIV, or lack of improvement in arterial blood gases and/or pH after 2 h; and 4) other complications, including metabolic abnormalities, sepsis, pneumonia, pulmonary embolism, barotrauma, massive pleural effusion, acute respiratory distress syndrome and severe arrhythmia [15].

Noninvasive ventilation NIV describes a technique which allows ventilation of a patient without application of an endotracheal tube. The interface between the tubing of the ventilator and the patient is, in most cases, a pressure-sealed mask, which is placed in front of the mouth and nose of the patient (fig. 1). NIV is not new. The first reports of NIV treatment, dating fromy75 yrs ago, describe patients with cardiogenic pulmonary oedema. The polio epidemic after World War II boosted the development of the iron lungs. At the beginning of the 1960s, invasive

Fig. 1. – Noninvasive ventilation. The interface is, in the majority of cases, a mask, which is tightly fixed in front of the nose and/or mouth of the patient. This picture shows a patient with a nasal mask. Exhaled air escapes through an exhalation valve between the mask and the flexible tube.

36


ventilation with endotracheal tubes became very popular, and all other techniques had not largely been performed. The renaissance of NIV or mask ventilation started at the beginning of the 1990s. The broad application of mask continuous positive airway pressure (CPAP) therapy in sleep medicine triggered a boom in the development of nasal and face masks. These masks soon spread into ICUs and were used with conventional ventilators to treat high-risk patients with NIV (see below). Presently, in many European counties, NIV is available in emergency departments, ICUs, and sometimes in ambulance vehicles. NIV can be applied within minutes. Even if invasive ventilation becomes necessary, NIV can be used until endotracheal intubation can be performed [16].

Reasons for application of NIV Successful application of NIV can spare the patient the burden and the risk of endotracheal intubation. The major risk lies in the acquisition of ventilator-associated pneumonia from hospital pathogens. The incidence of nosocomial pneumonia in patients with acute respiratory insufficiency was assessed in a number of clinical studies (fig. 2). These studies equivocally conclude that the application of NIV is associated with a significantly lower risk for acquisition of pneumonia than with invasive ventilation. In intubated patients, nosocomial pathogens are transferred from contaminated secretions from the hypopharynx into the lungs by silent aspiration. NIV is performed in awake patients with sufficient reflexes for swallowing and choking. These reflexes protect the patient from aspiration during NIV. Pathogens transferred with the air stream from the ventilator into the patient seem to play a minor role in all modes of ventilation [17, 20, 21]. NIV has been shown to be effective in COPD patients with acute respiratory failure [25]. A meta-analysis reviewed randomised, controlled trials of NIV in patients with acute respiratory failure who did not require immediate intubation [26]. Most subjects in these studies had acute exacerbations of COPD, and patients randomised to early use of NIV versus standard care had a lower rate of intubation (risk ratio 0.41; 95% confidence interval (CI) 0.33–0.53), a lower risk of death (risk ratio 0.52; 95% CI 0.35–0.76), a faster normalisation of pH (weight mean difference 0.03; 95% CI 0.02–0.04), and a shorter hospital stay (weight mean difference -3.24 days; 95% CI -4.42– -2.06). These

GUERIN [17] ANTONELLI [18] NAVA [19] NOURDINE [20] GIROU [21] CARLUCCI [22] FERRER [23]

n n n n n n n

Total#

n

0.01

1 10 100 RR 95% CI Favours NPPV Favours invasive ventilation 0.1

Fig. 2. – Relative risks (RRs) for the development of nosocomial pneumonia. Comparisons between invasive and noninvasive positive pressure ventilation (NPPV). CI: confidence interval. Modified from [24].

37


observations resulted in a level A recommendation of NIV by the British Thoracic Society [1]. The role of mechanical ventilation in patients with severe acute asthma is, despite some interesting and very promising preliminary results, uncertain [27]. The pathophysiological condition of acute respiratory failure in asthma is in many aspects similar to that of acute respiratory failure in COPD. Therefore, there is reason to believe that NIV could also be successful in patients with severe acute asthma [28]. Both NIV and invasive ventilation seem to be sufficient initial treatment options in severe asthma. However, the choice should be made dependent on the severity of illness, coexisting diseases, and the capacity and experience of the medical staff. NIV may be applied in simpler cases, but invasive ventilation is usually required in patients with more complex or more severe disease (Practice of invasive mechanical ventilation section). Analgo-sedation allows controlled ventilation and avoids asynchrony between the patient and the ventilator. In these patients, the strategy of ventilation is a prolonged exhalation time and carefully titrated extrinsic positive end-expiratory pressure (PEEP) to avoid dynamic hyperinflation [29]. Large, prospective, randomised controlled trials are needed to determine the role of noninvasive positive pressure ventilation in status asthmaticus.

Practice of NIV NIV is not a substitute for invasive ventilation, but an additional technique. Recent surveys on European ICUs revealed that in all patients with an indication for mechanical ventilation, NIV was applied as first-line therapy in 16% of all cases. NIV was successful in y60%, the remaining 40% had to be intubated. This demonstrates that NIV may be applied in patients with acute respiratory insufficiency only in places where an immediate switch to invasive ventilation is possible [30].

Technique (masks, ventilators) The mask or the interface provides the pressure-sealed connection between the ventilator tubing and the patient. The mask is placed onto the skin surface in front of the nostrils and/or the mouth. Head gear fixes the mask and keeps it in place (fig. 3). If the ventilator has one air tube for gas delivery only, the mask needs an exhalation valve or a separate exhalation valve must be inserted into the circuit close to the mask to allow the exhaled air to escape (fig. 1). Sufficient ventilation with a nasal mask requires closure of the patient’s mouth to avoid the air leaking through the mouth. This is a particular problem in patients whose cooperation is limited. Air leaks through the mouth can seriously diminish minute ventilation and reduce the efficacy of NIV. Face masks (fig. 3) have similar characteristics to nasal masks. Although they may have a greater dead space, this does not seem to have any relevance on daily use. Face masks are associated with a higher risk of skin lesions and the bridge of the nose is frequently affected. This disadvantage may have improved in the last few years due to the development of a better mask design. The most important aspect of fitting a mask is the correct positioning of the head gear and the avoidance of an overly high fixation pressure between the mask and the face. Even under optimised conditions, NIV is associated with a great loss of tidal volume (VT). The typical regions of air leaks are around the mask, especially when the patient is moving abruptly and the mask becomes displaced. A physiological minute volume of 7 L might be accompanied with a leak flow of i50 L (in pressure pre-set ventilation). 38


Fig. 3. – Noninvasive ventilation with face masks.

Greater leaks can diminish the efficacy of ventilation. However, modern ventilators can compensate air leaks of small or moderate size with gas flows of w200 L?min-1 [30]. The most recent development of interfaces is the so-called helmet. This is a cylindrical transparent bag, which is placed around the head of the patient and is positioned air tight on both shoulders (fig. 4). Compared with face masks, the helmet at least allows similar effective ventilation of patients with acute hypoxaemic respiratory insufficiency. Patients’ tolerance is slightly better than with masks. Complications such as skin lesions, gastric distension, or conjunctivitis have rarely been or are never observed [31]. The large amount of dead space in the helmet carries the risk of carbon dioxide

Fig. 4. – The helmet: a new interface for noninvasive ventilation.

39


re-breathing. Rapid gas wash-out must be provided with ventilator gas flows of i100 L?min-1.

Selection of the mask/interface. There are only a small number of clinical trials investigating the advantages or disadvantages of certain interfaces, which could provide information for daily clinical practice. A direct comparison between nasal masks and face masks showed equal efficacy for the treatment of acute respiratory insufficiency. The nasal mask was better tolerated by all patients. The application of face masks resulted in the greatest improvement in hypercapnia. In acute respiratory or ventilatory insufficiency, face masks should be used as first-line interface. Only in cases of absolute noncompliance should a switch to a nasal mask be recommended. These results were found to be independent of the underlying pulmonary disease [32].

Selection of ventilators. Theoretically, every ventilator can be used for NIV. However, common ICU ventilators are designed for invasive ventilation and air leaks activate alarms. NIV is always associated with air leaks; therefore, alarm signals are very frequent. Besides that, the weight of the double air tubing is very high, which results in displacement of the mask when the patient is moving. For acute and chronic NIV, ventilators that are specifically designed for mask ventilation are available. Their characteristics include a very high trigger sensitivity and sufficient amount of leak compensation. The air tubing is low weight, since in most situations only a single air tube is necessary, while the exhaled gas is blown out close to the patient’s mask.

Modes of ventilation. In NIV, positive pressure ventilation is nearly always performed with pressure-controlled ventilation (PCV) or pressure-support ventilation (PSV or bilevel positive airway pressure (BIPAP1)). In both modes, the patient triggers the ventilator to cycle from a higher to a lower pressure level. The latter is also called PEEP or CPAP. The resulting VT varies with each breath. If spontaneous breathing is absent in the patient, PCV allows a determination of the respiratory frequency and the ratio of inspiration/expiration. PSV is completely triggered by the patient. The cycling from inspiration to expiration is triggered by the air flow in the system. In both modes (PCV and PSV), a minimum respiratory rate can be determined. As long as the spontaneous breathing frequency of the patient is higher than the minimum frequency, the patient is ventilated in an assisted mode. If the patient’s breathing frequency drops below the minimum rate, the patient is ventilated in a controlled mode with the minimum frequency and the pre-set pressure levels. In assisted ventilation, sensitive triggers can minimise the reaction time of the ventilator (v30 ms), thereby minimising the work of breathing of the patient. Flow triggers seem to be advantageous compared with pressure triggers [33, 34]. NIV can also been performed with pre-set values of VT. The disadvantage of volumedriven ventilation is the high probability of air leaks in the system. The applied VT might partly escape through air leaks of varying dimensions, diminishing the efficacy of ventilation. Mask leaks are more common during volume-driven ventilation, since the ventilator may enlarge the inspiratory pressure if the patient’s airways resistance grows. In addition, the risk of aerophagia rises with higher ventilatory pressures and the risk of skin lesions increases if the masks are fitted tighter [35]. Proportional-assist ventilation (PAV) is a ventilatory mode which combines the characteristics of volume- and pressure-driven ventilation. During a ventilatory cycle, pressure and volume are continuously adapted. This technique intends to serve best the ventilatory or metabolic requirements of the patient [36]. Apart from some smaller clinical studies, the role of PAV has not yet been precisely defined. 40


Application of inhaled drugs during NIV. Inhaled bronchodilators represent one of the most important therapeutic approaches for the treatment of severe obstructive airway disease. Inhaled bronchodilators can be administered during mechanical ventilation. Many factors influence drug delivery from pMDIs during mechanical ventilation, and minimal changes in the technique of administration can markedly alter aerosol deposition in the lower respiratory tract. However, when the technique of administration is optimised, the efficiency of drug delivery from pMDIs in mechanically ventilated patients is comparable to that in ambulatory patients [37, 38]. Details of application are given by Dhand and Tobin [39].

Limitations and contraindications of NIV in obstructive lung disease Understanding the pitfalls of the technique is a necessity and clearly defined criteria are essential before a switch from NIV to invasive ventilation can occur. The oxygen saturation can be quickly and continuously measured. If hypoxia does not improve within minutes, the indication for NIV must be reconsidered. Large air leaks and frequent asynchrony between the ventilator and the patient are other frequent problems. If the patient does not show clinical progress, and if oxygenation does not improve within 10–15 min, intubation should be discussed. The same must be considered if the patient deteriorates during otherwise sufficient NIV, and if this situation cannot be managed with changes in the ventilatory parameters [40]. Non-cooperation is the most important contraindication for NIV. This applies for agitated patients as well as for patients with impaired vigilance (sopor or coma). Reflexes of coughing or choking must be sufficient to avoid aspiration. The only exceptions are patients with reduced vigilance due to hypercapnia. Two recent studies [41, 42] showed that NIV can be safely performed in patients with hypercapnic coma. In contrast to invasive ventilation with a blocked endotracheal tube, NIV does not protect the upper airways from aspiration. Massive secretions in the lower airways require frequent suctioning or bronchoscopy. Both are difficult, but not impossible during NIV. Invasive ventilation is recommended in such circumstances.

Invasive mechanical ventilation Invasive mechanical ventilation refers to the delivery of full or partial ventilatory support via an endotracheal tube or a tracheostomy tube. Invasive mechanical ventilation can also include the maintenance of positive airway pressure at the end of exhalation, i.e. PEEP [43]. As described earlier (Rationale and indication for mechanical ventilation section), ventilation has two therapeutic targets: 1) to improve gas exchange; and 2) to decrease the work of breathing. The application of positive pressure to the respiratory system can improve ventilation–perfusion matching and decrease intrapulmonary shunting, both of which relieve hypoxaemia and diminish hypercapnia, if present. Exacerbation of underlying obstructive airways disease is a frequent indication for the initiation of conventional mechanical ventilation. Refractory hypoxaemia, ventilatory failure, or both may serve as an indication for conventional mechanical ventilation. However, NIV should be considered as a first-line treatment in the presence of ventilatory failure (see above) [28]. Mechanical ventilation in a patient with obstructive airway disease may be a life-saving measure, but it may also be associated with significant morbidity and mortality [44]. 41


Particularly in advanced, severe respiratory failure, intubation and primary care should be performed by experienced staff. The potential complications of mechanical ventilation in this group of patients must be considered and avoided (e.g. resulting from excessive production of airway secretions, severe cardiogenic comorbidity, or obesity) [45].

Practice of invasive mechanical ventilation Sedation. Invasive mechanical ventilation can cause a significant amount of distress and anxiety in a patient, regardless of the aetiology of respiratory failure. Rapid diagnosis and treatment of anxiety should be made, whether it is directly or indirectly caused by the ventilator. Sedation is generally required in order to perform mechanical ventilation in intubated patients. The application of appropriate ventilatory patterns to correct acidosis and hypercapnia may be hindered in awake patients with interference from their own ventilatory drive [46]. The most frequently used sedatives in patients with acute respiratory failure during mechanical ventilation are opioid analgesics, propofol, midazolam and ketamine. Opioid analgesics have been shown to be less depressive on the control of breathing than previously anticipated [47]. Propofol may result in earlier extubation and earlier ICU discharge when compared with midazolam [48], but both substances can cause significant loss of muscle mass in patients with prolonged sedation. Ketamine has bronchodilatory effects similar to those of halothane and has been used to sedate mechanically ventilated patients with refractory bronchospasm, but, in general, it should be considered as a second-line sedative drug [49]. Protocols involving a once-daily interruption of sedation have been shown to be associated with a decreased length of stay in the ICU (mean 3.4 days) and a decreased number of days on the ventilator (mean 2.4 days), without any increase in associated complications [50].

Strategies of invasive mechanical ventilation. The basis of ventilating patients with acute obstructive lung disease is to minimise minute ventilation, maximise time for expiration, and avoid hyperinflation of the lung. In contrast to NIV performed in awake patients, slow gas flow into the lungs can be provided to allow a more homogeneous gas distribution in the lungs and a better recruitment of alveoli [51]. The body of evidence is very small in this area, but it is important to avoid ventilatory complications of dynamic pulmonary hyperinflation and excessive intrinsic PEEP (PEEPi). Careful ventilation might also reduce the risk of hypotension and barotrauma. Initial ventilator settings should include an expiratory flow rate of 8–10 L?min-1, a VT of 8–10 mL?kg-1 and a respiratory rate of 11–14 breaths?min-1, as well as an inspiratory flow rate of 100 L?min-1. Further adjustments have to be made on the basis of gas exchange and pulmonary mechanics [52]. In patients ventilated due to obstructive lung diseases, auto-PEEP or PEEPi is a frequent occurrence. The easiest way to assess persistent exhalation at the time of the initiation of the next breath is auscultation, which can confirm PEEPi, but is less useful in confirming its absence [53]. Many ventilators display flow versus time graphs. Incomplete exhalation can be detected if the expiratory flow rate does not return to zero when the next cycle is initiated by the ventilator. In assisted ventilated patients, the triggering of the ventilator is dependent on the generation of some flow in the airways. The higher the PEEPi, the higher the magnitude of the drop in airway pressure that the patient must generate in order to trigger a breath. In cases of severe weakness of the ventilatory muscles, the patient frequently fails to trigger the ventilator. PEEPi can be counterbalanced by external PEEP, and, therefore, 42


the magnitude of work the patient must generate to trigger the ventilator decreases. The application of PEEP is an indirect means to unload the respiratory muscles [54]. In clinical practice, the amount of external PEEP should be less than the assumed PEEPi. The recommended level of external PEEP should be 50–85% of the PEEPi. This level of PEEP increases the intrathoracic pressure only marginally, avoids worsening of air trapping and dynamic hyperinflation, which would further impair the ventilatory situation, reduces the risk of barotrauma and avoids haemodynamic instability [55, 56]. Clinical studies of PEEP in patients with obstructive airway diseases have revealed improved expiratory airway resistance, opening of closed small airways and recruitment of atelectases, leading to the conclusion that it improves expiratory lung deflation [57, 58]. Assessment of expiratory flow limitation and PEEPi is difficult in routine clinical practice. Measurement would require neuromuscular paralysis and specialised techniques [59, 60]. Caramez et al. [61] recommended an empirical PEEP trial investigating plateau pressure response in patients with obstructive airway diseases. In selected patients, the application of external PEEP levels of 0.4–0.8 kPa was found to be a reasonable strategy with minimal side-effects. In contrast, high levels of PEEP might cause hyperinflation and detrimental effects to the lung tissue. Once all small airways are opened, overdistension of emphysematous lung regions might occur, resulting in potentially irreversible organ damage [62]. Caution should be taken when providing assisted ventilation. Some modes of ventilation, which allow the patient’s own efforts at breathing, may increase intrathoracic hyperinflation. This is the case with the BIPAP1 mode in Dra¨ger ventilators, which is designed to increase functional residual capacity. Only thoroughly sedated patients should be treated with BIPAP. In the weaning period, patients should be switched to PSV [63].

Clinical management. Prolonged expiratory phase of respiration is the preferred ventilatory intervention for patients with obstructive airway diseases and a clinical suspicion of PEEPi and dynamic hyperinflation. Therefore, the inspiratory time must be shortened; this might be achieved by higher inspiratory flow rates, decreasing VT and decreasing respiratory rate. The inspiratory fraction of oxygen must be adapted, and tolerance to so-called permissive hypercapnia is required. The high inspiratory flow rates have the disadvantage of possibly inhomogeneous distribution of the applied VT in the lung [64]. Unconventional therapies, such as the use of Heliox, magnesium sulphate, ketamine and inhalational anaesthetics, may be attempted in severe cases that do not respond to conventional management. This is discussed in more detail in chapter 2. For a review, see Jain et al. [65]. Early tracheotomy must be considered in patients with potentially longer ventilation periods. The best timing of tracheotomy in patients requiring mechanical ventilation is unknown, but early tracheotomy (within 48 h after initiation of mechanical ventilation) seems to outweigh the risks of prolonged translaryngeal intubation [66]. The period of invasive ventilation should be kept as short as possible. If the underlying pathology has resolved, weaning attempts from invasive ventilation should be made. Early weaning of patients with obstructive airway disease can be facilitated with NIV. Two strategies have been proposed: 1) early extubation and continuing ventilation noninvasively [67, 68]; or 2) extubation with close monitoring of the patient and initiation of NIV in cases of ventilatory deterioration. In the latter strategy, NIV was found to be less successful than standard medical treatment [69], but clinical trials are under way to define the role of NIV in patients with obstructive airway disease who are difficult to wean. 43


Outcome of invasive mechanical ventilation The application of mechanical ventilation to patients with severe obstructive lung disease carries a high risk of mortality. Conventional medical treatment of COPD patients with acute respiratory failure was associated with an overall mortality of 12– 29%. When mechanical ventilation via an endotracheal tube becomes necessary, mortality ranges 21–54%. Factors significantly associated with mortality in the ICU are comorbidity and the severity of the acute illness. Forced expiratory volume in one second, albumin and sodium concentrations are independently associated with survival. The occurrence of extubation failure or the need for mechanical ventilation w72 h are also associated with a poor prognosis. Patients with severe obstructive airway disease who have been treated with NIV have significantly lower mortality rates of 6–25% [70–72].

Summary Mechanical ventilation is the treatment of choice in patients with acute, severe obstructive airway disease and respiratory insufficiency. The most frequent underlying diseases are chronic obstructive pulmonary disease and bronchial asthma. The therapeutic target of ventilation is to improve gas exchange, to unload the ventilatory pump and to relieve respiratory distress of the patient. Today, noninvasive ventilation (NIV) is the first-line treatment. NIV provides similar ventilatory support like invasive mechanical ventilation, but is associated with a significantly lower risk of ventilator-associated pneumonia, shorter periods of mechanical ventilation and shorter stay in the intensive care unit. Invasive ventilation allows the application of controlled ventilation with optimised ventilatory patterns to improve blood gases and to reduce hyperinflation. However, weaning procedures from invasive ventilation in patients with underlying lung diseases are difficult and time consuming. Keywords: Hypercapnia, hypoxaemia, intubation, noninvasive ventilation, obstructive airway disease.

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Youssef-Ahmed MZ, Silver P, Nimkoff L, Sagy M. Continuous infusion of ketamine in mechanically ventilated children with refractory bronchospasm. Intensive Care Med 1996; 22: 972– 976. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471–1477. Leatherman JW. Mechanical ventilation in obstructive lung disease. Clin Chest Med 1996; 17: 577–590. Pingleton SK. Invasive mechanical ventilation in exacerbations of chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1998; 53: 337–342. Kress JP, O’Connor MF, Schmidt GA. Clinical examination reliably detects intrinsic positive endexpiratory pressure in critically ill, mechanically ventilated patients. Am J Respir Crit Care Med 1999; 159: 290–294. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J Appl Physiol 1989; 65: 1488–1499. Ranieri VM, Giuliani R, Cinnella G, et al. Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 1993; 147: 5–13. Rossi A, Santos C, Roca J, Torres A, Felez MA, Rodriguez-Roisin R. Effects of PEEP on V/Q mismatching in ventilated patients with chronic airflow obstruction. Am J Respir Crit Care Med 1994; 149: 1077–1084. Guerin C, LeMasson S, de Varax R, Milic-Emili J, Fournier G. Small airway closure and positive end-expiratory pressure in mechanically ventilated patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 155: 1949–1956. Kondili E, Alexopoulou C, Prinianakis G, Xirouchaki N, Georgopoulos D. Pattern of lung emptying and expiratory resistance in mechanically ventilated patients with chronic obstructive pulmonary disease. Intensive Care Med 2004; 30: 1311–1318. Leatherman JW, Ravenscraft SA. Low measured auto-positive end-expiratory pressure during mechanical ventilation of patients with severe asthma: hidden auto-positive end-expiratory pressure. Crit Care Med 1996; 24: 541–546. Gay PC, Rodarte JR, Hubmayer RD. The effects of positive expiratory pressures on isovolume flow and dynamic hyperinflation in patients receiving mechanical ventilation. Am Rev Respir Dis 1989; 139: 621–626. Caramez MP, Borges JB, Tucci MR, et al. Paradoxical responses to positive end-expiratory pressure in patients with airway obstruction during controlled ventilation. Crit Care Med 2005; 33: 1519–1528. Nieszkowska A, Lu Q, Vieira S, Elman M, Fetita C, Rouby JJ. Incidence and regional distribution of lung overinflation during mechanical ventilation with positive end-expiratory pressure. Crit Care Med 2004; 32: 1496–1503. Calzia E, Bein T. Breath by breath, spontaneously or mechanically supported: lessons from biphasic positive airway pressure (BIPAP). Intensive Care Med 2004; 30: 744–745. International consensus conference in intensive care medicine: Ventilator-associated lung injury. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999; 160: 2118–2124. Jain S, Hanania NA, Guntupalli KK. Ventilation of patients with asthma and obstructive lung disease. Crit Care Clin 1998; 14: 685–705. Rumbak MJ, Newton M, Truncale T, Schwartz SW, Adams JW, Hazard PB. A prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med 2004; 32: 1689–1694. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients. Crit Care Med 2005; 33: 2465–2470.

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Ferrer M, Valencia M, Nicolas JM, Bernadich O, Badia JR, Torres A. Early noninvasive ventilation averts extubation failure in patients at risk: a randomized trial. Am J Respir Crit Care Med 2006; 173: 164–170. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004; 350: 2452–2460. Nevins ML, Epstein SK. Predictors of outcome for patients with COPD requiring invasive mechanical ventilation. Chest 2001; 119: 1840–1849. Ambrosino N. Ventilation techniques: invasive versus noninvasive. Monaldi Arch Chest Dis 1994; 49: 513–515. Anon JM, Garcia de Lorenzo A, Zarazaga A, Gomez-Tello V, Garrido G. Mechanical ventilation of patients on long-term oxygen therapy with acute exacerbations of chronic obstructive pulmonary disease: prognosis and cost-utility analysis. Intensive Care Med 1999; 25: 452–457.

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CHAPTER 4

Acute respiratory distress syndrome J.J. Haitsma* Correspondence: J.J. Haitsma, Interdepartmental Division of Critical Care, University of Toronto, St. Michael’s Hospital, 30 Bond Street, Queen Wing 4-042, Toronto, ON, Canada M5B 1W8. Fax: 1 4168645117; E-mail: [email protected]

History The first mention of the term acute respiratory distress syndrome (ARDS) was in 1967 in an historic article by Ashbaugh et al. [1]. Although ARDS was then defined as adult respiratory distress syndrome, this was later changed to acute respiratory distress syndrome. Ashbaugh et al. [1] described 12 patients with severe dyspnoea, tachypnoea, cyanosis, loss of lung compliance and diffuse alveolar infiltration seen on the chest radiograph. They observed and reported several clinical and pathological similarities with neonates with respiratory distress syndrome, notably surfactant dysfunction [1]. ARDS and acute lung injury (ALI) were defined by the American-European Consensus Conference in 1999 as a "syndrome of inflammation and increased permeability which are associated with a constellation of clinical, radiologic, and physiological abnormalities that cannot be explained by, but may coexist with, left atrial or pulmonary capillary hypertension" [2]. The current definition of ARDS and ALI was recommended by the American-European Consensus Conference Committee [2]. ALI, according to the American-European Consensus Conference on ALI/ARDS, is characterised by: 1) acute onset; 2) arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) v300 mmHg; 3) bilateral infiltrates seen on a frontal chest radiograph; and 4) pulmonary artery wedge pressurev2.39 kPa (18 mmHg) or no clinical evidence of left atrial hypertension [3]. ARDS is simply ALI with greater hypoxaemia; the criteria are the same except that Pa,O2/FI,O2 v200 mmHg (table 1). The advantage of the consensus definition is that it allows easy recognition of the syndrome by simple clinical guidelines, and it recognises to a certain extent that the severity of clinical lung injury varies between patients (severity of hypoxaemia). With this guideline, the standardisation of clinical research and trials has become easier and resulted in many trials and studies in ARDS patients. However, this simplicity is also a disadvantage, since factors that influence the outcome, such as the underlying cause and whether other organ systems are affected, are not assessed. Moreover, disregarding ventilation settings (particularly positive endexpiratory pressure (PEEP) levels) while measuring hypoxaemia allows for significant differences in the inclusion of patients and outcome [4–6].

Epidemiology In 2005, Rubenfeld et al. [7] reported an incidence of ALI in the USA of 78.9 cases per 100,000 person-yrs, and the incidence of ARDS was 58.7 cases per 100,000 person-yrs. The in-hospital mortality rate was 38.5% for ALI and 41.1% for ARDS [7]. They estimated that each year in the USA there are over 190,000 cases of ALI, which are Eur Respir Mon, 2006, 36, 49–63. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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Table 1. – Definition of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ventilator-induced lung injury (VILI) and ventilator-associated lung injury (VALI) ALI [3]

ARDS [3]

VILI [2] VALI [2]

Acute onset Pa,O2/FI,O2 v300 mmHg Bilateral infiltrates seen on a frontal chest radiograph Pulmonary artery wedge pressure v18 mmHg or no clinical evidence of left atrial hypertension Acute onset Pa,O2/FI,O2 v200 mmHg Bilateral infiltrates seen on a frontal chest radiograph Pulmonary artery wedge pressure v18 mmHg or no clinical evidence of left atrial hypertension Acute lung injury directly induced by mechanical ventilation in animal models Acute lung injury that resembles ARDS, in patients receiving mechanical ventilation VALI may be associated with pre-existing lung pathology, such as ARDS VALI is associated only with mechanical ventilation

Pa,O2: arterial oxygen tension; FI,O2: inspiratory oxygen fraction. 1 mmHg=0.133 kPa.

associated with 74,500 deaths and 3.6 million hospital days. In 1999, Luhr et al. [8] in a north European 8-week prospective cohort study showed a 90-day mortality of 42.2% for ALI not fulfilling ARDS criteria, and 41.2% for ARDS. The incidence of ALI was 17.9, and for ARDS 13.5 patients per 100,000?yr-1 [8]. Although ARDS is defined by the Pa,O2/FI,O2 ratio in the American-European Consensus conference on ARDS [3], patients do not usually die from hypoxaemia but rather from multi-organ failure [9, 10]. The most common risk factor for ALI in the study by Rubenfeld et al. [7] was severe sepsis with a suspected pulmonary source (46%), followed by severe sepsis with a suspected nonpulmonary source (33%). Mortality varied according to the risk factor from 24.1% among patients with severe trauma, to 40.6% in patients with severe sepsis with a suspected pulmonary source [7]. Although incidence and short-term outcome have been studied, long-term outcome data for ARDS are almost unknown. Herridge et al. [11] looked at survivors of ARDS and found that patients were generally young (median age 45 yrs), severely ill (median acute physiology and chronic health evaluation (APACHE) score of 23) and required a long stay in the intensive care unit (ICU; median 25 days). Patients suffered from significant weight loss (18%), altered lung volume and spirometric measurements (which normalised by 6 months) and reduced exercise ability compared with matched controls up to 24 months [11, 12]. However, health-related quality-of-life measurement still showed severe impairment up to 2 yrs after ARDS compared with the "normal" population [11, 12].

Organ failure Although a cardinal feature of ARDS is hypoxaemia, patients who go on to die from ARDS usually do not succumb to severe hypoxaemia but die from multi-organ failure [9, 10]. Tremblay and Slutsky [13, 14] postulated that the ventilatory strategy used to ventilate ARDS patients might in fact be a cause of this late multi-organ failure. Data in support of this hypothesis were obtained by Ranieri et al. [15] in 2000 in a study in which they linked increased levels of serum inflammatory mediators to organ failure in patients suffering from ARDS. Higher serum levels of inflammatory mediators were observed in patients ventilated with conventional ventilation compared with patients treated with a lung-protective ventilation strategy consisting of higher levels of PEEP and smaller tidal volumes (VT; fig. 1). Patients ventilated with the latter strategy had a decreased inflammatory response and subsequently had a lower incidence of organ failure [15, 16]; similar observations were also made by Villar et al. [6], who showed that lung-protective 50

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Fig. 1. – Mean levels of tumour necrosis factor (TNF)-a, interleukin (IL)-8 and IL-6 in bronchoalveolar lavage fluid (a, c and e) and plasma (b, d and f) in patients receiving either lung protective ventilation (&; tidal volume (VT) 8 mL?kg-1; positive end-expiratory pressure (PEEP) 15 cmH2O) or control ventilation (+; VT 11 mL?kg-1; PEEP 7 cmH2O). Time 0 indicates study entry, time 24 indicates sample between 24–30 h after study entry and time 36 between 36–40 h after study entry. Adapted from [16].

ventilation reduced the number of failing organs to 0.3 organs compared with 1.2 organs in the conventional ventilated group. Lavage fluid from the group ventilated with the conventional strategy led to activation of "normal" human polymorphonuclear leukocytes, correlating with inflammatory responses seen in these patients [17]. Tremblay et al. [18] demonstrated that ventilator-induced lung injury (VILI) can induce cytokine release. Increased levels of cytokines in the serum were also observed in the ARDS Network trial, in which higher levels of interleukin (IL)-6, IL-8 and IL-10 were observed after 3 days of ventilation in the control arm compared with the reduced VT [19, 20]. Similarly, the number of days without nonpulmonary organ or system failure (circulatory, coagulation and renal failure) was significantly higher in the group treated with lower VTs [19]. Elevated plasma levels of soluble tumour necrosis factor receptors are also associated with higher morbidity and mortality in patients with ALI [21]. To investigate potential mechanisms leading to end-organ dysfunction, Imai et al. [22] used a rabbit acid-aspiration lung injury model. They demonstrated that ventilation without PEEP and high VT resulted in increased levels of end-organ epithelial cell apoptosis (injurious ventilation 10.9%; noninjurious 1.86%) [22]. Renal tubular epithelial cells showed increased apoptosis, linking injurious ventilation with possible organ failure as observed in many patients with ARDS [22]. This is in keeping with studies 51

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demonstrating that the kidneys are amongst the first organs to fail during multi-organ failure [23]. Plasma obtained from rabbits that underwent the injurious ventilation strategy induced higher levels of apoptosis in cultured renal cells in vitro suggesting that circulating soluble factors associated with the injurious mechanical ventilation might be involved in this process [22]. Fas-immunoglobulin, a fusion protein that blocks soluble Fas ligand (a pro-apoptotic molecule), attenuated this induction of apoptosis in vitro. In plasma samples obtained from patients included in a previous randomised controlled trial [15, 16], lower levels of soluble Fas ligand were found in the group with lung protective ventilation compared with the conventionally ventilated group [22]. These data link distant organ changes/failure with mechanical ventilation, as discussed in a recent review on renal failure and ventilation [24]. Gurkan et al. [25] showed similar results in mice, in which injurious ventilation resulted in increased levels of IL-6 in the kidney and liver after acid aspiration.

Treatment An improved understanding of the pathogenesis of ALI and ARDS has led to the assessment of several novel treatment strategies. Although many specific therapies have not proven beneficial, these clinical trials have helped address several key issues in ARDS treatment.

Mechanical ventilation The key supportive treatment for ARDS patients is mechanical ventilation. However, the most appropriate method of mechanical ventilation in ARDS has been a matter of controversy since the syndrome was first described. Historically, a volume of 12– 15 mL?kg-1 has been recommended in patients with ALI and ARDS, although the VT in normal persons at rest is 6–7 mL?kg-1 [26]. The VTs used by clinicians over the past 1–2 decades have been progressively decreasing from w12 mL?kg-1 actual body weight (ABW) in the 1970s [27, 28] to v9 mL?kg-1 ABW (y10 mL?kg-1 predicted body weight (PBW)), as confirmed by recent epidemiological studies of ventilator practice in Europe and the Americas [8, 10, 29–32]. In 2000, the National Institutes of Health-sponsored ARDS Network showed unequivocally that lowering VTs improves patient outcome [19]. They compared two ventilation strategies: the first strategy used traditional VT (12 mL?kg-1 PBW, corresponding to y10 mL?kg-1 ABW) and a plateau pressure of 50 cmH2O; and the second used reduced VTs (6 mL?kg-1 PBW, corresponding to y5 mL?kg-1 ABW) with plateau pressures limited to 30 cmH2O. Using the protective strategy, the ARDS Network reduced mortality to 31% compared with 40% in the traditionally ventilated group [19]. One of the main reasons for improved outcome in the ARDS Network study was reducing the injury caused by mechanical ventilation, so-called VILI.

Ventilator-induced lung injury VILI was defined by the International Consensus Conference in Intensive Care Medicine on ventilator-associated lung injury (VALI) in ARDS [2], as "acute lung injury directly induced by mechanical ventilation in animal models" (table 1) [2]. Since VILI is usually indistinguishable morphologically, physiologically and radiologically from the diffuse alveolar damage of ALI, it can only be discerned definitively in animal models. 52


VALI is defined as lung injury that resembles ARDS and is thought to occur due to mechanical ventilation. VALI may be associated with pre-existing lung pathology, such as ARDS. However, unlike VILI, the physician cannot be sure that VALI is caused by mechanical ventilation. Insights into the pathophysiology of VILI and VALI came from several animal studies, which showed that mechanical ventilation with larger VTs rapidly results in pulmonary changes that mimic ARDS [33–35], including: 1) injurious ventilatory settings resulted in development of diffuse alveolar damage with pulmonary oedema [36, 37]; 2) the recruitment and activation of inflammatory cells [38, 39]; 3) local production of inflammatory mediators (e.g. cytokines) [18, 40]; and 4) leakage of such mediators into the systemic circulation [41, 42]. The propensity to injury is partly related to the inhomogeneity in distensibility of the injured lung [43, 44]. The open and thus relatively healthy lung parts will be prone to overinflation while the injured lung areas will not be inflated. The progression of the injury to the lung will result in atelectatic lung areas and patches of still open lung tissue [45]. When this lung is ventilated, even with small VTs, air will go preferentially to these still open compliant parts. This phenomenon has been described by Gattinoni and Pesenti [44] as a "baby lung", and the subsequent ventilation even with small VTs will result in overdistension [2]. Depending on the amount of collapsed lung tissue, even these small VTs will increase the actual VT delivered to the open lung areas several fold.

Improving lung aeration Techniques to improve lung aeration, such as recruitment manoeuvres, prone positioning, surfactant treatment and partial liquid ventilation have all been suggested. In the following section, the present author will discuss current knowledge and possible application of these therapies.

Recruitment Recruitment manoeuvres have been suggested to open up collapsed lung tissue to improve ventilation in ARDS patients [46]. In animal studies, the beneficial effect of recruitment manoeuvres translate into improved oxygenation, reduction of airway pressures and VTs, and reduced lung injury [47–52]. However, the use of recruitment manoeuvres is still very controversial in patients. Recently, Gattinoni et al. [53], in patients with ARDS, showed that the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP. Although several studies in patients with or at risk from ARDS have demonstrated improvement in oxygenation [54, 55] and some studies also improved outcome [56–59], other studies, especially the ARDS Network ALVEOLI trial, failed to demonstrate an improved outcome [60, 61]. Understanding how recruitment manoeuvres differ, and why lungs are more or less susceptible for collapse can help us improve lung recruitment. Grasso et al. [54] classified ARDS patients after recruitment manoeuvres with continuous positive airway pressure 40 cmH2O for 40 s into responders and nonresponders according to the occurrence (or not) of a 50% increase in Pa,O2/FI,O2 after the recruiting manoeuvre. After 2 min, the researchers observed a 20¡3% increase in Pa,O2/FI,O2 ratio in the nonresponder group (n=11) and a 175¡23% increase in the responder group. The responder group had a lower lung and chest wall elastance and had been ventilated for a shorter period of time with less haemodynamic impairment than the nonresponder group [54]. Patroniti et al. [62] also observed that recruitment potential in early ARDS is high. Recruitment manoeuvres also seem to work better in 53

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Table 2. – Guidelines for recruitment manoeuvres Recruitment manoeuvres should be applied as early as possible during the disease process Extrapulmonary ARDS is generally easier to recruit Apply intensive fluid resuscitation before the recruitment manoeuvre to minimise haemodynamic side-effects Maintain recruited lung tissue by adjusting ventilation (adjust PEEP levels and apply low VTs of 6 mL?kg-1)

ARDS: acute respiratory distress syndrome; PEEP: positive end-expiratory pressure; VT: tidal volume.

extrapulmonary ARDS, but a lung-protective strategy alone, without adjusting the PEEP level, does not provide full lung recruitment and best oxygenation [63]. Similar observations were made by Foti et al. [64] in ARDS patients, demonstrating that recruitment manoeuvres can improve oxygenation even at a relatively low PEEP, but are less effective than a continuous high PEEP level. Monitoring patients up to 6 h after a recruitment manoeuvre, Borges et al. [65] showed that recruitment manoeuvres reversed the hypoxaemia present in the majority of patients with early primary or secondary ARDS. This resulted in sustained recruitment of w95% of airspace on computed tomography analysis; the proposed maximum recruitment strategy (Pa,O2/FI,O2 w400 mmHg) was only applied after intensive fluid resuscitation and after excluding patients who were rapidly deteriorating [65]. Therefore, caution should be taken with its application to patients not intensively monitored and resuscitated. Amato and coworkers [58, 59] demonstrated that recruitment manoeuvres in limited studies can improve outcome; however, whether this will improve outcome or reduce VALI in other patients are matters for future study [65]. Current guidelines for the recruitment procedure are as given in table 2.

Prone positioning Placing patients with ARDS in a prone (face down) position improves their oxygenation 60–70% of the time [66]. Several mechanisms have been proposed to account for this effect, including alveolar recruitment, better ventilation–perfusion matching, and regional changes in ventilation associated with alterations in chest-wall mechanics [67]. In a multicentric randomised trial of 304 patients with ALI or ARDS, Gattinoni et al. [68] compared conventional treatment (in the supine position) with prone position for i6 h daily for 10 days. There was no difference in mortality rate at the time of discharge from the ICU between the prone group (50.7%) and the supine group (48%) [68]. Gattinoni et al. [68] concluded that "although placing patients with acute respiratory failure in a prone position improves their oxygenation, it does not improve survival". Similar findings were observed by Guerin et al. [69] in a multicentric randomised trial of 791 hypoxaemic acute respiratory failure (ARF) patients showing that early prone positioning did not reduce mortality and was associated with harmful effects (pressure sores, selective intubation and endotracheal tube obstruction incidences), although it improved oxygenation and reduced the incidence of ventilator-associated pneumonia [69]. Moreover, in children with respiratory failure, prone positioning failed to improve outcome (mortality and ventilator-free days) [70]. Thus, although prone position improves arterial oxygenation, routine use of the prone position in patients with ARF is not yet justified. The prone position might be considered useful for patients with severe hypoxaemia [68].

Surfactant Although a multitude of causes can lead to ALI/ARDS, the dysfunction of the endogenous surfactant system is a shared characteristic [71]. These alterations of the 54


surfactant system have been documented in several diseases and even prolonged mechanical ventilation induces these changes [71, 72]. Therefore, the use of surfactant replacement therapy has been suggested in patients with ARDS in order to overcome ongoing inactivation of endogenous surfactant by plasma proteins entering the alveolar spaces [73, 74]. Many case reports, uncontrolled studies and phase II studies have shown beneficial effects of surfactant on oxygenation and mortality of patients with ALI/ARDS [75–79]. However, randomised controlled trials could not demonstrate any improvement of survival in patients treated with surfactant [80, 81]. Interestingly, exogenous surfactant instillation has improved survival in paediatric patients [82]. This might be due to the lower incidence of multiple organ failure seen with these patients compared with adults, which contributes to mortality as an extrapulmonary component. It is too early to conclude that exogenous surfactant has no place in the treatment of ALI/ARDS, as other surfactant preparations may show different effects due to their different compositions. However, considering the available results, including a meta-analysis of all current available trials, exogenous surfactant is not recommended for routine use in patients with ALI/ARDS [83].

Partial liquid ventilation Partial liquid ventilation (PLV) using perfluorocarbons can improve oxygenation and decrease lung injury in various animal models [84, 85]. However, in a recent randomised controlled trial of 311 ARDS patients, Kacmarek et al. [86] compared two different dosages of perfluorocarbons with conventional mechanical ventilation; PLV at both high and low doses did not improve outcome in ARDS. Although perfluorocarbons might be used to facilitate recruitment manoeuvres [87, 88], they cannot be recommended at present for patients with ARDS [86].

Low tidal volume ventilation In 1990, Hickling et al. [89] demonstrated that mechanical ventilation could influence mortality in ARDS patients. In a retrospective analysis, Hickling et al. [89] showed that 50 ARDS patients ventilated with a low VT, and permissive hypercapnia, had decreased mortality compared with historical controls. The outcome of the study sparked renewed interest in lowering VT in ARDS patients. Three subsequent controlled trials using low VT strategies were simultaneously started, but all failed to demonstrate improved patient outcomes [90–92]. These studies used a VT ofy7 mL?kg-1 in their low VT arms and a VT of 10 mL?kg-1 in their control arms [90–92]. In contrast, using a VT of 6 mL?kg-1 in their treatment arm and a VT of 12 mL?kg-1 in their control arm (VT calculated by using PBW), the ARDS Network was able to reduce mortality [19]. In the ARDS Network study, PBW was y20% lower than measured body weight, resulting in a VT of y10 mL?kg-1 measured body weight for the control arm [93]. The explanation given by the ARDS Network trial for the beneficial effect on mortality was the greater difference in VT between the two arms of the study, the power of the study (ARDS Network studied 861 patients, while the other three studied a maximum of 120 patients), and the aggressive treatment/prevention of acidosis [19]. Other studies performed since then have demonstrated that higher VTs increase VILI and lead to the development of ALI [94, 95]. Two years earlier, another randomised controlled trial showed a reduction of mortality in ARDS patients. Amato et al. [59] reported that mortality in 53 patients was significantly reduced by applying a protective ventilation strategy. In the study, VT was also reduced to v6 mL?kg-1 in the low VT group compared with 12 mL?kg-1 VT in the 55

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control arm [59]. Villar et al. [6] also showed a reduction in ICU mortality in patients with severe and persistent ARDS [6]; the conventional ventilated arm (VT 9–11 mL?kg-1 PBW; PEEP i5 cmH2O) mortality was 53.3% and 32% in the lung protective arm (VT 5–8 mL?kg-1 PBW and PEEP was set on day 1 at 2 cmH2O above the inflection point on the pressure–volume curve) [6]. In contrast to the three negative studies [90–92], the PEEP level in the low VT group of the study by Amato et al. [59] was higher byy17 cmH2O, and 14 cmH2O in the study by Villar et al. [6], compared with 8–10 cmH2O PEEP in the studies by Brochard et al. [90], Brower et al. [91] and Stewart et al. [92]. Experimental data have shown that ventilation with low VTs by itself does not prevent lung injury and may even worsen lung injury when atelectrauma is not prevented [96]. In the ARDS Network trial, the low VT group had a slightly higher set PEEP of 9 cmH2O compared with a set PEEP of 8 cmH2O in the control group [19]. However, the increased respiratory rate (to help prevent acidosis) used in the low VT group may have resulted in intrinsic PEEP, which contributed to a higher total PEEP (16 cmH2O) in this group [97, 98] compared with 12 cmH2O in the traditional VT group. This higher total PEEP could help explain the decrease in mortality observed in this group, although the data addressing this issue are somewhat contradictory. In 2004, the ARDS Network published their follow-up study, investigating whether increased PEEP levels would decrease mortality [60]. Mean PEEP values for days 1–4 were 8.3 cmH2O in the lower PEEP group and 13.2 cmH2O in the higher PEEP group. Although no benefit in outcome was observed between the patient groups in the study (which was stopped early after enrolment of 549 patients), the mortality rate in both study arms was relatively low (24.9% lower PEEP and 27.5% higher PEEP) [60], providing supportive data that adjusting the ventilatory settings decreases mortality in ARDS/ALI patients. Unfortunately, patients randomised to the higher PEEP group also had more characteristics at baseline that predict a higher mortality; adjustment for these differences in baseline covariates did not alter the final outcome but did favour the higher PEEP group [60]. The main conclusion from these studies in taking care of ARDS patients is the need to use lower VTs of 6 mL?kg-1 PBW. A number of recent studies further strengthen this message because they suggest that the use of ventilatory strategies with relatively large VTs is associated with the secondary acquisition of ALI/ARDS [29, 94, 95], particularly in patients at risk for development of this syndrome.

Fluid management Optimal fluid management in patients with ALI is unknown. Diuresis or fluid restriction may improve lung function but could jeopardise extrapulmonary organ perfusion. The rationale for restricting fluids in patients with ARDS is to decrease pulmonary oedema. Studies in animals with ALI indicate that the degree of oedema is reduced if left atrial pressure is lowered [99]. In 2006, the ARDS Network reported their findings on either liberal or restricted fluid management in 1,000 ARDS patients [100]. Although there was no significant difference in the primary outcome of 60-day mortality (25.5% in the conservative strategy group and 28.4% in the liberal group), the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary organ failures [100]. Previous smaller trials already showed similar results where liberal fluid correlated with poor outcome [101]. Mitchell et al. [102] randomly assigned 89 patients with pulmonary oedema to receive diuretics and fluid restriction based on extravascular lung water or routine fluid management; the 56


Table 3. – Keynote messages in the treatment of acute respiratory distress syndrome (ARDS) Reduce tidal volumes to 6 mL?kg-1 predicted body weight Use feedback and education to optimise lung-protective ventilation Use restrictive fluid management in ARDS Consider recruitment manoeuvres, but use them as early as possible in combination with lung protective ventilation Prone positioning should only be considered in severe ARDS Surfactant, partial liquid ventilation and corticosteroids are not recommended in ARDS

group with fluid restriction had a lower fluid balance, fewer days of ventilator use and fewer days in the ICU. These results support the use of a conservative strategy of fluid management in patients with ARDS.

Glucocorticoids Due to the inflammatory nature of the lung injury in ARDS, interest in using antiinflammatory treatments, particularly glucocorticoids for treatment have been extensive. Glucocorticoids have no benefit when they are given before the onset of the disease or early in its course [103], or when used to treat the later, fibrosing alveolitis phase of the disease. Encouraging results were reported in preliminary studies and in a small randomised trial of 24 patients [104]. In an ARDS Network randomised controlled trial of 180 patients, methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled i14 days after the onset of ARDS [105]. Annane et al. [106], in a post hoc analysis of 177 patients, showed that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS. The inconclusiveness of these studies may reflect the complexity of the inflammation in ALI or the inability to deliver these agents early enough in the course of the illness. Therefore, they currently cannot be recommended for patients with ARDS and additional trials are needed to elucidate a possible role for corticosteroids in ARDS.

Keynote messages The only proven therapy in reducing mortality in ARDS patients is the use of lower VTs, according to the ARDS Network study (table 3) [19]. However, wide variation in practice persists and the proportion of patients receiving VTs within recommended limits (VTs ƒ8 mL?kg-1) remains modest at 16% [107]. Implementation of feedback and education concerning lung-protective mechanical ventilation, with special attention to the importance of closely adjusting VTs to predicted body weight, can help improve physician compliance in the use of lung-protective ventilation [108, 109]. Recruitment procedures can be performed to increase oxygenation, but are not yet recommended. In severe ARDS (Pa,O2/FI,O2 ratio v100), prone positioning can be contemplated. Fluid management should be conservative, to reduce the duration of ventilation and improve lung function.

Future directions A major problem in improving patient care in ARDS patients is the heterogeneity of the patient population. Recent studies demonstrated that different populations exist 57

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within ARDS patients [4–6]. Ferguson et al. [4] showed that patients who had "transient ARDS" (improved oxygenationw200 mmHg, under standard ventilatory settings, within 30 min) had a significant lower mortality of 12.5% versus 52.9% in persistent ARDS. Further stratification of ARDS patient populations should help in improving the power of studies, and thus help to identify improved ventilation techniques. Currently, several studies are being performed addressing the therapies (e.g. recruitment manoeuvres, prone positioning and exogenous surfactant) discussed in this chapter, and these studies will help us in further determining the optimal treatment for ARDS patients.

Summary Acute respiratory distress syndrome (ARDS) is characterised by inflammation and increased permeability. The incidence of ARDS is still high with up to 60 cases per 100,000 person-yrs, as well as a mortality of 40%. Using the nearly 10-yr-old definition of ARDS, a multitude of clinical trials have addressed possible therapies and increased current knowledge. The only proven therapy in reducing mortality in ARDS patients is the use of lower tidal volumes (VTs), using the ARDS Network study as a guideline. Implementation of feedback and education concerning low VT ventilation, with special attention to closely adjusting VTs to predicted body weight, can help improve physician compliance in the use of this strategy. Additional therapies that can be taken into consideration in treating patients include: recruitment procedures to increase oxygenation, but these are not yet recommended; and, in severe ARDS (arterial oxygen tension/inspiratory oxygen fraction ratio v100), prone positioning can be contemplated. Furthermore, fluid management should be conservative, using the 2006 ARDS Network study as a guideline. Other therapies, such as exogenous surfactant, partial liquid ventilation and corticosteroids, are not recommended in ARDS. Keywords: Acute respiratory distress syndrome, organ failure, prone positioning, recruitment, surfactant, ventilator-induced lung injury.

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Inhalation injury U. Molitoris*, P.M. Vogt#, K. Raymondos* *Dept of Anaesthesiology, and #Plastic and Reconstructive Surgery, Burn Centre, University Hospital Hannover, Hannover, Germany. Correspondence: K. Raymondos, Dept of Anaesthesiology, University Hospital, Carl Neuberg Str. 1, 30625 Hannover, Germany. Fax: 49 5115323642; E-mail: [email protected]

Epidemiology and mortality Hypovolaemic shock is no longer the major cause of death in burn patients as adequate fluid substitution therapy is routinely performed. In addition, prevention of burn infection is tackled through immediate surgical intervention. At present, inhalation injury represents the major cause of death in cases of burns [1] and, therefore, is the prognostic determining factor [2–5]. Consequently, inhalation injury has a much greater influence on mortality than the patient’s age or the extent of burned body surface. A total of 20–30% of all burn victims suffer from inhalation injury [5–7]. The incidence of an inhalation injury isv10% in patients with a burned body surface of 5% and rises to w80% with a burned body surface of 85%. If burns or inhalation injury occur in isolation, the mortality rate isv10%. Inhalation injury, though, rarely occurs in isolation. It represents the major cause of death in burn patients and increases mortality by 20% and to even more than 50% in severe burns [8]. Bacterial pneumonia [9, 10] is the major complication of an inhalation injury and its presence increases the mortality rate. In patients with burns, inhalation injury increases the risk of pneumonia by 40%. If pneumonia develops after an inhalation injury, mortality then rises by 40%; therefore, mortality in patients with burns rises to 60% [11]. Children and elderly people represent a group particularly at risk due to limited physiological reserves [5, 12] and are additionally at risk because of frequent loss of orientation in flames [13], which cause more severe burns and inhalation injury.

Pathophysiology Direct lung injury through thermal and/or flue gas-induced damage causes interstitial and alveolar fluid streams via capillary leakage. This effect is intensified by indirect pulmonary damage with i30% of burned body surface [14, 15]. In addition, a 20-times higher increase in bronchial circulation and bronchial oedema appear. This was proven in animal studies by interrupting the bronchial perfusion, which resulted in more sufficient gas exchange [16–18]. Furthermore, histologically traceable changes in the lung tissue appear with up to a 10-fold increase in pulmonary lymph flow [17, 18]. All recorded changes are associated with obstruction of the respiratory tract. Further obstructions of the respiratory tract result from fibrin cast, neutrophilic conglomeration, mucus and epithelial cell debris deposition. This accumulation can cause complete obstruction of the respiratory tract. Bronchial fibrin formations transform into clots successively by particularly high pro-coagulatory activity within Eur Respir Mon, 2006, 36, 64–83. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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the respiratory tract. Fibrin is the most effective inhibitor of pulmonary surfactant function [19]. Therefore, fibrin causes the neutralisation of the surfactant-dependent stabilisation of the respiratory tract, which then results in distinctive obstructions at all levels of the bronchial tree through fluid intake and also disturbances of endobronchial clearance [20, 21]. Post-obstructive lung collapse causes hypoventilation by reducing pulmonary gas exchange, and can furthermore be accompanied by overexpansion of the remaining ventilated areas. In addition to direct pulmonary damage, this particular overexpansion causes the synthesis and distribution of pro-inflammatory mediators, such as interleukin (IL)-8, which further increases pulmonary damage [22]. In patients with burns of 22¡13% (mean¡sd) of the body surface, the initial IL-8 concentration in bronchoalveolar lavage correlates with the oxygenation disturbances in the further clinical course [23]. Cytokines activate nuclear factor (NF)-kB, which induces the inducible nitric oxide synthase (iNOS) synthesis and increases the release of nitric oxide (NO) in an exponential manner [24]. Due to a lack of corresponding factors and substrates like arginine, iNOS can catalyse the formation of superoxide (O2-) [24], which then causes the formation of peroxynitrite (ONOO-) at a high level of NO [25]. The resulting greater capillary damage increases oedema formation, which subsequently limits gas exchange by intra-alveolar fluid influx and increases obstruction through swelling of the bronchial mucosa [26, 27].

Different kinds of inhalation injury Smoke Material containing carbon in smoke is not directly responsible for pulmonary injury even though it may function as a carrier for other substances [28].

Toxic substances of incomplete product of combustion The formation of toxic noxa depends on the substance that is on fire, with aldehydes, sulphur and nitrogen oxides among the most injurious substances present in burning cotton [29, 30]. Burning polyvinylchloride releases i75 potentially toxic components, such as hydrochloric acid and carbon monoxide (CO) [31].

Direct heat exposure Injuries caused by direct heat exposure are usually limited to the oropharyngeal tract and are caused by the poor conduction of air and a high heat adsorption of the upper respiratory tract. Animal studies have shown that hot air of 142uC cools down to 38uC after inhalation when reaching the tracheal bifurcation. Steam, which is more heat conductive than dry air, volatile or explosive gas and aspirated hot fluids, can overcome the extremely efficient heat absorption of the upper respiratory tract and can, therefore, cause extensive thermal injuries to the lower respiratory tract [32].

Localisation of injuries The localisation of the injury in the respiratory tract depends on how hydrosoluble the inhaled substances are. Readily soluble substances, such as acrolein, sulphur dioxide, ammonia and hydrogen chloride, all cause injuries to the upper respiratory tract. 65

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Intermediate soluble substances, such as chlorine and isocyanate, cause injuries to both the upper and the lower respiratory tract. Phosgene, nitrogen oxide and aldehyde are lipophilic and cause diffuse injuries to the pulmonary parenchyma. In particular, incomplete burning produces substances that cause parenchymal injury. Furthermore, CO is formed which reduces the capacity of oxygen transportation and damages the parenchyma through tissue hypoxia.

Chemical burns The direct injurious effect depends not only on hydrosolubility and particle size but also on the acid–base status of the inhaled substances. Ammonia causes an alkaline injury, as opposed to sulphur dioxide and chlorine gas which can cause acid corrosion. Chemical burns can also cause injuries via other mechanisms. For instance, acrolein causes the formation of free radicals and denaturation of proteins. Chemical fires can also be associated with systemic poisoning.

Diagnosis of inhalation injury For the diagnosis of an inhalation injury within the acute state, clinical signs and the patient’s history especially are crucially significant because most symptoms develop progressively, usually within the initial 24 h. An inhalation injury should be suspected when a fire occurs within an enclosed space. An inhalation injury becomes more likely if burns are present on the face, lips, in the mouth or on the pharyngeal or nasal mucosa [33]. The incidence of an inhalation injury following burns on the nose, lips and eyebrows is twice as high compared to isolated peripheral burns. However, extensive peripheral burns indicate that the patient could not escape from the flames, which in turn increases the risk of an inhalation injury. At the initial stage, coughing and the appearance of soot in sputum, nose or mouth can represent important symptoms for inhalation injury, even without external burn marks. Stridor, hoarseness, changes in voice, painful pharynx and odynophagia all indicate damage to the upper respiratory tract, which can be very distinctive. Asphyxia or the formation of CO can cause hypoxaemia resulting in confusion and clouding of consciousness. Reports on patients who lost consciousness or died at the scene of fire can give initial valuable indication about the high risk of hypoxia. Hypoxia, rales, rhonchi and wheezing are rarely present on admission and indicate a very distinctive injury and a poor prognosis [34]. As they might not be recognisable until after 24 h, chest radiographs do not show significant changes. Between the 5th and 10th day post-inhalation injury, two-thirds of patients show diffuse or focal infiltrates [35]. Symptoms are often absent on admission; therefore, tight monitoring of vital signs, and especially of pulmonary function, must be applied on suspected inhalation injury.

Bronchoscopy Flexible bronchoscopy is the current gold standard for the diagnosis of inhalation injury in most burn centres [36]. Damage of the upper respiratory tract can only be diagnosed using this method. Findings include soot, charring, mucosal necrosis, oedema and inflammation [37]. Due to the common use of bronchoscopy in burn patients, inhalation injuries are diagnosed about twice as often as opposed to applying traditional clinical signs. 66

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Xenon Damage of the parenchyma can be assessed through xenon scintigraphy [38]. This safe and quick method requires only minimal cooperation from the patient. After an intravenous injection of radioactive xenon, areas of reduced alveolar gas washout can be recognised by serial thorax scintigraphies. As a result of this, damages to the alveolar areas and distal respiratory tracts caused by oedema and fibrin formation are displayed. False positive or false negative findings mostly occur when patients with pre-existing lung injuries are examined after i4 days. Transferring the patient to the nuclear medicine unit is one of the major logistic challenges. Only few burn centres make use of xenon scintigraphy for the purpose of diagnosing an inhalation injury.

Pulmonary function testing Changes in pulmonary function can be shown after inhalation injuries [39]. In 1943, Aub and Pittman [40] reported a reduced vital capacity (VC) by as much as 73%, which they confirmed in 19 patients 1-week post-burn. Although Petroff et al. [41] observed no differences in VC and compliance, compared with patients with pathological xenon scintigraphy, they did discover significantly increased airway resistance with corresponding decreased flow in patients following smoke inhalation. A newer method for estimating pulmonary damage is represented by the determination of extravascular lung water in combination with thermal and dye dilution measurements. With this method, the degree of severity of the pulmonary damage cannot be quantified but it can differentiate between the damage to pulmonary parenchyma and the upper airway [42].

Scores of illness severity Recording the degree of severity and the prognostication of outcome conventionally occur on the basis of clinical statistical evaluated scoring methods. Diverse systems are applied in critical care that facilitates the classification of the degree of severity, comparability between centres and mortality prognostication. Methods with easily computable variables that are swiftly available are the most commonly used. Amongst those scoring systems are the simplified acute physiology score (SAPS) II and III [43–45], acute physiology and chronic health evaluation (APACHE) score II and III [46, 47] and the mortality probability model (MPM) [48, 49], which are often clinically evaluated and ubiquitously accepted. Systems that evaluate and record the course on a daily basis have also been established, such as the therapeutic intervention scoring system (TISS) [50], MPM II [51], sepsis-related organ failure assessment (SOFA) [52, 53] and the lung injury score (LIS) [54]. In addition to these, trauma scores categorise the degree of injury severity, such as the abbreviated injury scale [55], injury severity score (ISS) [56], paediatric trauma score (PTS) [57], trauma injury severity score (TRISS) [58], revised trauma score (RTS) [59] and a severity characterisation of trauma (ASCOT) [60]. The degree of severity and outcome-influencing features of the burn patient are not covered by any of these scores. Therefore, different scoring systems were established for burn patients, such as the abbreviated burn severity index (ABSI) that was constituted in 1982 by Tobiasen et al. [61, 62]. This scale includes factors such as age, sex, extent of burns and presence of third-degree burns as well as inhalation injury, and is furthermore classified to value points. In comparison to the rating of cutaneous injuries, the presence of an inhalation injury has only a small share of the total score. The studies by Tobiasen 67

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et al. [61, 62] for the establishment of the scores included only 51 (8.6%) of 519 patients suffering from inhalation injury. Of the validation group’s total of 762 patients, 68 (8.9%) suffered from the same injury. Two of the following four criteria form the diagnosis of inhalation injury: 1) fire in enclosed spaces; 2) facial burns including the vibrissae; 3) soot in the sputum; or 4) stridor or increased work of breathing. For validation, a bronchoscopy was not performed. This clarifies the crucial difficulty for the initial and definite diagnosis of an inhalation injury. The minor evaluation of inhalation injury in the ABSI score of Tobiasen et al. [62] leads one to the assumption that its importance is only minimal for the outcome in burn patients. This has to be at least critically questioned due to a tentative diagnosis’ missing confirmation via bronchoscopy and furthermore due to the minor share of v9% of patients with inhalation injury. Three years before the ABSI score was published, Zawacki et al. [63] proved by an analysis of multiple factors in w1,500 patients that pulmonary damage is of central importance for the prognosis of burn patients. Three out of six identified independent predictors for an increased mortality could be assigned to the respiratory system: preexisting pulmonary diseases, hypoxaemia on admission, and a detectable oedema of the respiratory tract at the initial bronchoscopy. Zawacki et al. [63] developed a model for the outcome’s prognosis including these and three additional factors. This model was superior to others, which were only based on traditional factors, such as age and the extent of the burned body surface. In accordance with this, Ryan et al. [64] regarded such models that did not include inhalation injury as obsolete, but also regarded newer models as being too complicated. They consequently developed a simplified model for the prognosis of outcome, in which inhalation injury is of crucial importance. An inhalation injury was presumed with exposure to fire in enclosed spaces, if subglottic soot was present, or if initial carboxyhaemoglobin values were increased. Ryan et al. [64] included 1,665 patients for the assessment of their model of prognosis and evaluated this method in 530 patients. This model only consists of three factors, including: age w60 yrs; burns w40% body surface area; and the presence of an inhalation injury. Ryan et al. [64] classified these three variables as being equally important. In order to estimate mortality, the presence of the following three factors is examined: the presence of one factor makes up a mortality of 3% (95% confidence interval (CI) 2–5%), two factors make up 33% (26–41%), and finally mortality rises to 87% (78–93%) with three factors present. Evidently, special cases can be made up, such as a child with a 100% burned body surface without inhalation injury, which meets only one factor and according to that would have a mortality prognosis of 3%. Since such special cases are extremely rare, the model is particularly efficient due to its simplicity.

Carbon monoxide intoxication The inhalation injury’s early lethality is closely related to the inhalation damage caused by smoke:w80% of those deceased at the scene of fire primarily suffocate or suffer from a lethal inhalation injury; they fall victim to asphyxia as a result of an oxygen deficiency or by inhaling gases which are toxic to the system like CO and cyanide. The inhalation injury caused by the converted gases belongs to those complications that decisively influence the burn patient’s prognosis [65, 66]. CO is a colourless, odourless and nonirritant gas. It is a product of an incomplete combustion of hydrocarbon. The absorbed amount depends on the minute ventilation, the time of exposure and the relative concentration within the surrounding area. CO has 68

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a 200–250-times higher affinity to haemoglobin and causes a leftward shift of the oxyhaemoglobin dissociation curve [67]. The result of this is a shortage of oxygen at the tissue level followed by tissue hypoxia. About 10–15% of the absorbed CO is linked to proteins, such as myoglobin and cytochrome-C-oxidase, and v1% is dissolved in blood [68, 69]. Smokers intermittently have carboxyhaemoglobin (COHb) levels of y10–15%, whereas in nonsmokers it is y1–3%. The elimination of CO exclusively occurs unchanged via the lungs with v1% oxidised to carbon dioxide. The elimination half-life of CO in room air takes 4–6 h [70], under 100% normobaric oxygen it takesy40–80 min [71–73], and only 15–30 min in hyperbaric oxygen [74]. The half-life period depends on diverse influences, such as tissue perfusion, cardiac output, pulmonary gas exchange area and ventilation–perfusion ratio. The acute toxicity of CO is largely based on a reduction of the blood’s oxygen-carrying capacity. CO intoxication is accompanied by nonspecific clinical symptoms that are caused by cellular hypoxia and cerebral vasodilatation [75]. Amongst these symptoms are headache, nausea, vomiting, exhaustion and fatigue (possibly leading to a loss of consciousness). As a consequence, an increase in pulmonary shunt fraction is the result of an explicable loss of hypoxia-induced pulmonary vasoconstriction [76, 77]. Furthermore, symptoms such as angina pectoris, pulmonary oedema and cardiac dysrhythmia can arise. Depending on pre-existing diseases, these symptoms are concomitantly aggravated by an increased cardiac output, which in itself is caused by tissue hypoxia, reduced oxygen release and CO–myoglobin bonding [78]. In addition to early symptoms, central nervous system (CNS) symptoms associated with hypoxic pulmonary vasoconstriction consecutively arise, but usually not until after 3–10 days, and recurrently in elderly patients, in a total of 10–30%. These CNS symptoms include disturbance of memory and coordination, incontinence, psychosis, dementia and signs of parkinsonism [79–81]; these can be traced back to reoxygenation injury, lipid peroxygenation with reversible demyelinisation of CNS lipids [82] or to oxidative stress with release of oxygen radicals [83]. Images prevalently show lesions on the globus pallidus and within the white brain matter [84]. Most of these symptoms (up to 75%) are reversible within 1 yr. The severity of the symptoms does not correlate with the COHb concentration [85, 86]. However, it determines the extent of reduction of the oxygen-carrying capacity and hereby validated symptoms. An animal study showed that, by infusing blood saturated with 50% of CO without any free CO, free CO plays a major role for tissue toxicity [85, 87]. In particular, the time of exposure has a major influence on the CO toxicity [88]. Therefore, it is mandatory to record the facts both anamnestically and clinically [89]. Besides traces of soot in the upper respiratory tract or cutaneous burns, details about the whereabouts of the patients, or possibly other involved persons with similar symptoms, can lead to a diagnosis. Apart from obvious indications like suicide attempts in enclosed spaces, there are often only hidden or even chronic indications of the accident’s course [90]. This increasingly occurs during wintertime caused by broken ovens, and by seasonal factors governed by viral illnesses, which then can lead to a false diagnosis. Pregnant females are particularly at risk to developing CO intoxication due to a reduced oxygencarrying capacity [91, 92]. The CO intoxication therapy aims at a rapid elimination of CO. The elimination halflife of CO in room air of 4–6 h decreases to 40–80 min by increasing inspiratory oxygen fraction to 1.0. An additional significant reduction to 15–30 min can be achieved by applying hyperbaric oxygen. Due to the risks of transportation, the time factor has to be meticulously considered. Hyperbaric oxygen accelerates the elimination of CO from the haemoglobin bond and the eradication of asphyxia-induced symptoms. Studies regarding outcome improvement, especially with mild intoxications, produce different results [93, 94]. Other effects of the hyperbaric oxygenation are described in the removal of CO out of protein bonds 69

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on the cellular level [85, 95] and the elimination of the dissolved part [82, 83, 94, 96, 97]. In particular, the studies proved that neurological delayed symptoms could be attenuated with hyperbaric oxygen [98–100]. Application starts as soon as possible, at least within the first 24 h, usually in several sessions up to 3 bar (300 kPa), which corresponds to a diving depth of 20 m. It is commonly agreed upon that this therapy should be applied with critical CO intoxications, loss of consciousness or coma after distinct indication. With the presence of concomitant diseases, such as coronary heart disease or in pregnant females, an early CO elimination via hyperbaric oxygenation must be urgently considered even with mild intoxication. CO intoxication frequently appears in combination with cyanide [101]. Toxic concentrations of CO and cyanide can be traced in 35% of all victims of domestic fires [102, 103]. Cyanide blocks the cytochrome peroxidase. The intake of 1–2 mg?kg-1 bodyweight can cause respiratory arrest within seconds. The effects of CO and cyanide intensify mutually and can cause severe symptoms prior to reaching toxic blood levels of the individual substances [104, 105]. Due to the short half-life of cyanide, patients with stabilised vital functions can spontaneously recover via rapid endogenic detoxication [106].

Airway management Acute upper airway obstruction occurs in y20–30% of the hospitalised burn victims with inhalation injury. It represents a large threat to patients with inhalation injury since a minor pharyngeal oedema can rapidly develop into complete upper airway obstruction with subsequent asphyxia [107]. The lesions of the upper airway, which are accompanied by upper airway obstruction within the first 12 h, can be caused by either direct thermal damage or a chemical irritation. Progressive upper airway oedema is particularly prominent in the supraglottic laryngeal area because of early and complete airway occlusion [108–110]. In patients with large surface burns that receive rapid volume resuscitation, the tendency to develop oedema can be increased. Burns of the neck, especially in children, can cause mature eschars that externally compress and obstruct the airway. Whenever suspecting upper airway obstruction, the most experienced clinician should perform endotracheal intubation. The burn wound and rapid swelling, occurring within the first 72 h post-burn, can hinder fixation of the endotracheal tube [111], which may require special techniques. Incomplete de-epithelialisation in the tracheobronchial regions can be evaluated microscopically. Distinctive lesions can extend as far as the lower respiratory tract. Progressive epidermolysis of the trachea and main bronchi and the formation of pseudomembranes can finally cause complete airway obstruction [112]. Fibrin can accumulate in the airway and cause lethal complete obstruction [113].

Tracheobronchial hygiene therapy Tracheobronchial hygiene therapy is essential to the respiratory management of patients with inhalation injury. Coughing, physiotherapy, early mobilisation, airway suctioning, therapeutic bronchoscopy and pharmacological agents represent important components in mobilising and removing secretions and fibrin cast. Retained secretion may cause life-threatening airway obstruction. An increased mortality in patients with inhalation injury may be triggered by atelectasis, ventilation–perfusion mismatch and pneumonia [9–11, 108, 114]. 70

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Tracheobronchial suctioning and lavage is imperative when patients with limited mucociliary clearance or ineffective cough can only clear secretions and fibrin cast insufficiently. Suctioning, due to a pressure drop in ventilated patients, favours collapse and atelectasis; therefore, subsequent recruitment should be performed. If thickened and dry secretions are adherent to the airways, routine suctioning should be complemented by bronchial lavage. In order to prevent a washing out of surfactant, excessive use of lavage fluid shall not be applied. Coughing might be provoked by nasotracheal suctioning in unintubated patients. Furthermore, mucosal irritation, bleeding, hypoxaemia and vagal stimulations with bradycardia may arise. Chest physiotherapy and 2-h interval positioning represent effective methods for secretion removal but are frequently limited by skin lesions. Early mobilisation of burn patients with inhalation injury is important for the improvement of lung function. If all techniques for secretion removal fail, flexible bronchoscopy becomes the most effective method and is of crucial importance for the care of a patient with an inhalation injury. Other methods sometimes fail to remove thickened secretions and fibrin cast from the tracheobronchial tree. Flexible bronchoscopy enables a thorough clearance of retained secretions via visualisation of the airway.

Corticosteroids For a long time, the administration of inhaled steroids was recommended for the prophylactic prevention of a dangerous initial swelling of the upper airway. It was intended to suppress the mobilisation of prostaglandins and leukotrienes and to prevent oedema. Even today, fire fighters are equipped with emergency packs of dexamethasone aerosol cans, which can be inhaled in case of contact with an irritant gas. Studies on prophylactic use of inhaled steroids did not show any improvement in the mortality rates suggesting that this particular application must be opposed [115–117]. Dexamethasone, for instance, primarily leads to systemic actions, which successively favours infectious complications. In contrast, there are evident indications for steroid therapy while treating concomitant diseases in the intensive care unit. An improvement in the outcome was achieved by concomitant low-dose methylprednisolone therapy during the fibroproliferative phase of acute respiratory distress syndrome [118–122]. Besides therapy with activated protein C, a supportive therapy with low-dose hydrocortisone is the only pharmacological therapy for sepsis that has shown any significant improvement in the outcome [123–128].

Acute renal failure The intensive care course among burn patients is often complicated by acute renal failure. This complication represents one of the most important causes of death [129]. It develops as a result of myoglobin agglomeration with concurrent burns [130, 131], secondary to volume deficiency, sepsis-related direct organ failure or administration of nephrotoxic drugs, e.g. antibiotics. Acute renal failure is still associated with a high mortality rate, which varies depending on the studies’ main focus. Multicentric evaluations show a hospital mortality of up to 60% [132, 133]. The extent of burned body surface and the appearance of an inhalation injury directly correlate with the incidence of an acute renal failure. Muscular injuries often cause early onset of acute renal failure [131], while late onset of acute renal failure is often the result of sepsis. 71

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There is no general consensus in studies comparing early- and late-onset acute renal failure [134]. In order to avoid volume deficiency, a thorough monitoring of fluid balance is essential [135]. Apart from clinical parameters, pulmonary artery catheterisation, multiple thermodilution techniques, transoesophageal aortic Do¨ppler ultrasound and the pulse contour analysis are methods in use. These allow precise monitoring of the intravascular volume status and the cardiac output and thereby enable accurate volume regulation and catecholamine therapy. It is especially important to carefully monitor catecholamine therapy administered to inhalation injury patients considering that these patients frequently present with reduced cutaneous perfusion. A balanced intravascular volume status is essential to prevent acute renal failure [135–137]. Also, a high-caloric nutrition [138] aimed at enteric feeding at an early stage plays a major role. With an increased myoglobin agglomeration, volume deficiency must be avoided under all circumstances in order to prevent renal failure [137]. Furthermore, sufficient urine output must be guaranteed even if it necessitates administration of diuretics. Diuretics should only be administered if the volume status is adequate and a deficiency can be ruled out. Consequently, increasing mortality could not be observed during diuretic administration [139]. Renal replacement should also be considered at an early stage [140]. Continuous renal replacement permits a more balanced volume management. With regards to bleeding complications caused by anticoagulation, an intermittent method seems to be more practical. This kind of method revealed no [141] or at best only a slightly increased mortality rate [142] when compared with continuous methods. In contrast, high ultrafiltration rates showed better survival rates [143].

Selective intestinal decontamination The development of pneumonia proved to be a risk factor for a higher mortality rate in patients with severe burns [9–11, 114, 144]. A prospective study illustrated that endogenous pneumonia in particular, which was caused by traceable germs on admission, is associated with a higher mortality rate [114]. Meta-analyses pointed out that both pneumonia rate and mortality rate could be decreased by selective intestinal decontamination [145, 146]. In 20 patients with a burned body surface of 44% on average, Jarrett et al. [147] decreased the infection rate by 50% in comparison with 10 control patients by using selective intestinal decontamination with the administration of neomycin, erythromycin and nystatin. Mackie et al. [148] also showed a reduced pneumonia rate as well as a lower mortality rate in patients with a burned body surface ofw30% in comparison with a historic control group. de La Cal et al. [149] performed the first major prospective study on the effects of selective intestinal decontamination in burn patients. The extent of the burns in the examined patients amounted to 36¡21% (mean¡sd) of the body surface; 66% showed a bronchoscopically confirmed inhalation injury indicated by inflammatory changes and 77% of the patients received mechanical ventilation. de La Cal et al. [149] were able to reduce the intensive care mortality by 75% and the hospital mortality rate by 50%. Selective intestinal decontamination was associated with a significant reduction of the intensive care (relative risk (RR) 0.25; 95% confidence interval (CI) 0.08–0.76) mortality rate as well as the hospital mortality rate (RR 0.28; 95% CI 0.1–0.8). Primary endogenous pneumonia did not develop in patients with selective intestinal decontamination, which was already elicited by traceable germs on admission. In contrast, 31% of the control patients developed primary endogenous pneumonia within the first 3–6 days, almost exclusively caused by Staphylococcus aureus, 72

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Haemophilus influenza and Streptococcus pneumoniae. These infections in particular are associated with an increased mortality rate in patients with severe burns and inhalation injury [114]. The incidence of urinary tract infections caused by selective intestinal decontamination could be reduced by w50%. Only 11% of the patients who received selective intestinal decontamination developed urinary tract infections compared with 26% of those in the control group.

Mechanical ventilation High inspiratory oxygen concentration has to be applied until CO intoxication can be ruled out in order to accelerate the CO elimination out of the haemoglobin bond. Despite all conservative efforts to support spontaneous respiration in patients with burns, patients with moderate inhalation injury can develop respiratory insufficiency, which requires mechanical ventilation. A distinctive risk for iatrogenic ventilationinduced lung injury is evident in patients with severe inhalation injury. In these patients, the airway resistance is increased by oedema formation of the bronchial mucosa; therefore, higher airway pressures are required for ventilation in order to reach enough flow for sufficient minute ventilation. Ideally, the best possible treatment of any illness should stop and reverse the pathophysiological process without causing further damage. This cannot be achieved if an inhalation injury is serious enough to require conventional mechanical ventilation. Conventional mechanical ventilation does not reverse the pathological process, does not improve the clearance of secretions and, therefore, can intensify the present damage [150]. Conventional ventilation in patients with an inhalation injury should be instituted at a tidal volume of 6–8 mL?kg-1 of ideal bodyweight. Even with this ventilatory set-up, peak pressures are often elevated, especially when large amounts of fluid are substituted or remobilised [151]. During the past 30 yrs, and particularly over the last 10 yrs, new ventilation techniques have been developed that pose as alternatives for treating burn patients with inhalation injury. Even though the options of ventilation seem to have exponentially increased for the clinician, no controlled prospective study is available at present that could define the specific role and allow comparisons between ventilation modes. Alternatives for volume-controlled ventilation in inhalation injuries have already been examined in both experimental and clinical studies. Pressure-controlled ventilation with and without inversed inspiration/expiration ratio was tested in sheep [152]. Although the gas exchange was not improved by diverse modes of ventilation, an adequate minute verntilation with lower mean airway pressures could be achieved, which presumably reduces ventilation-induced lung injuries. Sheridan et al. [153] applied pressure-controlled ventilation in paediatric burn patients. These results indicated that in comparison with an historical control group, the incidence of barotrauma, development of pneumonia and even mortality could be reduced [153].

High-frequency oscillatory ventilation High-frequency oscillatory ventilation enables oxygenation and delivery of an adequate minute volume at lower peak and mean pressures. In addition, some reports indicated a better secretion clearance with some forms of high-frequency oscillatory 73

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ventilation. CIOFFI et al. [154] reported that high-frequency oscillatory ventilation with flow interruption caused less parenchymal damage compared with conventional volumecontrolled ventilation in tests with primates. In comparison with historical control groups with inhalation injury being ventilated in a volume-controlled manner, Rue et al. [7] and CIOFFI et al. [151] observed a reduced pneumonia rate and mortality rate in patients receiving high-frequency oscillatory ventilation.

Early complications In the early phase of inhalation injury, above all, mechanical and infectious complications arise. An immediate recognition of these complications is warranted so that adequate therapy can be initiated rapidly and, thus, decreases their severity. Barotrauma is the most prominent mechanical complication caused by a variety of injuries, especially with high peak inspiratory pressures in combination with valvetype obstructions. Sloughing off of the tracheobronchial mucosa causes these obstructions, often developing in patients with inhalation injury. This type of obstruction allows the mechanically ventilated volume to enter the lungs, but can only partially be exhaled. If left untreated, barotrauma can develop and pneumothorax may result. Tracheobronchitis and pneumonia are amongst the most prominent infectious complications. The airway damaged by inhalation injury is at a high risk for developing infection. Airway infections are the most prominent complications following inhalation injury [155]. Diagnosing tracheobronchitis and pneumonia can be difficult when inhalation injury and bacterial colonisation of the airway is present.

Late complications Late complications of inhalation injury are associated with complications via mechanical damage and the consequences of the inflammatory process. Mechanical complications most often occur iatrogenicly, resulting from endotracheal or tracheostomy tube cuffs. Consequently, the tracheal cartilage is damaged and tracheomalacia may follow. Injuries to the tracheal epithelium may result in fibrosis and stenosis, which particularly leads to serious complications in subglottic areas. These changes often develop slowly and are sometimes difficult to diagnose. Tube instability, high cuff pressures (w20 cmH2O) and prolonged duration of intubation add to airway damages. High attention to tube fixation and cuff pressure can reduce the occurrence of mechanical damage. Inflammatory complications, such as bronchiectasis and bronchial stenosis, are attributed to neutrophil activation in the area of the airway damaged by inhalation injury. Activated neutrophils produce proteases and oxygen radicals, which additionally cause severe damage to the already damaged bronchial mucosa and the extracellular matrix. Although most proteases are produced by neutrophils, other cells, such as alveolar macrophages, eosinophils and fibroblasts, may also participate in protease secretion. Regular defence mechanisms protecting mucosal integrity are limited after inhalation injury [156]. Tissue damage caused by proteases and radicals, as well as by inhalation injury, can lead to persistent activation of inflammatory response, which may then limit the healing process. 74

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Outcome Varying results are available regarding long-term pulmonary function. Whitener et al. [157] reported that in 28 burn patients with inhalation injury, initial changes of the lung function could not be observed after 5 months. Acutely, they observed distinctive obstructions in patients with inhalation injury, as opposed to patients with inhalation injury and additional burns, where they observed a mixed obstructive and restrictive ventilation disorder. A total of 9 h after inhalation injury, distinctive airway obstructions were reported. Burn patients showed significant restrictive ventilation disorders, correlating with the size of burned body surface, the extent of chest burns, volume substitution and the reduction of the colloid osmotic pressure [157]. These damages decreased over the observation period of 5 months. In contrast, Mlcak et al. [158] could still trace changes of lung function in 17 children with inhalation injury and burns, even after 8 yrs. None of the children suffered from a pre-existing lung injury. Third-degree burns covered 62¡32% (mean¡sd) of the body surface and 13 children suffered from a bronchoscopically proven inhalation injury. After 8 yrs, two children suffered from obstructive, five from only restrictive and another nine children from both obstructive and restrictive ventilation disorders. Impaired gas exchange was proven in one patient. In addition to persisting direct pulmonary injuries, chest wall scarring and respiratory muscle weakness contribute to the observed changes. A mean¡sd time of 2.6¡1.9 yrs post-burn, Mlcak et al. [159] evaluated the cardiopulmonary function of 40 children with a burned body surface of 44¡22% (mean¡sd). During stress testing, the dead space/tidal volume ratio increased, which is compatible to asymmetric ventilation–perfusion ratios. Desai et al. [160] reported a decrease in maximum heart rate and an increased respiratory rate in this group of patients. In burn patients with inhalation injury, expiratory volume, respiratory rate and the dead space/tidal volume ratio increased in comparison with burn patients without inhalation injury. This indicates an increased use of the respiratory system. A pathological pulmonary function was diagnosed in 27% of burn patients without inhalation injury and in 64% of burn patients with inhalation injury [37]. Even after several years, a limited resistance to stress can be the result of the observed physiological changes. These findings indicate that, especially in children with burns, persisting cardiopulmonary impairment can be expected.

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Summary Inhalation injury represents the major cause of death from burns and has a much greater influence on mortality than age or the extent of burned body surface. A total of 20–30% of all burn victims suffer from inhalation injury that increases mortality to w50% in severe burns. Inhalation injury plays a key role in recently developed outcome prediction models, reflecting its outstanding importance on mortality in burned patients. Traditional clinical signs include burns on the face, lips, in the mouth or on the pharyngeal or nasal mucosa, coughing, and soot in the sputum, nose or mouth. However, with flexible bronchoscopy, inhalation injury is diagnosed about twice as often compared with traditional clinical signs. As symptoms are often absent on admission, tight monitoring is mandatory. First of all, in all burn victims, carbon monoxide (CO) intoxication has to be considered and high inspiratory oxygen concentration has to be applied in order to accelerate CO elimination until CO intoxication can be ruled out. Acute upper airway obstruction occurs in y20–30% of hospitalised burn victims with inhalation injury. A minor pharyngeal oedema can rapidly develop into complete upper airway obstruction with subsequent asphyxia. Tracheobronchial hygiene therapy is essential after inhalation injury. Coughing, physiotherapy, early mobilisation, airway suctioning, therapeutic bronchoscopy and pharmacological agents mobilize and remove secretions and fibrin cast. Bacterial pneumonia represents the major complication of inhalation injury raising mortality to 60%. Primary endogenous pneumonia can be avoided with selective intestinal decontamination that decreases intensive care mortality by 75%. The intensive care course is often complicated by acute renal failure that represents one of the most important causes of death. Barotrauma represents the most prominent mechanical complication caused by a variety of injuries, especially with high peak inspiratory pressures in combination with valve-type obstructions. Late pulmonary complications include tracheal damage and tracheomalacia. Keywords: Bacterial pneumonia, barotrauma, burns, carbon monoxide, flexible bronchoscopy, inhalation injury.

References 1. 2. 3. 4. 5. 6. 7.

Cope O, Rhinelander FW. The problem of burn shock complicated by pulmonary damage. Ann Surg 1943; 117: 915–918. Brown JM. Respiratory complications in burned patients. Physiotherapy 1977; 63: 151–153. Linares HA. A report of 115 consecutive autopsies in burned children: 1966–80. Burns Incl Therm Inj 1982; 8: 263–270. Moylan JA. Inhalation injury: a primary determinant of survival. J Burn Care Rehab 1981; 3: 78– 84. Thompson PB, Herndon DN, Traber DL, Abston S. Effect on mortality of inhalation injury. J Trauma 1986; 26: 163–165. Herndon DN, Barrow RE, Linares HA, et al. Inhalation injury in burned patients: effects and treatment. Burns Incl Therm Inj 1988; 14: 349–356. Rue LW 3rd, Cioffi WG, Mason AD, McManus WF, Pruitt BAJ. Improved survival of burned patients with inhalation injury. Arch Surg 1993; 128: 772–778.

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Extrapulmonary causes of respiratory failure including acute neuromuscular disorders A.K. Simonds Correspondence: A.K. Simonds, Royal Brompton & Harefield Trust, Sydney Street, London SW3 6NP, UK. Fax: 44 2073518911; E-mail: [email protected]

Although there is a major emphasis on the management of acute exacerbations of chronic obstructive pulmonary disease (COPD), patients with extrapulmonary disorders comprise a significant proportion of those experiencing ventilatory decompensation. It is likely that this group will grow with the increased availability of noninvasive ventilation (NIV), which has extended life expectancy, and, therefore, the prevalence of conditions such as Duchenne muscular dystrophy (DMD) [1] and other congenital neuromuscular diseases. The chief extrapulmonary causes of respiratory failure are listed in table 1. They lead to respiratory failure by reducing the capacity of the respiratory system (neuromuscular disease), increasing respiratory load and impairing mechanical efficiency (chest wall disorders, morbid obesity), decreasing ventilatory drive (central hypoventilation disorders) or a combination of these factors.

Inherited neuromuscular disease When assessing patients with neuromuscular disease in the clinic, it is helpful to bear in mind the probability of developing respiratory insufficiency (table 2).

Predictors of ventilatory failure in inherited neuromuscular disease Simple predictors of ventilatory failure include pulmonary function measurements and assessment of respiratory muscle strength. In DMD, Cox regression analysis shows that a vital capacity (VC) of v1 L is highly predictive of the development of ventilatory decompensation [2]. Not surprisingly, survival is also correlated with arterial carbon dioxide tension (Pa,CO2; r= -0.72) and minimum nocturnal arterial oxygen saturation (Sa,O2; r=0.62) [2]. Hukins and Hillman [3] found that a forced expiratory volume in one second of v40% predicted and base excess level in venous blood of w4 mmol were predictive of diurnal hypercapnia. Consensus conference guidelines suggest that pulmonary function should be assessed every 6 months with further evaluation required if VC isv60% predicted or maximum inspiratory or expiratory mouth pressures v60 mmH2O [4]. Children with neuromuscular disease aged w5 or 6 yrs can usually complete lung function measurements. Use of noninvasive assessment of sniff inspiratory pressure and whistle expiratory muscle strength is possible in quite small children, unless bulbar problems limit achieving an adequate mouth seal around the equipment. Bach [5] Eur Respir Mon, 2006, 36, 84–94. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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Table 1. – Extrapulmonary causes of respiratory failure Inherited neuromuscular disease Muscular dystrophies Myopathies Sensory motor neuropathies Myotonic dystrophy Acquired neuromuscular disease ALS/motor neurone disease Polymyositis/dermatomyositis Guillain–Barre´ syndrome/polyneuritis Myasthenia gravis Spinal cord injury Congenital chest wall disorders Early onset idiopathic scoliosis/kyphosis Pectus excavatum Jeune’s syndrome Acquired chest wall disorders Scoliosis secondary to poliomyelitis Thoracoplasty Chest en cuirasse Trauma/chest wall resection Morbid obesity Congenital central hypoventilation CCHS Prader–Willi syndrome Myotonic dystrophy Acquired central hypoventilation Encephalitis Brain stem lesion

ALS: amyotrophic lateral sclerosis; CCHS: congenital central hypoventilation syndrome.

Table 2. – Probability of developing respiratory failure in neuromuscular disease High probability Duchenne muscular dystrophy Type 1, intermediate SMA Merosin-negative CMD Motor neurone disease/ALS Early-onset scoliosis/polio Spinal cord lesions above C6 Variable probablity Limb girdle MD Myopathies: nemaline metabolic Facioscapulohumeral MD Lower probability Type III SMA Low thoracic spinal cord lesions

SMA: spinal muscle atrophy; CMD: congenital muscular dystrophy; ALS: amyotrophic lateral sclerosis; MD: muscular dystrophy.

has reported that a cough peak expiratory flow of v160 L?min-1 puts the individual at risk from recurrent chest infections. As the natural history of respiratory decline usually progresses from normal blood gases during the day to sleep-disordered breathing and finally daytime ventilatory failure, if values for pulmonary function or respiratory muscle strength fall below the values given above, and especially if the child or adult with 85

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neuromuscular disease exhibits symptoms of sleep-disordered breathing, then monitoring of respiration during sleep (a sleep study) [4] should be carried out. Symptoms and signs suggestive of sleep-disordered breathing include: 1) morning headaches and sluggishness; 2) waking with a sensation of panic; 3) a frequent need for nocturnal turning in bed; 4) excessive nocturnal sweating; 5) daytime somnolence; 6) breathlessness; 7) cyanosis on transferring position or when eating; and 8) failure to thrive.

Acquired neuromuscular disorders Acquired neuromuscular conditions embrace a diverse range of disorders including amyotrophic lateral sclerosis (ALS; motor neurone disease), polymyositis/dermatomyositis and other autoimmune conditions, such as myasthena gravis (MG), systemic lupus and Guillain–Barre´ syndrome (GBS). Spinal cord lesions comprise an additional group and other aetiological factors include infections (acute poliomyelitis, botulism, tetanus) and toxins (organophosphate nerve agents, e.g. sarin, etc.). Clinical considerations in the management of the commonest of these disorders will be discussed later; general supportive principles can be extended to rarer conditions. In a limited number of situations, specific treatments or antidotes (e.g. pralidoxime for organophosphate poisoning) should be employed.

Predictors and treatment of ventilatory failure in motor neurone disease/ amyotrophic lateral sclerosis Most patients with motor neurone disease (MND)/ALS die of respiratory complications. Bulbar symptoms can be problematic to manage successfully and affect up to 30% of patients at presentation. Median survival is y2.5 yrs, but 25% may live i5 yrs. Prognosis tends to be more favourable in younger patients. The progression of respiratory muscle weakness can be measured by serial VC and respiratory muscle strength measurements. Orthopnoea is suggestive of diaphragmatic involvement, which can be confirmed by a fall of w15% in VC on assuming the supine position. Sleepdisordered breathing, often a mixture of nocturnal hypoventilation and obstructive hypopnoeas due to bullbar weakness, can fragment sleep significantly as a result of recurrent arousals secondary to respiratory events leading to poor sleep quality, daytime somnolence and morning headaches. Use of NIV in MND/ALS can improve survival [6, 7] and quality of life [8]. However, Bourke et al. [9] have shown that the most powerful determinant of quality of life is respiratory muscle strength. One important message is that an MND/ALS patient with a daytime Pa,CO2 value at the upper limit of normal, or just elevated, is in imminent danger of precipitous ventilatory decompensation, especially if a chest infection develops. These individuals should be assessed urgently for ventilatory support. Although bulbar weakness can limit the efficacy of NIV and make it more difficult to tolerate [10], this should not be viewed as an absolute contraindication as bulbar patients may also derive palliation of symptoms. For example, in some individuals, a combination of NIV and cough insufflation/exsufflation can be helpful. Nutritional support is vital and insertion of a percutaneous gastrostomy tube facilitates feeding, and may decrease problems with aspiration. Tracheostomy ventilation should be considered in those with moderate-to-severe bulbar problems, but will depend on individual circumstances and the wishes of the patient and family (see Advance directives section). 86


Prediction and management of ventilatory failure in Guillain–Barre´ syndrome Up to 30% of patients with GBS develop respiratory failure [11], but this figure can be reduced by around a half with the use of plasma exchange and immunoglobulin therapy. Effective management depends on the anticipation of ventilatory failure. Predictors of the need for mechanical ventilation include: rapidity of progression; bulbar involvement; bilateral facial weakness; and dysautonomia. VC and mouth pressure measurement can be used to assess ventilatory capacity [11]. Respiratory failure is almost inevitable in the face of a VC ofv20 mL?kg-1, maximum inspiratory pressurev30 cmH2O and maximum expiratory pressurev40 cmH2O. In a series of 120 children with GBS [12], the odds ratio (OR) for respiratory failure was 4.9 (95% confidence interval 1.3–18.5) if symptoms began within 8 days of a preceding infection. As in adults, cranial nerve involvement was a strong predictive factor. A cerebrospinal fluid protein level of w800 mg?L-1 during the first week was associated with an OR for assisted ventilation of 3.1. Lawn et al. [13] examined factors determining duration of assisted ventilation in GBS and found that only 22% of patients could be weaned within 3 weeks; those ventilated for longer tended to be older (pv0.04) and have underlying chronic pulmonary disease. Chevrolet et al. [14] found that weaning attempts in GBS were not successful when VC was v7 mL?kg-1, and choose to wean their patients once VC excedes 15 mL?kg-1. It should not be forgotten that GBS may be associated with variability in blood pressure and heart rate due to autonomic involvement, even in the absence of respiratory compromise. Power spectral analysis [15] of heart rate shows a marked decrease in the high frequency (respiratory range), but also a reduction by w50% of the low-frequency component. It is thought these changes result from demyelination of the reflex loop controlling respiratory oscillations and from a desensitisation of the arterial tree to elevated levels of plasma noradrenaline. While NIV may be useful in some individuals with ventilatory failure as a result of GBS, clearly the situation can change rapidly, and further progression, cranial nerve and bulbar involvement and profound autonomic problems should provoke the application of conventional intubation and ventilation.

Predictors of ventilatory failure in myasthenia gravis While some forms of myasthenia are congenital, in most patients this presents as an acquired condition. Several groups have examined the predictive power of repeated VC measurements in determining ventilatory decompensation. In MG patients who required intubation, Rieder et al. [16] found that VC decreased in the 48 h before intubation, and this was required when VC was v15 mL?kg-1. A subsequent study showed that VC monitoring in this group is a relatively insensitive guide. Almost certainly this is due to the underlying variability of the disease, nature of drug therapy and use of steroids. In a small series of MG patients who developed ventilatory failure, NIV was used in 11 episodes in nine patients, resulting in the avoidance of intubation in seven trials. The presence of a Pa,CO2 level w6.7 kPa (50 mmHg) was predictive of NIV failure. Careful management is required in the post-operative care of MG patients to avoid atelectasis and pneumonia, and prevent myasthenic or cholinergic crises. Resection of a thymoma in MG may affect phrenic nerve function, further complicating the picture.

High spinal cord injury Velmahos et al. [17] have looked at the factors determining the need for intubation in spinal cord injury (SCI) patients. In a series of 68 patients with cervical cord lesions, 50 subjects required intubation and ventilation and 40% had a pneumonia. A total of 87.5% 87

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of those with a lesion above C5 required intubation, but in the group with a lesion at C5– C8 only 60% needed intubation (p=0.026). Of around 30 patients who did not present with ventilatory failure, 42% later decompensated requiring emergency intubation. The three independent risk factors for the need for intubation were: a severity score w16; a lesion above C5; and complete quadriplegia. Several groups have investigated the role of NIV in SCI patients. Bach and Alba [18] reported the use of noninvasive options in 25 traumatic quadriplegic patients who had initially been treated with tracheostomy ventilation. It was possible to convert 17 patients to NIV, despite the fact that some had minimal or zero ventilator-free time. Mouth interface-delivered NIV was often used during the day. Other options such as facemask delivery NIV, phrenic nerve pacing, and body suits can be applied. Viroslav et al. [19] report a similar experience in that conversion of patients to NIV resulted in an improvement in their quality of life, abolished local tracheostomy complications and decreased pulmonary morbidity. Clearly NIV is not possible in all patients with high cervical injury. It is important to note that inappropriate weaning and late ventilatory failure can occur in SCI patients [20]. Respiratory failure can occur up to several decades after the injury. On this theme, Lu et al. [21] found severe apnoeic episodes in eight patients out of a series of 36 with mid to lower cervical SCI. Involvement of C4 (e.g. higher lesions), the presence of transient bradycardia and dyspnoea differentiated the group with apnoeas from those who did not. Not surprisingly, these episodes are worse during sleep, so that SCI patients who are intermittently bradycardic or are dypsnoeic should undergo a sleep study.

Chest wall disorders Longitudinal studies have confirmed that severe, unfused idiopathic scoliosis is associated with an excess morbidity and mortality. Death was due to cor pulmonale in 30% of patients with untreated idiopathic scoliosis followed for 50 yrs in one series [22]. Patients with unfused idiopathic scoliosis and a VC of v50% predicted at presentation may develop a disproportionate loss of lung volume with age, thereby putting them at particular risk [23]. The age of onset of scoliosis is also important as those acquiring a curvature at v5 yrs of age are at most risk of cardiorespiratory decompensation [23]. This is probably related to a reduced alveolar duplication and the detrimental impact of the scoliosis on maturation of the pulmonary vasculature and chest wall growth. In addition, there is an increased incidence of congenital heart defects in individuals with early onset scoliosis. Pehrsson et al. [24], in a 20-yr follow-up of lung function in adult idiopathic scoliosis, found that respiratory failure occurred in 25% of patients, and in all of these VC was v45% predicted and the thoracic curve w110u. A high thoracic curve seems to have a more marked adverse effect than a mid or low thoracic curve as presumably this places the respiratory muscles, including accessory muscles, at a greater mechanical disadvantage. The peak age of respiratory failure in UK [25] and Swedish [24] studies was during the fifth decade. For individuals with scoliosis secondary to neuromuscular disease, e.g. old poliomyelitis, minimum Sa,O2 during sleep was correlated with VC and percentage fall in VC when changing from erect to supine position [26]; however, maximum inspiratory mouth pressures were not closely correlated with nocturnal saturation.

Other chest wall conditions While other chest wall conditions, such as pectus excavatum and kyphosis, may result in a restrictive ventilatory defect, it is unusual for respiratory to failure to occur in the 88


absence of other contributory factors. However, acquired conditions, such as thoracoplasty and chest en cuirasse from systemic sclerosis, can provoke ventilatory decompensation. A progressive, asphyxiating form of chest wall deformity (Jeune’s syndrome) can cause respiratory failure in early childhood.

Central hypoventilation syndromes Congenital central hypoventilation syndrome (CCHS) is relatively rare, but these cases comprise a significant proportion of children receiving ventilatory support worldwide. CCHS is usually diagnosed at birth or shortly after. In affected individuals, metabolic control of ventilation is abnormal, but behavioural control is retained. There are several children with central drive defects acquired in the first year of life due to encephalitis e.g. caused by herpes infection. Most require tracheostomy ventilation but a few may be managed with noninvasive techniques. Diaphragm pacing has been used in CCHS. Adults and children using diaphragm pacing may require additional ventilatory support during sleep or at the time of acute chest infections. Acquired hypoventilation syndromes can also result from acute cerebrovascular events affecting the brainstem. Slow recovery may occur, but is often incomplete.

Obesity hypoventilation syndrome The prevalence of this condition will inevitably increase with rising levels of obesity in Western societies. It is less common in children but may affect 1–3% of obese children, and one should bear in mind that 20–27% of children and adolescents from the USA are obese. Obesity hypoventilation syndrome (OHS) is defined by extreme obesity and alveolar hypoventilation during wakefulness (i.e. Pa,CO2 w6.0 kPa). It is estimated that the co-presence of obstructive sleep apnoea (OSA) worsens the pathophysiological consequences of increased mechanical load from obesity iny90% of cases. In contrast to patients with a combination of COPD and OSA (overlap syndrome) and those with alveolar hypoventilation secondary to respiratory muscle weakness, obesity hypoventilation patients can usually correct Pa,CO2 by voluntary hyperventilation during wakefulness. In a prospective study of a cohort of 34 consecutive OHS cases, Kessler et al. [27] showed that, in comparison with "pure" OSA cases, diurnal blood gases were significantly worse and pulmonary hypertension was more frequent in the OHS group. Not surprisingly, in those with significant daytime hypercapnia, bilevel NIV is likely to be more effective than continuous positive airway pressure therapy [28]. OHS patients are heavy users of healthcare resources with more physician visits and hospitalisations per year than controls [29]. Use of bilevel ventilation decreased hospital days per year by 68% in OHS patients in one study [29]. Ventilatory support may be a valuable adjunct in the peri-operative period in patients undergoing gastric stapling to control obesity.

General principles of management Acute respiratory failure Where possible, infections should be prevented; influenza and pneumococcal vaccination are strongly indicated. In patients with neuromuscular disease and recurrent chest infections (e.g. w3 per year), some guidelines [30] recommend prophylactic 89

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antibiotics on pragmatic grounds, although there is little in the way of controlled trials to support this idea. In patients with significant chest wall or neuromuscular disease, there should be a low threshold for measuring arterial blood gas tension, especially if Sa,O2 is v94%. Oxygen therapy should be used with caution and close monitoring of carbon dioxide tension levels in case uncontrolled hypercapnia is provoked. Secretion clearance is a problem in many congenital and acquired neuromuscular disorders. Physiotherapy with "huffing" to promote movement of secretions is important. A series of studies have shown that the cough insufflator/exsufflator can augment cough peak flow [5, 31]. Although clinically this is likely to aid resolution of acute chest infections, there have been no controlled trials of the addition of the cough insufflator/ exsufflator to standard therapy. The percussionaire is a device that combines positive pressure breathing with high-frequency oscillation. Early work suggests that it may help mobilise peripheral secretions in neuromuscular patients. Use of the device may need to be combined with cough-assist devices in patients with marked expiratory muscle weakness as rapid movement of secretions into the large airway may overwhelm clearance mechanisms unless this is supported by cough assistance.

NIV in acute respiratory failure Unlike use in acute exacerbations of COPD, there have been few randomised trials of NIV in acute respiratory failure (ARF) due to neuromuscular disease. The British Thoracic Society (BTS) guidelines for NIV in ARF [32] state that "NIV is indicated in acute or acute-on-chronic respiratory failure due to chest wall deformity or neuromuscular disease" (level of evidence: C). Martin et al. [33] have carried out a randomised, prospective evaluation of NIV in ARF in patients with mixed aetiology, including neuromuscular disease. Patients in the non-COPD category had a lower rate of intubation than with standard medical care (8.45 versus 30.3 intubations per 100 intensive care unit (ICU) days; p=0.001). Vianello et al. [34] prospectively investigated the efficacy of NIV combined with minitracheotomy versus tracheostomy ventilation in 14 neuromuscular patients compared with 14 matched historical controls. Vianello et al. [34] found that intra-hospital mortality and treatment failure were lower in the NIV group and duration of ICU stay was shorter (13.6 versus 47.1 days). Clearly tracheostomy ventilation may be required in patients with multisystem failure, severe bulbar weakness leading to aspiration, and/or inability to cooperate with NIV.

Combination of noninvasive respiratory muscle support

inspiratory

and

expiratory

Bach and co-workers have a reported a series of cohort studies comparing a protocolised combination of bilevel pressure support and cough insufflator/exsufflator in DMD [35] and spinal muscular atrophy (SMA) [36]. In a study comparing Duchenne patients [35] using the noninvasive protocol and those receiving tracheostomy ventilation, hospitalisations and length of stay per year per patient were significantly reduced in the protocol group, although it should be noted that this was not a randomised study and could be subject to selection bias. In a study of 11 children with type I SMA [36], survival until the age of 66 months has been demonstrated without the need for intubation. Nine children required intubation for ARF but were successfully extubated back onto NIV on 23 out of 28 occasions, compared with a lower success rate 90


in patients not using the protocol. The aim of the work by Bach et al. [36] was to avoid tracheostomy ventilation, although it is clear that the necessity for intermittent ICU admission and endotracheal intubation is likely to place a significant burden on patients, families and ICU resources alike.

Complications of management Complications of NIV in non-COPD patients are similar to the COPD group, although adapting the interface to facial shape may be more difficult in some neuromuscular conditions due to facial wasting and contractures. As a result, very careful attention should be given to mask fit, with regular skin examination to ensure pressure sores are not created. In patients with jaw contracture, a facemask or mask covering the face totally is likely to be required. Many patients are better served by customised masks, which can improve fit and reduce dead space. Some thought should also be given to providing interfaces that patients with upper limb/hand weakness can easily put on and take off otherwise autonomy can be severely reduced. For example, some over-the-head nasal plug systems are easier for patients with upper limb weakness to don and doff. Other common side-effects, such as rhinitis, can be managed by humidification, and nasal steroid sprays. Gastric distension may be more common in those with neuromuscular disease, but exact figures are difficult to establish. Pressuretargeted ventilators (rather than volume-targeted ventilators) seem less likely to provoke aerophagia. Mid facial hypoplasia can occur as a result of long-term NIV use in children. Here too, individually customised masks have been shown to reduce facial skeletal deformity.

Weaning Just as NIV can reduce the need for intubation, it ought to be able to facilitate weaning in neuromuscular, central hypoventilation and chest wall patients. Early consideration should be given to extubation onto NIV (i.e. before a tracheostomy is formed), providing bulbar function is reasonable. In a recent study from a long-term weaning centre, Pilcher et al. [37] showed that patients with neuromuscular/chest wall disease were associated with a lower mortality (OR 0.36) compared with those with COPD (OR 1.24) or weaning problems due to surgical complications (OR 4.04). Conversely, this group were more likely to require long-term venitlatory support than COPD patients. Indeed, BTS acute NIV guidelines [32] suggest that all patients with chest wall, neuromuscular disease and obesity hypoventilation who have an episode of ARF should be referred to a centre specialising in long-term ventilatory support to see if this is indicated.

Issues with standardisation of care Hardart et al. [38] have highlighted the fact that information on the outcome from noninvasive-assisted ventilation in neuromuscular disease is not disseminated uniformly. It is particularly the case in severe or progressive conditions such as type I SMA and DMD. This means that decisions on care may vary from centre to centre, which is clearly inequitable. Further outcome information including that on quality of life of patients and families would be helpful to facilitate decision making. 91

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Advanced directives As respiratory failure is a predictable end-point in many neuromuscular/extrapulmonary conditions, it is helpful for patients and families to consider treatment plans for their care should acute decompensation occur. For valid, informed decisions to be made, information on all treatment options should be made available to affected individuals and their families, and not withheld on the false assumption that the quality of life that results from some interventions would necessarily be unacceptable. For example, Albert et al. [39] have shown that palliative care plans are underused in MND/ ALS patients and should be offered by medical teams. Patients can participate in these care plans fully by making advance directives, and most view these as a positive tool [40].

Conclusions Respiratory failure is a relatively common complication in patients with neuromuscular disease, chest wall disorders and hypoventilation syndromes when respiratory load exceeds capacity and/or ventilatory drive is inadequate. In many cases, acute and chronic ventilatory decompensation is predictable. Use of NIV in acute and chronic respiratory failure can improve morbidity and mortality. Finally, advance directives allow patients to participate in decision making.

Summary Acute ventilatory decompensation is an inevitable feature of some inherited neuromuscular diseases that involve the respiratory muscles, such as type I spinal muscular atrophy and Duchenne muscular dystrophy, and is a common cause of morbidity in others, including severe chest wall disease and central hypoventilation syndromes. It can complicate acquired neuromuscular disorders such as Guillain– Barre´ syndrome, motor neurone disease (amyotrophic lateral sclerosis) and polymyositis. An anticipatory care plan can be employed in which high-risk cases are identified, respiratory function assessed, and ventilatory failure treated promptly. Noninvasive ventilation, combined with cough-assist techniques, has considerably improved the outlook and reduced the need for invasive ventilation in these conditions, unless severe bulbar compromise is present. Patients should always be involved in decision making and advance care planning where possible. Keywords: Acute respiratory failure, central hypoventilation syndromes, chest wall disorders, neuromuscular disease, noninvasive ventilation, obesity hypoventilation.

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Sawicka EH, Branthwaite MA. Respiration during sleep in kyphoscoliosis. Thorax 1987; 42: 801– 808. Kessler R, Chaout A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001; 120: 369–376. Resta O, Guido P, Picca V, et al. Prescription of nCPAP and nBIPAP in obstructive sleep apnoea syndrome: Italian experience in 105 subjects. A prospective two centre study. Respir Med 1998; 92: 820–827. Berg G, Delaive K, Manfreda J, Walld R, Kryger MH. The use of health care resources in obesityhypoventilation syndrome. Chest 2001; 120: 377–383. Manzur AY, Muntoni F, Simonds A. Muscular dystrophy campaign sponsored workshop: recommendation for respiratory care of children with spinal muscular dystrophy type II and III. Neuromusc Disord 2003; 13: 184–189. Chatwin M, Ross E, Hart N, Nickol A, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients with neuromuscular weakness. Eur Respir J 2003; 21: 502–508. British Thoracic Society Standards of Care Committee. Non-invasive ventilation in acute respiratory failure. Thorax 2002; 57: 192–211. Martin TJ, Hovis JD, Costantino JP, et al. A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure. Am J Respir Crit Care Med 2000; 161: 807–813. Vianello A, Bevilacqua M, Arcano G, Gallan F, Serra E. Non-invasive ventilatory approach to treatment of acute respiratory failure in neuromuscular disorders. A comparison with endotracheal intubation. Intensive Care Med 2000; 26: 384–390. Bach JR, Ishikawa Y, Kim H. Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1998; 112: 1024–1028. Bach JR, Niranjan V, Weaver B. Spinal Muscular Atrophy Type I. A noninvasive respiratory management approach. Chest 2000; 117: 1100–1105. Pilcher DV, Bailey MJ, Treacher DF, Hamis S, Williams AJ, Davidson AC. Outcomes, cost and long term survival of patients referred to a regional weaning centre. Thorax 2005; 60: 187–192. Hardart MKM, Burns J, Truog RD. Respiratory support in spinal muscular atrophy type I: a survey of physician practices and attitudes. Pediatrics 2002; 110: e24. Albert S, Murphy PL, Del Bene ML, Rowland LP. Prospective study of palliative care in ALS: choice, timing, outcomes. J Neurol Sci 1999; 169: 108–113. Moss AH, Oppenheimer EA, Casey P, et al. Patients with amyotrophic lateral sclerosis receiving long-term mechanical ventilation. Advance care planning and outcomes. Chest 1996; 110: 249–255.

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CHAPTER 7

Management of massive haemoptysis J. Theron*,#, A.H. Diacon#, C.T. Bolliger# *Panorama Medi-Clinic, Panorama, and Tygerberg, Cape Town, South Africa.

#

Faculty of Health Sciences, University of Stellenbosch,

Correspondence: C.T. Bolliger, Respiratory Research Unit, Clinical Building, Faculty of Health Sciences, University of Stellenbosch, 19063 Tygerberg 7505, South Africa. Fax: 27 219323105; E-mail: [email protected]

Haemoptysis is the expectoration of blood or of blood-stained sputum [1]. There is no specific definition of massive haemoptysis. In the literature, the amount varies from 200– 1,000 mL per 24 h, but is usually defined as w600 mL of expectorated blood in 24 h [2–5]. Any amount of haemoptysis that causes respiratory compromise and/or haemodynamic instability is life threatening and constitutes a medical emergency. The mortality ranges 7–30% for non-massive haemoptysis, and up to 80% for massive haemoptysis [6–8]. Massive haemoptysis is a frightening experience for both doctors and patients alike. The objective of the present chapter is to guide clinicians in the approach and management of this potentially lethal event.

Aetiologies It is important to determine the origin of the bleeding. It can be difficult to distinguish between haemoptysis, haematemesis and epistaxis. Therefore, careful history and clinical evaluation are essential. Alkaline pH (as determined with pH indicator paper), foaminess, or the presence of pus may help to direct the physician that the lungs are the primary source of the bleeding. In 90% of cases, haemoptysis originates from the bronchial arteries, in 5% from the pulmonary arteries, and in the remainder from nonbronchial collaterals [9]. The common causes for massive haemoptysis are listed in table 1. There are differences between demographic areas in the local disease profile of patients presenting with haemoptysis. In a South African study, the most common causes were tuberculosis and post-tuberculous bronchiectasis (73%), followed by bronchogenic carcinoma (5%) [10]. In a study in New York, USA, the causes were more evenly spread with bronchiectasis in 25%, tuberculosis in 16%, aspergilloma in 12% and bronchogenic carcinoma in 12% [11]. Overall, tuberculosis, bronchiectasis and aspergilloma are the most common causes for massive haemoptysis [10, 12–15]. Bronchogenic carcinoma rarely causes massive haemoptysis but frequently milder haemoptysis. Tuberculosis can cause haemoptysis via various mechanisms. Active tuberculosis, defined as sputum positivity for acid-fast bacilli and/or culture for Mycobacterium tuberculosis, can cause both minor and massive haemoptysis. Occasionally, formation of Rasmussen’s aneurysm is observed, which is caused by erosion of the pulmonary artery and leads to bleeding from the pulmonary arterial circulation when ruptured. More frequently, residual (post-tuberculous) damage leads to bronchiectasis, broncholith formation or predisposes to the formation of an intracavitary mycetoma, all of which cause bleeding from bronchial arteries. Eur Respir Mon, 2006, 36, 95–107. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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In bronchiectasis, the development of tortuous and hypertrophied bronchial arteries, which are subjected to systemic blood pressure, can lead to massive bleeding. The most common causes for bronchiectasis are post-tuberculous changes (not active), other previous lung infections, cystic fibrosis, immune defects or Kartagener’s syndrome. Systemic and immunological diseases (table 1) cause diffuse alveolar bleeding. In the latter situation, the degree of bleeding tends to be underestimated because alveolar bleeding does not induce a cough reflex to the same extent as does bleeding from the larger airways; thus the amount of expectorated blood is less.

Diagnostic evaluation Initial evaluation Blood tests. A venous blood sample should be taken to evaluate the platelet count,

haemoglobin and the clotting profile as well. Haemoglobin should be kept atw10 g?dL-1. Repeat haemoglobin measurement helps to better quantify the significance of the blood loss. Initial readings may be higher than subsequent values due to haemodilution across compartments and infusion of intravenous fluids. Table 1. – Common causes for massive haemoptysis Neoplastic Bronchogenic carcinoma Bronchial adenoma Pulmonary metastasis Infectious Tuberculosis# Fungal infections, especially aspergilloma# Necrotising pneumonia Lung abscess Hydatid cyst Paragonomiasis Pulmonary Bronchiectasis# Cystic fibrosis Vascular Pulmonary thrombo-embolism AV malformation (Osler–Weber–Rendu syndrome) Mitral stenosis Thoracic aorta aneurysm Pulmonary artery rupture due to balloon-tip catheter Systemic diseases Behcet’s disease Wegener’s granulomatosis Goodpasture’s syndrome Systemic lupus erythematosus Coagulopathies Disseminated intravascular coagulation Thrombocytopenia Haemophilia Von Willebrand’s disease Anticoagulant therapy Miscellaneous Lymphangioleiomyomatosis Catamenial (endometriosis) Broncholith

AV: arteriovenous. #: most frequent causes. 96

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It is essential to send blood for typing and crossmatching, and to order an adequate number of packed cells [5]. Arterial blood gases assess the patient’s respiratory compromise [5]. Renal and liver function tests may be of use in pulmonary–renal syndromes and liver failure.

Sputum examination. Sputum should be examined for organisms. A Gram stain and a stain for acid-fast bacilli should be performed and sputum sent for culture, especially for mycobacteria and fungi. In contrast to a common belief, acid-fast bacilli can often be found in the expectorated blood or bloody sputum of patients with active tuberculosis. Sputum should also be sent for cytological examination, especially in patients at risk for lung cancer (aged w40 yrs with a smoking history).

Chest radiograph. Chest radiographs are readily available and may help to localise the bleeding site, as well as give clues to underlying disease. In 20–46% of patients with haemoptysis, the chest radiograph fails to localise a lesion because the chest radiograph is either normal or shows bilateral disease [16].

Subsequent evaluation Computed tomography. Computed tomography (CT) is especially useful in the identification of small bronchial carcinomas and bronchiectasis [11, 17, 18]. Contrasted CT scan may help in the identification of vascular lesions, such as aneurysms and arteriovenous malformations [19, 20].

Bronchoscopy. Bronchoscopy is useful in both the diagnostic work-up as well as a therapeutic modality. The timing of performing bronchoscopy is controversial. One suggestion is to perform urgent bronchoscopy when there is rapid deterioration and elective bronchoscopy within 24–48 h in stable patients [5]. In patients with massive haemoptysis, rigid bronchoscopy is the method of choice due to its better suction ability [21]. The major limitation of rigid bronchoscopy is that it is difficult or even impossible to visualise the upper lobes or peripheral lesions [22]. The current authors perform flexible bronchoscopy via the bevel of the rigid bronchoscope and thus overcome the above-mentioned problem. Rigid bronchoscopy is usually performed under general anaesthesia, but in experienced hands it can also be attempted under local anaesthesia and conscious sedation [21]. Angiography. Angiography helps to visualise bronchial and non-bronchial arterial anatomy. It is especially helpful as the physician can immediately proceed to bronchial artery embolisation (BAE) as a therapeutic option. Remy-Jardin et al. [23] recently showed that multi-detector row helical CT angiography provided better visualisation of the bronchial and non-bronchial systemic arteries than conventional angiography (figs 1 and 2). They also concluded that it could provide the interventional radiologist with a precise road map as a guide when performing endovascular treatment [23].

Management There are three important steps in the management of patients with massive haemoptysis. 1) Resuscitation and airway protection are the first priority. 2) Localisation of the site and establishing the cause of bleeding is the next step. 3) The final step is 97

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Fig. 1. – Multi-detector row helical computed tomography angiogram (3-dimensional reconstruction). Arrows demonstrate bronchial arteries arising from descending aorta.

Fig. 2. – Multi-detector row helical computed tomography angiogram. Grey arrows demonstrate bronchial artery. White arrow demonstrates aspergilloma.

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directed at specific and definitive treatments to stop the haemoptysis and to prevent rebleeding [24].

Airway protection and resuscitation. Basic resuscitation should be performed and the necessary baseline tests ordered. Patients with massive haemoptysis should be admitted to either high care or intensive care units. If the site of bleeding can be localised, the patient should be positioned with the bleeding side down to protect the unaffected lung; this is a theoretical belief and has not been scrutinised in any controlled study [5, 24]. Cough suppressants can be used but present a hazard of favouring the retention of blood in the lungs [5]. The present authors use i.v. morphine 5–10 mg and codeine phosphate syrup 5 mL (25 mg?5 mL-1) every 6 h. Patients with ongoing massive haemoptysis should always be intubated with the largest possible endotracheal tube to allow both flexible bronchoscopy and suction [4]. Selective intubation of one lung can be performed by a rotational technique. After intubating the trachea, the tube is rotated through 90u in the direction of the desired placement until resistance is felt. The tube placement should be confirmed both clinically and radiologically. In a cadaveric model, this technique has been reported to have a success rate of 72% when directed at the left main bronchus and 94% when directed at intubating the right main bronchus [25]. Alternatively, a double-lumen endotracheal tube can be passed to protect the unaffected lung (figs 3–5). This requires experienced operators and positioning should be checked with the assistance of a bronchoscope [4, 26, 27]. Some double lumen tubes have very small lumens that do not allow suction catheters or even very small bronchoscopes. The current authors routinely occlude one lumen thereby causing tamponade of the bleeding lung. This necessitates adjusting ventilator settings for ventilation of a single lung.

Localisation of site and cause of bleeding. Localisation of the bleeding site directs definitive treatment. This can be achieved by combining the various imaging techniques with bronchoscopy.

Definitive and specific treatments. Bronchoscopic treatment. Instillation of numerous substances has been used in the treatment of massive haemoptysis. The instillation of adrenaline (1:20,000) is advocated but the efficacy in massive haemoptysis is uncertain [4].

Trachea

Proximal cuff Double lumen endotracheal tube

Right main bronchus Left main bronchus

Distal cuff Fig. 3. – Schematic drawing of a left-sided, double-lumen endotracheal tube in position.

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Fig. 4. – Left-sided, double-lumen endotracheal tube.

Fig. 5. – Ventilator connection piece for double-lumen endotracheal tube. The black piece is connected to the ventilator.

Ornipressin (5 IU) or terlipressin (0.5 mg) are both recommended for procedure-related bleeding during bronchoscopy, but their efficacy has not been validated in patients with massive haemoptysis [28]. The present authors use ornipressin and cold saline mixture (ornipressin 5 IU in 20 mL 0.9% NaCl) given as 2.5 mL boluses; this empirical therapy has not been validated either. Endoscopic administration of fibrinogen-thrombin or thrombin via flexible bronchoscopy has been tried [29, 30]. However, the published data are not convincing as the studies included very few patients and lacked standardisation of methodology. When confronted with patients with massive haemoptysis, it can be very difficult or even impossible to perform flexible bronchoscopy, which renders 100


administration of haemostatic substances problematic. In massive haemoptysis endobronchial tamponade with a balloon catheter is widely used as a temporary measure to control bleeding. A size 4–7 Fr 200-cm-long balloon catheter can be passed through the working channel of a flexible bronchoscope and inflated in the bleeding segment, thus isolating the bleeding site [4]. The 4 Fr 80-cm-long Fogarty catheter can also be passed through a flexible bronchoscope (fig. 6). The proximal hub needs to be cut off to allow for the removal of the bronchoscope by sliding it over the catheter. The pressure in the balloon is secured by inserting a pin into the proximal end of the catheter [31]. Freitag et al. [32] used a 6 Fr 170-cm-long, double-lumen balloon catheter via a flexible bronchoscope in 27 patients. These balloons have a detachable valve at the proximal end facilitating easy removal of the bronchoscope with minimal risk of dislodging the catheter. The balloons were inserted for up to 7 days while definitive therapy could be administered. Freitag et al. [32] concluded that the device was safe and that the technique was practicable. The various balloon catheters can also be inserted via a rigid bronchoscope.

Bronchial artery embolisation. The first report of its use came from Remy et al. [33] in 1973. There has been an increase in the use of BAE in the past decade [17]. Currently, it is the most effective non-surgical treatment for massive haemoptysis [5]. BAE is a technically demanding procedure and should always be performed by skilled interventional radiologists [34]. Arteriography is performed initially to locate the bleeding bronchial artery (fig. 7a and b). Various signs can be used to determine the site of bleeding such as vessel size, vascular blush, the degree of hypervascularity, as well as evidence of vascular shunting [35–37]. As alluded to earlier, multi-detector row helical CT angiography could be used as a road map guiding the interventional radiologist. This is particularly useful in centres where BAE is not regularly performed. Subsequent to localisation of the bleeding, vessel embolisation is performed. First, the bronchial arteries are embolised. Initial embolisation of the bronchial arteries facilitates visualisation of the non-bronchial collaterals, which might have to be embolised as well. Various materials are used to perform BAE. The most commonly used agent is polyvinyl alcohol (PVA) with particles sized 350–500 mm in diameter. These particles are suspended in x-ray contrast medium. As they are not absorbable, they prevent

Endotracheal tube

Right upper lobe bronchus Left main bronchus

Fogarty catheter

Bronchus intermedius Fig. 6. – Endotracheal tube with Fogarthy catheter in the right bronchus intermedius.

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a)

b)

Fig. 7. – a) Tortuous right-sided intercostal artery: pre-embolisation. b) Right-sided intercostal artery: postembolisation.

recanalisation. Another agent, absorbable gelatin sponge, is unfortunately fraught with a high degree of recanalisation and is, therefore, used as a supplement to PVA particles only. Isobutyl–2 cyanoacrylate, as well as absolute ethanol, is not recommended because of the high risk of developing tissue necrosis [34, 38–40]. Immediate response rates after BAE range 73–98% [38, 41–48]. Numerous complications have been described of which chest pain is the most common. Chest pain is most likely ischaemic in origin and usually transient. The most feared complication is spinal cord ischaemia with a prevalence of 1% [5, 39]. This complication has been reduced from as high as 6.5% due to the invention of coaxial microcatheter systems that can be used for more selective, so-called supra-selective embolisation [34, 49].

Surgery. Up to two decades ago, surgery was seen as the treatment modality of choice in patients with massive haemoptysis, in whom the site of bleeding could be localised, provided the patient had sufficient cardiopulmonary reserves. Currently, surgery represents one of a few treatment options, but still represents the only definitive one [5, 25]. Surgical mortality ranges 1–50% [3, 4]. There has been no study directly comparing surgery with medical management. Surgery remains the procedure of choice in patients with localised bronchiectasis, trauma, hydatid cyst, arteriovenous malformations, thoracic aneurysm and aspergilloma, because it is curative for these underlying diseases. Disease-specific approaches. 1) Aspergilloma. A patient with an aspergilloma should undergo surgical resection. Unfortunately, such patients often have significant concomitant bronchiectasis that may preclude them from surgery due to insufficient pulmonary reserves. In these patients, other modalities have been tried. Reports mostly consist of case series with small numbers. In one such study, intracavitary sodium or potassium iodide was used in 11 patients. Haemoptysis abated within 72 h and all patients were alive after 1 yr [50]. Intracavitary instillation of amphotericin B with or without Nacetylcysteine or iodine has also been used in patients with aspergilloma. Access to the cavity was either percutaneous or via transbronchial catheter [51]. External beam 102


irradiation has been successfully applied to five patients with aspergilloma, in fractions of 3.5 Gy once a week, and continued for one fraction after haemoptysis stopped. The authors reported no significant acute or late side-effects [52]. Systemic antifungal therapy has been disappointing in the treatment of aspergilloma [53]. 2) Immunological diseases. Some of the immunological diseases, such as Goodpasture’s disease, can present with massive haemoptysis. These diseases do not need invasive procedures and are usually treated with high-dose corticosteroids, cytotoxic agents or plasmapheresis. It is important that plasmapheresis is performed with fresh

Stabilising O2 mask, i.v. access Correct clotting profile Keep Hb >10 g·dL-1

Massive haemoptysis

Contact lung unit Intubation if necessary Antibiotics and TB Rx Strict bed rest Position bleeding side dependant Cough suppressants POR-8 inhalations

Stabilising

Investigation

Good response#

Poor response

Investigation WBC, BUN, electrolytes Typing and crossmatching Coagulation profile Chest radiograph Localisation of bleeding site: Bronchoscopy? CT scan? Good response No more haemoptysis or expectoration of minimal amounts of mainly blood clots Poor response Ongoing haemoptysis

Embolisation Grade 34 dyspnoea or insufficient cardiopulmonary reserve

Grade 02 dyspnoea or adequate cardiopulmonary reserve¶

Bleeding site not localised and/or not operable

Bleeding site localised and operable

Watchful waiting

Conservative (individual assessment)

Surgery

Fig. 8. – A management algorithm for massive haemoptysis (developed by the current authors). The lung unit: pulmonology is responsible for the management of massive haemoptysis. Antibiotics may be given depending on what the local guidelines suggest (i.e. for chronic obstructive airway disease or bronchiectasis). TB Rx (tuberculosis therapy) may be administered if the chest radiograph and clinical picture is suggestive. Other treatments, such as cough suppressants and ornipressin (POR-8) inhalations, may be used (see text). In active tuberculosis, anti-tuberculous therapy has a good response and the current authors do not advocate surgery. Hb: haemoglobin; WBC: white blood cell counts; BUN: blood urea nitrogen; CT: computed tomography. #: Aspergilloma: if documented on chest radiograph the definitive therapy is surgical resection because of the high incidence of re-bleeding with a watchful waiting approach; }: as evaluated with algorithm (full pulmonary function testing with or without maximal oxygen consumption) [58].

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frozen plasma. Plasmapheresis depletes clotting factors, which can aggravate haemoptysis [54]. 3) Bronchogenic carcinoma. Laser bronchoscopy has been a major advance in the treatment of massive haemoptysis, especially in patients with endoscopically visible bronchogenic carcinoma. It can be performed with both rigid as well as flexible bronchoscopy, although rigid bronchoscopy would be preferred [55]. Endobronchial electrocautery using a rigid bronchoscope with a rigid suction probe for monopolar electrocautery is at least as good as laser [56]. The present authors have used both laser and electrocautery but prefer electrocautery when using the rigid bronchoscope. This is because the rigid probe combines suction and electrocautery, which obviates the need for an additional suction probe and, therefore, shortens the procedure. Argon plasma coagulation is another modality that works well and can be used both with rigid as well as flexible bronchoscopy [56].

Management algorithm The proposed management algorithm (fig. 8) has been established in the hospital of the current authors with an average yearly incidence of 80–100 patients with massive haemoptysis. Thus far, it has been evaluated retrospectively (unpublished data) and found to be highly useful. It is based on the concept of a stepwise approach. After stabilisation and investigation, the initial response is assessed. In patients with a good response, defined by no more haemoptysis or expectoration of minimal amounts of mainly blood clots, a watchful waiting attitude can be adopted. The exception is aspergilloma where the risk for re-bleeding is high and surgery is the definitive therapy. Patients with a poor response, defined as ongoing haemoptysis, undergo bronchial arteriography and, if suitable, a BAE is performed. BAE is not regarded as definitive therapy in massive heamoptysis, surgical resection is therefore indicated. To determine operability, a functional assessment is performed to determine adequate cardiopulmonary reserve; this can be done by using an algorithm, as described by Bolliger et al. [57]. Patients can then undergo elective surgery. In the difficult cases with ongoing haemoptysis where emergency surgery is required, the physician has to rely on the historical grading of dyspnoea pre-haemoptysis. The current authors have used an arbitrary cut-off of grade II (Medical Research Council dyspnoea scale) for patients that would qualify for surgery. Patients with inadequate cardiopulmonary reserve or dyspnoea grade III/IV would be managed conservatively. Conservative or palliative measures include re-embolisation or any of the experimental or unproven modalities already mentioned.

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Summary The expectoration of blood is a frightening experience for both patients and doctors. The definition of massive haemoptysis varies from 200–1,000 mL of blood per 24 h. In patients with underlying lung disease, even a small amount of haemoptysis can cause respiratory compromise. A stepwise approach to the management of life-threatening haemoptysis is needed. Careful history and examination are essential for both diagnostic as well as therapeutic work-up. Initial management consists of proper resuscitation, basic blood testing (haemoglobin) and chest radiograph. In the next step, bronchial artery angiography/embolisation is performed as the procedure of choice. Depending on its success and on an individual risk assessment for the recurrence of bleeding, a decision should be taken regarding the need for surgery. If surgery is needed, lung function assessment should be done to evaluate operability. If emergency surgery is needed, the history of the degree of dyspnoea prior to haemoptysis has to be relied on. An algorithm encompassing all necessary steps in the management of massive haemoptysis is proposed at the end of the current review. Keywords: Bronchial artery embolisation, bronchoscopy, massive haemoptysis, multidetector row helical computed tomography angiography. Acknowledgements. The authors would like to thank B. Joshi (Dept of Radiology, Tygerberg Hospital, Tygerberg, South Africa) for supplying the radiological figures and captions.

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CHAPTER 8

Tracheobronchial aspiration O. Dikensoy*, H. Misra#, E. Ekinci*, R.W. Light# *Dept of Pulmonary Diseases, Gaziantep University, Gaziantep, Turkey. #Allergy and Pulmonary and Critical Care, Vanderbilt University, Nashville, TN, USA. Correspondence: O. Dikensoy, Dept of Pulmonary Diseases, Gaziantep University, Gaziantep, 27035, Turkey. Fax: 90 3423603921; E-mail: [email protected]

Aspiration is the inhalation of solid or liquid materials into the airways. It occurs when solids or liquids are introduced into the supraglottic area rapidly or in large volumes or when airway defences are diminished by structural abnormalities or neurological impairment. Aspiration may cause no complications or may result in a range of complications from paroxysms of coughing to respiratory failure and death [1, 2]. Tracheobronchial aspiration syndromes are usually defined by the aspirated material and, in some instances, by the mechanism or sequelae of aspiration: foreign body aspiration (FBA), aspiration of oropharyngeal or gastric content (aspiration pneumonia and aspiration pneumonitis), aspiration of hydrocarbons or lipids (lipoid pneumonia) and neardrowning.

Foreign body aspiration The aspiration of a foreign body is an important clinical event requiring immediate recognition and treatment to minimise complications [1–3]. The majority (y80%) of recognised cases occur in patients agedv15 yrs [2]. However, multiple retrospective case series of paediatric FBA suggest that most events occur in patients aged v3 yrs, with males affected more frequently than females [3–7]. In the USA in 2001, w17,000 children aged ƒ14 yrs were treated in emergency departments for choking, and w100 emergency room visits occurred for every chokingrelated death [8, 9]. Children agedv1 yr and adults agedw75 yrs are at an increased risk of death following FBA [10]. Across all age groups, suffocation due to FBA is the fifth most common cause of death by unintentional injury in the USA [8, 9].

Aetiology and pathogenesis Although FBA occurs most commonly in toddlers, a bimodal age distribution exists within the paediatric population. The second peak occurs around 10 yrs of age [11]. The younger group’s vulnerability is due, in part, to inadequate dentition and immature swallowing coordination. Other risk factors include access to improperly shaped and sized foods, access to small objects and the presence of older siblings. Additionally, toddlers introduce objects into the mouth as they explore the world. The second peak around 10 yrs of age occurs as a result of the oral cavity being used as a repository for school supplies, such as pen-caps, and inadequately preparing and chewing food. FBA is particularly common in this age group if oesophageal abnormalities are also present [11]. Eur Respir Mon, 2006, 36, 108–124. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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Table 1. – Underlying conditions that predispose to aspiration Chronic debilitating disease Cancer Oropharyngeal or airway instrumentation Orogastric or nasogastric tube feeding Prolonged mechanical ventilation Upper gastrointestinal endoscopy Tracheostomy Feeding gastrostomy tube Altered mental state General anaesthesia for emergency surgery Generalised seizure Cardiopulmonary resuscitation Electroconvulsive therapy Trauma Alcohol- or drug-induced stupor Cerebrovascular accident Disorders affecting swallowing Neuromuscular disease involving the oesophagus or pharynx Severe developmental disability Achalasia Oesophageal or pharyngeal carcinoma Hypopharyngeal (Zenker’s) diverticulum Benign oesophageal stricture, congenital or acquired Tracheo-oesophageal fistula

In adults, FBA occurs primarily due to the failure of airway protective mechanisms [2]. Conditions predisposing to FBA are listed in table 1. Less frequently, aspiration of an object in the oral cavity occurs in all age groups in association with laughing, crying, or sneezing. In adults, the right bronchial system is more likely to be obstructed by aspirated foreign bodies, owing to the more vertical angle and slightly larger diameter of the right mainstem bronchus. However, this is not true in children for two reasons: 1) the left mainstem bronchus branches at a less acute angle than in adults; and 2) the left mainstem bronchus is nearer in size to the right mainstem bronchus [7]. It is important to note that two-thirds of aspirated objects lodge in a main stem bronchus rather than a distal bronchus [12, 13]. When a foreign body lodges into the distal bronchial system, but does not cause an acute obstruction, the consequences can vary based on the nature of the foreign body. Organic materials can cause severe localised mucosal inflammation, and granulation tissue may develop within hours. Objects that can absorb water, such as beans, seeds, and corn, can swell, turning a partial obstruction into a total obstruction [14]. Grass influorescences have been known to migrate distally and result in chronic focal inflammation requiring lung resection [15]. On the contrary, individuals who have inhaled small inorganic objects can remain asymptomatic for a period of time unless total obstruction of an airway occurs [14].

Clinical presentation Symptom severity at the time of presentation of an aspirated foreign body varies depending on the site of impaction and the nature of the foreign body. Although uncommon, laryngeal occlusion by a foreign body often presents acutely and dramatically. It is characterised by a brief period of choking and gagging in association with hoarseness, aphonia or cyanosis [3, 16]. 109

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If the foreign body passes through the vocal cords and lodges in the subglottic region or trachea, inspiratory stridor with bouts of coughing may be noted. However, migration of the foreign body distally into the bronchi leads to a resolution of these symptoms. A relatively asymptomatic period may then begin [17]. Choking (defined as the sudden onset of cough, dyspnoea or cyanosis), witnessed in a previously healthy child, has a sensitivity of 79–88% for the diagnosis of FBA [5, 18, 19]. The choking phase occurs immediately and lasts seconds to minutes. In most instances, this acute phase is self-limited and may be followed by a symptom-free period. This asymptomatic period must not, however, be misinterpreted as a sign of resolution. In other children, respiratory distress, wheezing, or persistent cough may occur. Dyspnoea is uncommon in adults with confirmed FBA, occurring in only 25% of patients in one series [17]. Coughing occurs in up to 80% of all cases, while fever, haemoptysis, chest pain or wheezing may also be observed [10]. It has been reported that y50% of patients with FBA do not remember a choking episode, and 20% of children are treated for other disorders for w1 month before a diagnosis of FBA is made [19–21]. The long-term presence of a foreign body can result in recurrent haemoptysis or symptoms of recurrent bronchitis, pneumonia or bronchiectasis, such as a chronic productive or unproductive cough or wheezing [15–18]. The most common physical findings in cases of FBA are tachypnoea, stridor, unilateral or bilateral decreased breath sounds, localised wheezing or crackles, and fever [22]. Physical examination is normal in up to 40% of patients with FBA. Unusual presentations include pneumomediastinum, subcutaneous emphysema and pneumothorax [7]. Tracheobronchitis, asthma, recurrent pneumonia and tuberculosis are the most common diseases considered in the differential diagnosis [23–25].

Types of aspirated foreign bodies The type of foreign body aspirated depends largely on the patient’s age and the circumstances surrounding the aspiration event. In children, food items account for the majority of foreign bodies aspirated [8]; in adults, the nature of the foreign body is highly variable. Nail or pin aspiration occurs primarily in young and middle-aged adults engaging in "do-it-yourself" activities. Aspiration of dental debris, appliances or prostheses can complicate facial trauma or dental procedures. In all age groups, pill aspiration is common [26]. Aspirated objects can be organic or inorganic in nature. Most aspirated foreign bodies are organic materials, such as nuts and seeds in children, and food and bones in adults. The most common inorganic items aspirated by children are beads, coins, pins, small parts of toys and other small objects. In adults, dental prostheses and tops from beverage cans are among inorganic substances reportedly extracted from airways [25]. Additionally, some individual or cultural factors have a role in the type of aspirated material. For instance, in Western, Chinese, and Middle Eastern populations, vegetable matter, bones, and watermelon seeds, respectively, are the most frequently aspirated food particles [2, 17, 27, 28]. Turban pin aspiration has been reported in Muslim females who hold the pin between their lips while attaching their head scarves [29, 30]. Recently, an interesting case of a 2.5-yr-old child who aspirated a Christmas tree branch was reported [31].

Radiographic evaluation No prospective study has evaluated the diagnostic utility of clinical and radiographic abnormalities in adults with suspected FBA. So far, the best available evidence is drawn 110


from multiple retrospective case series of confirmed FBA. The most commonly described chest radiographic findings are hyperinflation or obstructive emphysema (44–64%), mediastinal shift (4–71%), pneumonia (4–23%), atelectasis (9–22%), radiopaque foreign body (3–16%), and unilateral whole-lung opacification (2%). However, the chest radiograph is normal in 12–25% of cases [32–34]. Although most foreign bodies are radiolucent, a standard radiographic work-up, including postero-anterior and lateral chest films, and a lateral soft-tissue neck radiograph should be performed in cases of suspected FBA (fig. 1) [25]. Obstructive emphysema, particularly when associated with decreased breath sounds ipsilaterally, has a positive predictive value w95% [7, 35]. It is noteworthy that chest radiographs may be normal for the first 24 h. Moreover, initial radiological findings of unilateral or segmental hyperaeration may be better visualised with expiratory radiographs or by fluoroscopic examination of the lungs [36]. In small children, bilateral decubitus radiographs may reveal hyperinflation of the dependent lung [37]. Complete obstruction of an airway will eventually result in atelectasis as air is resorbed from the distal alveoli over time, especially in children in whom collateral ventilation is not well developed. Infection often develops distal to an obstructed airway. Other studies, such as computed tomography (CT) scans and magnetic resonance imaging seldom contribute to the diagnosis of FBA, require patient cooperation and may delay treatment [38].

Suspected case of FBA

Chest radiograph: Posteroanterior Lateral (lateral decubitus in infants)

FB visible? Yes

No Lateral soft tissue neck radiograph

Bronchoscopy#

FB visible?

Yes Larengoscopy or flexible bronchoscopy

No

Bronchoscopy

Fig. 1. – Diagnosis of foreign body aspiration (FBA). #: type of bronchoscopy (flexible or rigid) depends on the patient’s age and the bronchoscopist’s experience. FB: foreign body.

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Complications The extent and severity of complications of FBA depend on the size, shape, composition, location and orientation of the aspirated object. Noncardiogenic, or reexpansion, pulmonary oedema may develop in a previously atelectatic lung following clearance of an obstruction; bleeding from granulation tissue can occur and may be massive [39, 40]. Relief of longstanding bronchial obstruction can result in soiling of the bronchial tree with purulent secretions. Delayed complications associated with a retained foreign body include unresolving pneumonia, lung abscess, recurrent haemoptysis, lung fibrosis, obstructive emphysema and bronchiectasis [15, 41]. Additional acute and chronic complications are outlined in table 2.

Management If a patient presents with acute asphyxia and complete airway obstruction, dislodgement should be attempted immediately. The recommendations of the American Heart Association [42] are to administer back blows and chest compressions to infants and the Heimlich manoeuvre to larger children and adults. The Heimlich manoeuvre lifts the diaphragm and forces enough air from the lungs to create an artificial cough. This cough is intended to move and expel an obstructing foreign body. Each thrust should be given forcefully with the intention of removing the obstruction. The Heimlich manoeuvre is not recommended for choking infants aged v1 yr [41]. When the obstructing foreign body is below the larynx and is not removed or dislodged so as to allow ventilation, intubation may allow some ventilation until rigid bronchoscopy is possible. Emergent rigid bronchoscopy should be performed to manage the obstruction definitively. In clinically stable patients, foreign body removal usually relies on bronchoscopic techniques. Despite the advances in optical technology, proper training and experience is crucial to optimise the outcome and minimise the risk of complications in tracheobronchial foreign body removal by a bronchoscope. Choosing the best instrument for the bronchoscopy depends primarily on the age of the patient and the experience of the bronchoscopist. Rigid bronchoscopy with general anaesthesia is still considered the safest procedure in most paediatric centres, as the use of a flexible bronchoscope with local anesthesia in young patients is very difficult. Using a short-acting agent, such as propofol, for general anaesthesia may increase the safety by allowing jet ventilation or manually assisted spontaneous ventilation, since the procedure Table 2. – Complications due to foreign body aspiration Acute (early)

Chronic (delayed)

Haemoptysis Asphyxiation Laryngeal oedema Pneumothorax Pneumomediastinum Tracheobronchial rupture Cardiac arrest

Obstructive emphysema Atelectasis Tracheo-oesophageal fistula Bronchial stricture Pneumonia Persistent cough Persistent haemoptysis Localised bronchiectasis Chronic post-obstructive pneumonia Lung abscess Bronchopleural fistula Tracheo-oesophageal fistula Mediastinitis

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rarely exceeds 10 min. In fact, a rigid bronchoscope provides greater access to the subglottic airways ensuring oxygen delivery and easy passage of the telescope and grasping forceps during the extraction of a large foreign body. Furthermore, a rigid bronchoscope allows efficient airway suctioning in case of a massive bleed [7]. Fibreoptic bronchoscopy is the preferred tool for the initial diagnosis of FBA in clinically stable adults [1, 25, 42]. It also has advantages over rigid bronchoscopy in patients who have distally wedged foreign bodies, are mechanically ventilated, or who have spine, jaw, or skull fractures preventing manipulation of the rigid bronchoscope [28].

Aspiration pneumonia/pneumonitis Aspiration of gastric or oropharyngeal content may result in one of two distinct entities: aspiration pneumonia or aspiration pneumonitis. Aspiration pneumonia is an infectious complication of aspiration in which colonised oropharyngeal material is aspirated into the tracheobronchial tree and an infection ensues. In contrast, aspiration pneumonitis is a sterile chemical pneumonitis, or pulmonary inflammatory state, frequently resulting from aspiration of gastric acid.

Aspiration pneumonia The true incidence of aspiration pneumonia is unknown. Many cases of pneumonia diagnosed as community-acquired or nosocomial in origin may actually be due to unrecognised aspiration [43]. Aspiration pneumonia is the most common cause of nosocomial pneumonia in elderly patients [44]. It occurs most commonly in hospitalised and chronically institutionalised adults, particularly those with risk factors, such as dysphagia secondary to stroke or another neurological disorder, seizure disorder, or anatomic abnormalities of the upper aerodigestive tract (table 1) [45].

Pathogenesis The normal swallowing mechanism and the cough reflex are important defences against oropharyngeal aspiration. Almost 50% of all healthy adults aspirate oropharyngeal secretions in small amounts during sleep [45, 46]. However, it is believed that bacteria of low virulence in pharyngeal secretions, along with an intact cough reflex, ciliary transport and normal humoral and cellular immune responses, prevent development of pneumonia in normal people. However, when any of these defence mechanisms are impaired or the aspirated inoculum is substantial, the risk of pneumonia increases. Although the aetiology of aspiration pneumonia is multifactorial, dysphagia plays an important role in its development [47]. Any patient with a degenerative central nervous system disorder may develop dysphagia [47]. Given the high prevalence of cerebrovascular disease and degenerative neurological disease in nursing home residents, a 50–75% annual incidence of pneumonia in this population is not surprising [48]. Although the presence of dysphagia and the volume and bacterial burden of the aspirate are the main factors predisposing to aspiration pneumonia, a number of other factors have important roles [49]. Oropharyngeal colonisation is important in the pathogenesis of aspiration pneumonia. Increased oropharyngeal colonisation with pathogens, such as Staphylococcus aureus and aerobic Gram-negative bacilli (e.g. Klebsiella pneumoniae and Escherichia coli), occurs in the elderly [50]. Other predisposing risk factors that may enhance oropharyngeal colonisation by these or other pathogens 113

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include decreased salivary clearance, poor oral hygiene and poor dentition [50, 51]. Reduction in mucociliary clearance, reduced pulmonary elasticity, decreased respiratory muscle strength, reduction in functional residual capacity, and a progressive decline in the integrity of the immune system all occur with ageing and are other characteristics of the elderly population that increase the risk of aspiration pneumonia [52, 53]. Additionally, nutrition has a profound effect on the strength of the immune system, and patients with dysphagia are likely to have a poor nutritional status [54].

Diagnosis There are no specific diagnostic tests for aspiration pneumonia. A high index of suspicion is critical in the diagnosis of aspiration pneumonia and is particularly important in a patient from a high-risk group with new onset hypoxaemia, tachypnoea, pulmonary infiltrates predominantly in dependent lung regions, fever, and leukocytosis following witnessed or suspected emesis or regurgitation. Fever and tachypnoea occur in most affected patients. Auscultation frequently reveals rales in the affected lung regions, and cough, wheezing or cyanosis may occur.

Management There is no unique treatment for pneumonia due to aspiration. Antibiotics and supportive care are the mainstays of management. In the case of acute aspiration, the upper airway should be suctioned if foreign material or secretions are still present in the oropharynx. Special care should be taken during suctioning to avoid induction of gagging or emesis. Gastric tube feeding should be discontinued. Supplemental oxygen should be administered during the initial assessment and continued if necessary to maintain oxygenation. Intubation and positive pressure mechanical ventilatory support may be required in severe cases. Lung injury after aspiration occurs rapidly. Therefore, while bronchoscopic removal of particulate matter or a foreign body may be necessary to relieve obstruction, it does not improve the clinical course of the pneumonia [55]. Antibiotic treatment in most patients with suspected aspiration pneumonia is started empirically. The patient’s risk factors, the likely pathogens and the setting in which the aspiration event occurred (community versus hospital or long-term care facility) are important considerations when selecting the empirical antibiotic regimen. Adjunctive corticosteroid therapy has not proven valuable in the treatment of aspiration pneumonia and may actually be harmful [56, 57].

Complications The primary complications of aspiration pneumonia are lung abscess formation, empyema and bronchopleural fistula formation. Most lung abscesses respond to prolonged antibiotic treatment. Most empyemas related to aspiration pneumonia are due to bronchopleural fistula. Adequate pleural drainage, in addition to proper antibiotic treatment, is essential in all patients with empyema [55].

Aspiration pneumonitis (chemical pneumonitis) Aspiration, or chemical, pneumonitis is a syndrome characterised by acute inflammation of the lung parenchyma due to aspirated material. Aspiration of various 114


materials, such as gastric acid, mineral oil or other hydrocarbons, may result in aspiration pneumonitis; aspiration of gastric contents occurs most commonly [55].

Aspiration of gastric content The pathogenesis of pulmonary damage caused by chemical aspiration of gastric content depends on the amount and nature of the material aspirated. The severity of the pulmonary damage is thought to be related to both the pH and the volume of the aspirated material. It is greatest when the pH is v2.5 and the volume is w25 mL. However, considerable evidence suggests that pulmonary damage may also occur when the pH of aspirated fluid is neutral or relatively high [58, 59].

Diagnosis If a patient aspirates a large amount of relatively pure gastric material of low pH, respiratory distress with gradually worsening hypoxaemia may precede radiographic changes. If the patient survives this acute stage of pulmonary oedema, an initially dry cough may supervene and become productive of copious purulent sputum; a variety of aerobic and anaerobic pathogens may be cultured from this material. In the early stages, diffuse crackles may be heard. Once consolidation develops, patchy areas of bronchial or tubular breath sounds may be detected. Chest radiography typically shows bilateral, patchy consolidation, similar to that seen with cardiac-related pulmonary oedema or the more diffuse permeability oedema observed in adult respiratory distress syndrome (ARDS) [60]. These abnormalities tend to worsen for several days. Improvement then occurs relatively quickly in uncomplicated cases. If radiographic abnormalities worsen after an initial improvement, this often reflects development of a complication, such as bacterial pneumonia, ARDS, or a pulmonary embolism [61]. When the aspirate contains a significant amount of admixed food, radiographic findings frequently demonstrate a segmental distribution, particularly involving one or more of the posterior segments of the upper or lower lobes. The patient’s position at the time of aspiration influences the location of the infiltrates [60]. Recurrent gastro-oesophageal reflux or a tracheo-oesophageal fistula may cause unexplained chronic cough or recurrent pneumonia without an obvious aetiology. In adults with oesophageal dysfunction, choking may be due to gastric acid reflux. Contrast studies, endoscopy, prolonged pH monitoring or laryngoscopy may be helpful in diagnosing reflux [61]. Serial radiological evaluation in such cases may reveal migratory pulmonary infiltrates. In chronic cases, irregular accentuation of linear markings, probably representing peribronchial scarring, and, rarely, reticulonodular or miliary patterns can also be seen on chest radiographs [62, 63].

Management and prognosis Uncomplicated chemical pneumonitis generally does not require antibiotic therapy. Prophylactic antibiotic treatment has no role in preventing subsequent infectious pneumonia and is not recommended [55]. The severity of the lung damage varies based on the acidity and amount of material aspirated, and it has an important role in predicting the patient’s prognosis. For instance, if ARDS occurs in association with the aspiration event, the death rate is as high as 50% [64]. If such a patient survives, recovery usually occurs without clinical, physiological or 115

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radiographic sequelae. However, recovery may be prolonged, lasting up to 18 months [65]. In other patients, respiratory insufficiency may persist [66].

Aspiration of hydrocarbons and lipids The aspiration of lipoid materials, such as mineral oil, various animal- or vegetablebased oils, or hydrocarbons, such as petroleum-based products, is defined as exogenous lipoid (lipid) pneumonia. Endogenous lipoid pneumonia can occur in the setting of bronchial obstruction when the lipid-dense surfactant is ingested by macrophages. In cases of exogenous lipid aspiration, the event can occur either at the time of initial ingestion or in association with emesis. Interestingly, the lungs are the primary organs damaged when hydrocarbons are ingested, but they are not the primary organs damaged in cases of hydrocarbon inhalation. Rather, the central nervous system and cardiovascular system are the primary organ systems affected by hydrocarbon inhalation [67]. Exogenous lipoid pneumonia can present in two different clinical forms: acute exogenous lipoid pneumonia (fire-eater pneumonia) and chronic exogenous lipoid pneumonia.

Acute exogenous lipoid pneumonia (fire-eater pneumonia) The aspiration of massive amounts of liquid paraffin or petroleum may lead to an acute and fatal form of exogenous lipoid pneumonia [68]. Acute pneumonitis following aspiration of petroleum-based products is usually related to accidental poisoning in children but is also seen in fire-eaters who use petroleum-based agents for the flameblowing portions of their acts. The performer blows out a mouthful of a flammable liquid petroleum-based product against a burning stick, thus creating an aerosol that burns around the stick [68]. Fire-eater pneumonia is rare. History, in particular, and radiographic findings can suggest the diagnosis. Radiologically, it is characterised by pneumatoceles, or thin-walled collections of air that develop as post-inflammatory lesions. These pneumatoceles have also been described as a late complication of other hydrocarbon aspirations and staphylococcal pneumonia [69].

Chronic exogenous lipoid pneumonia Repeated aspiration of mineral oil or similar substances into the distal lung can lead to chronic exogenous lipoid pneumonia. The clinical presentation and pathogenesis varies with different substances [70].

Mineral Oil. Mineral oil is the most common agent responsible for chronic exogenous lipoid pneumonia. Chronic exongenous lipoid pneumonia due to mineral oil occurs most frequently when the oil is used as a lubricant in infants who have feeding difficulties and in adults using mineral oil to treat constipation [70, 71]. Presumably, repeated subclinical episodes of aspiration result in accumulation of lipoid material and eventual clinical or radiological abnormalities. Vicks VapoRub1 [72], lip gloss [73] and petroleum jelly [74] have also been implicated in the development of this disease.

Animal lipids. Milk and milk products are the most commonly aspirated animal lipids, particularly in infants and young children during feeding [75]. Unlike the mineral oils, 116


animal fats are thought to be hydrolysed into fatty acids by lung lipases, and their presence in the lung can cause acute haemorrhagic pneumonitis [76].

Vegetable lipids. Aspiration of vegetable oils occurs most commonly during eating or in association with emesis of gastric contents. Therefore, the oil is unlikely to be the sole offending agent, and the damage to the lung caused by the oil itself is difficult to assess. The pathogenesis of pulmonary disease resulting from vegetable oil aspiration is not completely understood. Some oils remain for prolonged periods in alveolar spaces without causing fibrosis or a significant inflammatory response [76]. However, others cause tissue reactions similar to those associated with animal oils. As with the latter, hydrolysis can cause the release of fatty acids that may be important in the pathogenesis of lung injury [76].

Diagnosis Most patients who aspirate mineral oil are asymptomatic. Some patients complain of a chronic, typically non-productive, cough or pleuritic pain. Rarely, aspiration of a relatively large amount of liquid oil causes an acute illness resembling infectious pneumonia [77]. Occasionally, a patient develops hypercalcaemia, a complication speculated to have a pathogenesis similar to that seen in sarcoidosis [78]. Clinical findings in cases of animal or vegetable oil aspiration are usually those of acute pneumonitis. As indicated, many patients are likely have aspirated other gastric materials along with the lipid. Therefore, the clinical findings and course are similar to those of patients who aspirate gastric secretions. The diagnosis of exogenous lipoid pneumonia should be suspected in any patient with a history of exposure to a lipid-based substance, particularly if an underlying condition predisposing to aspiration is present. However, in adults, 25% of cases of exogenous lipoid pneumonia have been reported in individuals without any predisposing factors identified [71]. Alhough not diagnostic, the presence of lipid-laden macrophages in bronchoalveolar lavage fluid supports the diagnosis [72]. The diagnosis can be established in most cases by transthoracic needle aspiration or transbronchial biopsy. Laboratory tests may show peripheral blood polymorphonuclear leukocytosis with an elevated erythrocyte sedimentation rate. Radiographic findings are nonspecific, with alveolar consolidation and ground-glass opacities occurring most frequently [71]. The distribution of radiological changes is highly variable, ranging from unilateral focal defects to diffuse bilateral abnormalities. The diagnosis of lipoid pneumonia can often be made by reviewing CT images. In particular, the presence of areas of low attenuation or fat attenuation (a negative density between -150– -30 Hounsfield Units) in a "crazy paving" pattern is highly suggestive [79].

Prognosis and management The prognosis in cases of oil aspiration is variable. Aspiration of a small amount of material once or very infrequently can cause little or no clinical or functional impairment. Recurrent oil aspiration over a period of days to years may result in functional impairment due to restriction and, in severe cases, cor pulmonale [80]. Various treatments for lipoid pneumonia have been suggested. These include discontinuing exposure to the offending agent, treating complicating infections with antibiotics, and providing supportive care, including oxygen therapy [81]. 117

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Aspiration of water (near-drowning) Drowning is suffocation due to submersion in a liquid, commonly water. Neardrowning is defined as survival following a submersion event. Drowning is the third-commonest cause of accidental death worldwide, particularly in children aged v4 yrs. It has been estimated that nearly 140,000 such deaths occur worldwide each year, of which y7,000–9,000 occur in the USA [82]. Anoxic brain injury occurs in y25–35% of near-drowning victims who arrive at the hospital in a comatose state [83].

Pathogenesis The pathophysiology of the damage incurred by the lung in near-drowning events differs depending on the tonicity of the aspirated water. Aspiration of fresh water dilutes pulmonary surfactant resulting in alveolar collapse and development of atelectatic regions in the lung [84]. Hypoxaemia occurs secondary to shunting and ventilation– perfusion mismatch [85]. As the fresh water is hypotonic compared with blood, it is absorbed rapidly from the alveoli into the circulation. This causes an acute increase in intravascular blood volume and brief, transient alterations in serum electrolytes (hyponatraemia and hypokalaemia) [86, 87]. Nevertheless, clinically significant electrolyte abnormalities are unusual in freshwater near-drowning victims [86]. Further, as a result of fluid redistribution, patients who have been submerged in fresh water may have intravascular hypovolaemia upon admission to the hospital [86, 88]. Aspiration of fluid that is hypertonic relative to blood, such as sea water, draws intravascular fluid into the alveoli. This causes hypoxaemia due to physiological shunting, as fluid-filled alveoli continue to be perfused. Again, clinically significant electrolyte abnormalities are uncommon except in unusual circumstances, such as submersion in the Dead Sea [89] or industrially polluted waters [90].

Diagnosis Although respiratory failure is the most important consequence of near-drowning, damage to other organ systems, such as the central nervous system, may have a critical role in the clinical presentation (table 3) [91].

Table 3. – Other organ system pathologies caused by near-drowning Organ system

Pathology

Neurological

Cerebral oedema Elevated intracranial pressure Spinal cord injury Sinus bradycardia Atrial fibrillation Asystole Acute tubular necrosis Haemoglobinuria Acidaemia Freshwater-induced haemolysis Shock-related disseminated intravascular coagulation

Cardiac Renal Haematological

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Table 4. – In-hospital management of the near-drowning victim Admission versus observation (if initial chest radiograph normal, may observe for i4 h) Measure core temperature (use rectal probe) Intubate and mechanically ventilate patients with worsening hypoxaemia Treat hypothermia passively with submersion in 40uC bath water or actively with extracorporeal bypass Correct fluid and electrolyte imbalances Treat infection

The radiographic changes caused by near-drowning from fresh water and sea water aspiration are similar [92]. The most common finding is air-space consolidation, which, depending on the amount of water aspirated, can be as severe as complete opacification of both lungs. Consolidation is generally bilateral and symmetrical, but in mild disease can be predominantly perihilar and midzonal; an asymmetrical distribution can also occur. Appearance of pulmonary oedema may be delayed as long as 24–48 h [93]. Airspace consolidation due to aspiration of water in near-drowning events is expected to resolve completely within 7–10 days of developing. If resolution does not occur in this time-frame, a complication, such as bacterial pneumonia or ARDS, should be suspected [92, 94]. So-called "sand bronchograms" caused by sand aspiration (airways full of sand) can be seen on both plain radiographs and CT images [95].

Prognosis and management Most patients recover without any sequellae. However, some victims may exhibit radiographic evidence of lung fibrosis (linear opacities) months after clinical recovery [96]. Management of near-drowning victims is summarised in table 4.

Conclusion Tracheobronchial aspiration syndromes are among the leading causes of morbidity and mortality from accidents worldwide. Prompt diagnosis is crucial for proper and timely management to prevent complications. Therefore, all practitioners, should be familiar with particular aspects of these syndromes, including aetiological factors, predisposing factors, pathogenesis, variability of clinical and radiographic findings, and the proper management of each of these conditions as they relate to his or her specific field.

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Summary Tracheobronchial aspiration syndromes are the most important causes of accidental morbidity and mortality worldwide, particularly in infants. Children aged v2 yrs and individuals of any age with one or more predisposing risk factors, such as dysphagia, are the most vulnerable groups. As most aspiration events are unwitnessed, timely diagnosis relies on a high index of suspicion. The clinical presentation and radiographic features can vary depending on the nature and amount of the aspirated material or object. While a foreign body aspiration or a relatively large volume of aspirated material can cause an acute or subacute presentation ranging from choking and sudden death to acute pneumonia, repeated aspiration of gastric acid in small amounts can gradually progress to recurrent pneumonia, bronchiectasis or pulmonary fibrosis. Management varies depending on the clinical appearance (e.g. hypoxaemia or signs of infection) and the nature of the aspirated material (e.g. foreign body, gastric content or hydrocarbon). Bronchoscopy has a major role in the diagnosis and management of cases of foreign body aspiration. Drowning is the third most common cause of accidental death worldwide. The pathophysiology of the damage incurred by the lung in near-drowning events may differ depending on the tonicity of the aspirated water. Respiratory failure is the most important consequence of near-drowning. However, injuries to other parts of the body, especially head or cervical spine injuries, should be suspected and evaluated. Victims of near drowning recover without any sequellae in most cases provided that irreversible hypoxic brain damage did not occur. Keywords: Aspirations, foreign body, near-drowning, pneumonia, pneumonitis, tracheobronchial.

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Tabeling BB, Model1 JH. Fluid administration increases oxygen deliver;during continuous positive ventilation after fresh water near-drowning. Crit Care Med 1983; 11: 693–696. Yagil Y, Stalnikowicz R, Michaeli J, Mogle P. Near-drowning in the Dead Sea. Electrolyte imbalances and therapeutic implications. Arch Intern Med 1985; 145: 50–53. Fromm RE. Hypercalcemia complicating an industrial near drowning. Ann Emerg Med 1991; 20: 669–671. Modell JH. Near drowning. Circulation 1986; 74: Suppl. IV, 27–28. Hasan S, Avery WG, Fabian C, Sackner MA. Near drowning in humans: a report of 36 patients. Chest 1971; 59: 191–197. Putman CE, Tummillo AM, Myerson DA, Myerson PJ. Drowning: another plunge. Am J Roentgenol 1975; 125: 543–548. Hunter TB, Whitehouse WM. Freshwater near-drowning: radiological aspects. Radiology 1974; 112: 51–56. Putman CE, Tummillo AM, Myerson DA, Myerson PJ. Sand aspiration with near-drowning: radiographic and bronchoscopic findings. Am J Respir Crit Care Med 1997; 156: 292–295. Glauser FL, Smith WR. Pulmonary interstitial fibrosis following near-drowning and exposure to short-term high oxygen concentrations. Chest 1975; 68: 373–375.

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CHAPTER 9

Drowning D.A. Groneberg*, J-L. Vincent#, T. Welte* *Dept of Respiratory Medicine, Hannover School of Medicine, Hannover, Germany. #Dept of Intensive Care, Erasme Hospital, Free University of Brussels, Brussels, Belgium. Correspondence: D.A. Groneberg, Dept of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30623 Hannover, Germany. Fax: 49 5115323353; E-mail: groneberg.david@ mh-hannover.de

Nearly half a million children and adults die annually due to drowning and submersion, with much higher numbers of near-drowning accidents being recorded [1–3]. Although there are effective approaches to the management of these patients, too many children and adults still die due to drowning incidents or suffer from chronic sequelae after such accidents. The present chapter addresses issues related to neardrowning and submersion by reviewing the current literature using a PubMed search with the following terms: "drowning", "immersion" "near drowning", and "submersion". Numerous articles were reviewed, including comprehensive reviews and guidelines [4–57], which were used as expert opinions in summarising the pathophysiology, management and available prevention strategies.

Definitions Modell [58] introduced and discussed common definitions in 1981, and defined the term "drowning" as "suffocation by submersion, especially in water" and the term "neardrowning" as "survival, at least temporarily, after suffocation by submersion in water". Extending these two clear definitions, a number of other definitions have been used in the past, with terms such as "immersion" and "submersion" being introduced to the field. A general terminology was, therefore, needed and the World Congress on Drowning decided that the term "near-drowning" should no longer be used in order to avoid confusion, and defined the term drowning, in 2002, as "the process of experiencing respiratory impairment from submersion or immersion in a liquid" [5, 6].

Epidemiology of drowning events Drowning as a cause of death is estimated to have an annual incidence of y400,000. Younger children are more at risk of drowning accidents than older children, adolescents and adults. For children aged 1–4 yrs in the USA, 27% of the total number of deaths related to unintentional injury were due to drowning accidents. Therefore, drowning accidents are among the leading causes of accidental death in younger children in both developing and industrialised countries. Drowning accidents are more common in male children, more common at weekends and exhibit high interseasonal variation, with approximately two-thirds of accidental deaths occurring in the period May to August [59–62]. Eur Respir Mon, 2006, 36, 125–135. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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The location of accidental drowning incidents varies and includes swimming pools, baths, rivers, lakes and seawater in coastal regions [56, 62, 63]. In 1995, an investigation analysing the death certificates of USA victims of drowning aged 1–19 yrs revealed that 55% of infant (v1 yr) drowning deaths took place in baths, 56% of drowning deaths in children aged 1–4 yrs took place in swimming pools and 63% of drowning deaths in children/adolescents aged w4 yrs took place in natural freshwater collections [63]. Causes of drowning incidents include boating accidents, diving accidents and suicide [1, 63]. In addition, medical conditions, including mental or physical handicap, epilepsy, heart attacks, cerebral strokes, autism, or alcohol and the abuse of other drugs, may be related to an increased risk of drowning accidents [61, 62, 64–68].

Pathophysiological aspects of drowning The process of drowning is influenced by numerous factors (table 1) [70], and needs to be regarded as a continuous process that starts with the lowering of the nose and mouth below a liquid surface leading to active breath-holding. This active process may then be followed by episodes of laryngospasm if liquid is present in the laryngeal or pharyngeal cavities [71, 72]. Since gas exchange no longer occurs, the oxygen level is reduced and the carbon dioxide level increases, leading to initial hypercarbic hypoxaemic acidosis [73]. Reflexes then lead to increased respiratory movements, and, eventually, laryngospasm decreases, allowing various volumes of fluids to be inhaled into the lungs [71–73]. The exact underlying pathophysiological mechanisms occurring during human drowning accidents have still not been fully elucidated. However, considerable efforts have been undertaken to determine the effects of drowning on both airway and vascular functions using animal models [74]. Although, for a long time, it was believed that laryngospastic episodes occur in the event of apnoea, preventing excessive water aspiration, the impact and role of laryngospasm and the extent of aspiration are now debated [75, 76]. In early studies, it was reported that the properties of the aspirated fluid have a large impact on body electrolyte and fluid status [75, 77]. In this respect, seawater drowning was suggested to lead to hypovolaemia, hypernatraemia, and an increase in haemoglobin viscosity and concentration, whereas freshwater drowning was believed to lead to haemodilution, hypervolaemia and hyponatraemia. These concepts were extended between the 1940s and 1960s by the groups of Swann and co-workers [77–79] and Modell and co-workers [80–82], who analysed the effects of drowning in canine models. In contrast to the data obtained from animal experiments, case series studies demonstrated early that the pathophysiology of human drowning accidents does not completely coincide with the situation in experimental animal drowning studies [83, 84], and the differences between the type of water in which the drowning occurs may not be as Table 1. – Important factors influencing drowning events Factor

Relevance

Duration of submersion/immersion Quality of immediate CPR Quality of water

Favourable outcome associated if submersion for v5 min Favourable outcome if cardiopulmonary functions can be immediately restored Fresh water: ventilation/perfusion dysfunction more difficult to correct; river water: increased risk of infection Crash into shallow water: dislocation/fracture of cervical spine; fall from height: spinal, thoracic or intra-abdominal injuries

Means of entering water

CPR: cardiopulmonary resuscitation. Modified from [69]. 126

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Table 2. – Acute or subacute sequelae of drowning accidents Brain death due to a severe hypoxic or ischaemic brain injury Post-hypoxic encephalopathy Acute respiratory distress syndrome Multiorgan dysfunction secondary to severe hypoxic or ischaemic insult Sepsis syndrome due to an aspiration pneumonia or nosocomial infections

Modified from [6].

significant. In particular, the time course, phenomenon of hypervolaemia in animal freshwater drowning and quantitative amount of aspirated fluids seem to differ, and it is now clear that the majority of deleterious pathophysiological effects observed in drowning accidents are due to hypoxia, and that a number of acute and subacute sequelae exist (table 2) [5, 6]. Whereas, in the first moments after the drowning accident, hypoxia is secondary to apnoea, the later event that is crucial for hypoxia is the development of acute lung injury. Acute lung injury itself can lead to severe respiratory distress, and is due to the washout and dysfunction of surfactant leading to intrapulmonary shunting, atelectasis and collapse of alveoli [4]. With these pulmonary mechanisms at the centre of the pathophysiology of drowning accidents, a severe degree of hypoxaemia commonly results, which may even lead to the situation of severe cardiac dysfunction, including arrest, ventricular fibrillation or bradycardia [85]. In general, major changes occur in the respiratory tract, blood gas tensions, cardiovascular system, body fluids, electrolyte concentrations and acid–base balance. All of these changes are dependent on the quantity of fluid aspirated and the duration of the submersion [80, 82, 86, 87]. A common symptom associated with a poor prognosis that is encountered after drowning accidents is hypothermia. With decreasing body temperature, involuntary contraction of muscle groups starts as a reaction of the body to increase heat production. If a threshold body temperature ofy30uC is reached, involuntary shivering stops and all major functions decrease, leading to extreme bradycardia with the risk of ventricular fibrillation or asystole [88, 89]. The temperature of the water is also of major importance, since a cold shock response in case of immersion in cold water may worsen the situation due to triggering gasp reflexes followed by the inhalation of large amounts of water. In this respect, it is known that water temperatures of v10uC often lead to cardiovascular effects, such as an increased blood pressure or the development of ectopic tachyarrhythmias. However, in contrast to these detrimental reflexes occurring during cold water drowning, some reports have also indicated a paradoxically better outcome compared to drowning in warm water, and it has been suggested that hypothermia may have protective cerebral effects [90–93].

Treatment of drowning victims Outpatient treatment In general, it is most important to disrupt the ongoing hypoxia, secure cardiovascular functions and prevent a further decrease in body temperature [69, 94]. Therefore, patients need to be transferred to an emergency care unit immediately. If cardiopulmonary resuscitation of drowning victims is necessary, it should have already been performed by bystanders and is associated with an improved prognosis [94–96]. At least two adult persons are required to lift a drowning victim from the water into a boat. Conscious victims should be recovered from the water in the prone position, since vertical head-out 127


immersion is known to lead to an increase in cardiac output of 32–66%, due to the pressure caused by the surrounding water. In the event of lifting, the pressure of the surrounding water is immediately removed and severe circulatory collapse may occur due to venous pooling. This mechanism is suggested to play a major role in deaths occurring in conscious drowning victims who die within minutes after rescue from the water [69]. In victims who are recovered from the water after having fallen from a height, spinal, thoracic or intra-abdominal injuries are common and should be anticipated. By contrast, in victims who are recovered from shallow water, attention should be paid to additional injuries, such as head injuries or dislocation/fracture of the cervical/thoracic vertebral column [69]. If circulatory arrest occurs, patients should ideally be transferred to a facility that can perform bypass and extracorporeal rewarming procedures [90, 93, 97]. Aspiration of gastric contents is a major problem, often leading to aspiration pneumonia and worsening of the prognosis. Therefore, intubation of unconscious patients at an early stage should be performed if possible. When cardiac arrest occurs, compression of the chest should be performed continuously. Preventing further loss of body temperature is also important, but rewarming of deeply hypothermic patients throughout transportation is difficult to control and should only be performed at the hospital. In conscious patients, a further loss of heat can be prevented by removing wet clothing before wrapping in temperature-protective blankets. By contrast, ingestion of hot fluids is not helpful. A critical point is the removal of inhaled fluids from the respiratory tract. Measures for this are controversial. Since aspiration of gastric contents is a major problem, conscious patients may be positioned in the lateral decubitus position with a lowered head in order to prevent aspiration [69]. In the case of vomiting or during bag-mask or mouth-to-mouth ventilation, pressure on the cricoid cartilage may also reduce the risk of aspiration [98]. In this respect, the Heimlich manoeuvre or any abdominal compression may initiate vomiting and should, therefore, not be used unless foreign body obstruction is present [98–102].

Management in hospital On arrival in hospital, a number of early measures exist that should be immediately performed depending upon the state of the patient (table 3). Unconscious patients should be immediately transferred to an intensive care unit for monitoring, and warming may be Table 3. – Early measures in the hospital Measure Tests Arterial blood gas/lactate analysis Radiography ECG Blood cultures Interventions Tracheal intubation Nasogastric tube Rectal temperature monitoring Central venous line

Relevance Low arterial oxygen tension and raised blood lactate levels indicate impaired oxygenation Assessment of fluid aspiration and pulmonary oedema Monitoring bradyarrhythmias or ventricular fibrillation Analysis of secondary infections Secures airway in unconscious patients to prevent regurgitation Decompression of stomach to assist ventilation and prevent regurgitation Assessment of body temperature Essential for treating fluid imbalances and monitoring effects of fluid challenge

Modified from [69]. 128

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performed using warmed intravenous fluids, haemodialysis, or peritoneal, bladder, or gastric lavage. Cardiopulmonary bypass can be used in severely hypothermic patients [103–105]. If not already intubated on arrival, tracheal intubation should be performed immediately if ventilatory support seems necessary, since hypoxaemia and signs of metabolic/respiratory distress must be treated promptly and aggressively. Therefore, repeated blood gas measurements and additional pulse oximetry are important tools for monitoring the cardiopulmonary status of the patient. Repeated chest radiography is often necessary as radiographs taken on admission may not exhibit abnormal findings despite the pulmonary situation continuously progressing into acute lung injury. Therefore, further radiographs should be taken if clinical or laboratory findings deteriorate. In cases of developing acute respiratory distress syndrome, treatment should follow international standards. A common radiographic finding is the development of pulmonary oedema [106], which may necessitate the use of diuretics. However, since the fluid status may already be imbalanced due to the inhalation of fluids, careful and continuing attention should be paid to exact dosing. A further common pulmonary feature is the development of bacterial pneumonia, since gastric aspiration is common. However, the prophylactic administration of antibiotic drugs does not lead to a significantly improved outcome [107, 108]. In case of signs of infection, therapy using broad-spectrum antibiotics should immediately be initiated and specimens should be analysed in order to establish a specific therapeutic regimen. The prophylactic use of steroids to prevent the development of acute lung injury and acute respiratory distress syndrome has not been demonstrated to improve outcome, and corticosteroids should not be used prophylactically since they may also lead to an increased risk of developing infections [109]. Further to pulmonary symptoms, impairment of neurological function is often found in drowning victims due to deprivation of oxygen supply. Concomitant with pulmonary and cardiovascular hypoxia and hypoxaemia, cerebral blood flow decreases and ischaemic injury may develop [110, 111]. In order to reverse the primary hypoxic– ischaemic cerebral injury and prevent secondary neuronal damage, different strategies have been developed over the years [51, 112, 113]. However, randomised prospective studies failed to demonstrate the effectiveness of these protocols as routine treatment protocols. Recently, induced hypothermia, with temperature levels ranging 32–34uC, has been suggested to lead to improved neurological outcome after cardiac arrest due to ventricular fibrillation [114]. This strategy may also be helpful in drowning victims, but large clinical studies have not been performed. In the meantime, if patients are spontaneously hypothermic, aggressive methods of increasing body temperature should be avoided.

Outcome Prediction of outcome is very difficult in drowning patients, and there is no particular parameter that predicts good versus poor outcome [115–119]. The recommended guidelines for uniform reporting of data from drowning state that the primary outcome measure of drowning accidents should be categorised as either death or survival, with survival indicating that the patient remained alive after the drowning event and any acute or subacute sequelae [5, 6] (table 2). In this respect, a drowning event followed by a successful resuscitation but a death even months later due to a condition that is related to the drowning event needs to be categorised as death due to drowning. 129


The outcome may also be subdivided into types of morbid condition, such as respiratory or neurological impairment, and different outcome scores have previously been evaluated, including the Glasgow Coma Scale, the Glasgow–Pittsburgh cerebral performance categories, the awake, blunted, comatose score, and the overall performance categories [33, 113, 118, 120, 121]. In paediatric cases, the paediatric overall performance category scale or the paediatric cerebral performance category scale has been used [122, 123]. The prediction of outcome is of paramount interest [124], and factors that are related to an increased risk of poor outcome or death are alcohol abuse, seizures, male sex, lack of bystander cardiopulmonary resuscitation, resuscitation efforts of w25 min and prolonged duration of submersion, but not age [125–131]. After admission to hospital, risk factors related to a poor outcome or death are the level of consciousness, brainstem dysfunction, hypothermic conditions and elevated serum glucose levels, as well as the need for mechanical ventilation [18, 96, 132]. It is important to note that, although there are common risk factors, great heterogeneity exists among drowning events. In this respect, drowning events, such as an attempted suicide with or without substance abuse, accidental submersion of an infant in a bath or swimming pool, or a trauma-associated drowning event after a traffic accident, are very different and management strategies may differ.

Prevention of drowning events Prevention is an extremely important measure in the field of drowning accidents, and both site factors (table 4) and human factors (table 5) have to be taken into account [133]. The Arizona Child Fatality Review Program analysed 4,806 deaths of children aged v18 yrs during the period 1995–1999, and 187 deaths were found to be due to drowning. Out of these 187 cases, 86% (161 cases) were regarded as having been preventable by measures including pool fencing or adequate supervision [134, 135].

Conclusion Drowning represents a common cause of accidental death at all ages, and is especially frequent in the very young and very old. Since the prolonged hypoxia leads to not only Table 4. – Relevant site factors in the prevention of accidental drowning Fencing of private swimming pools to prevent unsupervised entry Swimming pool alarm systems as additional measures to fencing Baths with nonslip surfaces and handrails Regularly checked life jackets/preservers

Modified from [4].

Table 5. – Relevant human factors in the prevention of accidental drowning Continuous surveillance of children and subjects with known risk factors Children should be taught to swim as early as possible Lifeguard services should be present CPR training for all involved Alcohol consumption and abuse should be discouraged/forbidden Use of life jackets in aquatic sports

CPR: cardiopulmonary resuscitation. Modified from [4]. 130

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respiratory but also deleterious central nervous system symptoms, immediate and aggressive clinical management of drowning victims is crucial. In addition to the optimal management of patients, it is extremely important to implement strict water safety practices, which include adequate surveillance and measures such as fences surrounding swimming pools.

Summary Drowning is one of the major causes of accidental paediatric death, and is also a relatively common accident in adulthood. Drowning can be defined as a loss of respiratory function due to submersion or immersion, with the main pathophysiological characteristic being hypoxia. Since prolonged hypoxia leads not only to respiratory but also to irreversible central nervous system symptoms, immediate and aggressive clinical management of drowning casualties is pivotal for optimal survival rates. In the present chapter, definitions, epidemiological and pathophysiological aspects, and management of drowning accidents are discussed. Keywords: Asphyxia, aspiration of water, drowning, hypoxaemia, immersion injuries, submersion-related injuries.

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Pulmonary embolism and the consequences for the right heart F. Reichenberger*, C. Nachtmann#, F. Grimminger* *University of Giessen Lung Centre, and Germany.

#

Dept of Radiology, University Hospital Giessen, Giessen,

Correspondence: F. Reichenberger, University of Giessen Lung Centre, University Hospital Giessen, Klinikstrasse 36, 35392 Giessen, Germany. Fax: 49 6419942599; E-mail: Frank.Reichenberger@ innere.med.uni-giessen.de

Pulmonary embolism (PE) and venous thromboembolism (VTE) are a major issue in clinical medicine and research. Since 1994, y2,000 articles about pulmonary embolism have been published. PE is a frequent cause of morbidity, and often considered as a differential diagnosis in everyday clinical practice. However, there are still significant uncertainties in the diagnostic approach to and therapeutic management of patients with acute PE. Therefore, national and international societies for thoracic medicine, cardiology and radiology have published guidelines and review papers, including diagnostic and therapeutic algorithms, since the early 1990s, which provide the basis of the present article [1–4].

Epidemiology and risk factors Acute PE is a frequent, underdiagnosed and potentially life-threatening disease. The clinical spectrum ranges from an acute emergency to a chronic developing process. The incidence of PE is currently believed to be 50–200 cases per 100,000 population [5]. As much as 1% of hospital admissions are supposed to have PE. Considering post mortem findings, there has been an unchanged high prevalence of PE over the last 40 yrs, and only a third of patients with PE on autopsy have been previously diagnosed [6, 7]. Although some statistics mention a death rate due to PE of up to 17–30%, most within the first 2 h after onset of symptoms [8], other studies report a mortality rate of 1–2.5% [9, 10]. The Management Strategy and Prognosis of Pulmonary Embolism Trial (MAPPET) registry showed that mortality is dependent upon severity and haemodynamic stability at the time of diagnosis [11]. Nevertheless, the large International Cooperative Pulmonary Embolism Registry (ICOPER) revealed a PE-related cumulative mortality over 3 months of as high as 45% [12]. This mortality can be significantly reduced by rapid initiation of anticoagulation therapy, which underlines the importance of early diagnosis and adequate management [3, 12]. In 50–70% of cases, PE arises from a deep venous thrombosis (DVT). The more proximal the location of the DVT the higher the incidence of PE [13]. Both PE and DVT are regarded as different manifestations of the same entity of VTE [1]. In up to 70% of PE cases, smaller thromboembolic events precede a more severe PE [14]. Other forms of pulmonary embolisation due to tumour cells, air, fat or other small foreign particles are much less common [15]. Eur Respir Mon, 2006, 36, 136–164. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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To date, a variety of risk factors are known for VTE, as listed in table 1. The most important are immobilisation, thrombophilic predisposition, malignancy and postoperative state. Cigarette smoking is currently not regarded as a single risk factor for PE. However, it should be carefully assessed in conjunction with the overall risk profile [1–3]. The rate of VTE during hospital stay with immobilisation, especially after surgery, but also during acute medical illness, has been significantly reduced by the introduction of prophylactic anticoagulation therapy with heparins, heparinoids and oral thrombin inhibitors [16–20]. Further improvement can be achieved by the use of a computer-based alert program for initiation of VTE prophylaxis [21]. Association of VTE with long-distance journeys and the increased risk of VTE during therapy with oestrogens have raised public awareness of the medical problem. The overall risk seems to be increased 2–4-fold [1, 22, 23].

Table 1. – Risk factors for pulmonary embolism Major (relative risk 5–20) Major abdominal and pelvic surgery# Hip/knee surgery, lower limb fracture# Post-operative intensive care# Late pregnancy/following delivery Prolonged immobilisation/hospitalisation History of venous thromboembolism Advanced malignancy (abdominal, pelvic) Varicose veins Minor (relative risk 2–4) Oestrogen therapy Obesity Long-distance travel Indwelling central vein catheter Superficial thrombosis Chronic medical conditions Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Long-term renal dialysis Congestive cardiac failure Eisenmenger’s syndrome Neurological disability Chronic obstructive pulmonary disease Systemic hypertension Occult malignancy Thrombophilia Antithrombin III deficiency Protein C deficiency Protein S deficiency Prothrombin G20210A mutation Factor V Leiden Anticardiolipin antibody syndrome Lupus anticoagulant Hyperhomocysteinaemia Excessive plasminogen activator inhibitor Disorders of plasminogen Factor XII deficiency Additional factors Age w40 yrs Family history of venous thromboembolism #

: without appropriate prophylaxis. Data taken from [1–3]. 137

F. REICHENBERGER ET AL.

Thrombophilic factors are found in 25–50% of patients [24]. In the main, an additional component is required to explain acute thromboembolism, e.g. immobilisation or ingestion of oestrogens [25]. Screening for thrombophilia is not required in all patients, but should be performed in all patients agedv50 yrs and in those with a family history of thromboembolism [1, 26–28]. Tests for thrombophilia should be performed after the acute event during a warfarin-free period of i8 weeks. The presence of thrombophilic risk factors might influence the duration of anticoagulation therapy [29]. Idiopathic or recurrent thromboembolic events could indicate an underlying malignancy. In 7–12% of patients with idiopathic PE, a malignant process is found within 12 months [1, 30]. Thromboembolic events have been described especially in cancer of the breast, colon and lung, but also in prostate and pancreatic cancer [31, 32]. Therefore, patients with idiopathic thromboembolism should be assessed for underlying malignant disease. The search should include at least careful clinical examination, chest radiography and laboratory testing [1, 33, 34].

Signs and symptoms Acute PE cases can present over a broad clinical spectrum, ranging from a gradually developing condition to a dramatic acute event. There is only a weak association between clinical severity and grade and localisation of vascular obstruction, varying between small embolisation in the peripheral pulmonary vasculature to massive obstruction of the central pulmonary vessels [35]. Therefore, diagnosis of PE requires a high grade of clinical suspicion, especially in preexisting cardiopulmonary disease. The typical signs of PE are sudden-onset pleuritic chest pain, dyspnoea, tachypnoea (w20 breaths?min-1) and cough, with or without haemoptysis. However, symptoms are highly variable in PE with low specificity [36–38]. Additional signs of DVT or the presence of thromboembolic risk factors increases the clinical probability of PE. In order to improve clinical assessment for PE, several diagnostic scores have been developed. Among them, the scores of Wells et al. [37] and Miniati et al. [38] are prospectively validated, easy to apply and currently used in clinical practice (tables 2 and 3). In ventilated patients in an intensive care unit setting, haemodymamic instability, deterioration of gas exchange and low central venous oxygen saturation might indicate pulmonary vascular events [36, 39].

Table 2. – Clinical assessment score (Wells) Wells score Signs of DVT Other diagnoses unlikely fc w100 beats?min-1 Immobilisation/surgery in previous 4 weeks Previous DVT/PE Haemoptysis Malignancy Probability of PE High Medium Low

3.0 3.0 1.5 1.5 1.5 1.0 1.0 w6.0 2–6 v2.0

DVT: deep venous thrombosis; fc: cardiac frequency; PE: pulmonary embolism. Data from [37]. 138


Table 3. – Clinical assessment score (Miniati) Signs/symptoms

Clinical ECG/radiology

Sudden onset of dyspnoea Chest pain Fainting RV overload on ECG Hilar amputation Regional oligaemia Amputation of hilar artery

Probability of PE High (90%)

Intermediate (50%)

Low (10%)

Any one

Any one not otherwise explained

None or explained by alternative diagnosis

Any two

None

RV: right ventricular. Data taken from [38]. Table 4. – Assessment of severity of acute pulmonary embolism Nonmassive Symptoms

Dyspnoea, chest pain

Tn I/BNP ECG

Normal Normal RV, normal Ppa

Therapy

Anticoagulation

Degree of vascular obstruction % Mortality %

Submassive Dyspnoea, chest pain, dizziness, hypotension Increased RV dysfunction, Ppa slightly elevated Anticoagulation, thrombolysis?

Massive Shock, resuscitation

v20

w30

Increased RV dysfunction and decompensation, increased Ppa Thrombolysis, embolectomy (?), anticoagulation w50–75

v4

5–10

30

Tn: troponin; BNP: brain natriuretic peptide; RV: right ventricle; Ppa: pulmonary artery pressure. Adapted from [3, 36, 40].

Clinical classification includes assessment of severity of PEs and their haemodynamic consequences, which directs further diagnostic procedures and therapy (table 4) [36, 40]. Although considerable progress has been made in the diagnosis of PE since the early 1990s, most of the currently published diagnostic algorithms are guided by clinical probability [1–3].

Diagnostic procedures ECG Signs of acute PE are nonspecific. The SIQIII (McGinn–White) pattern and sinus tachycardia are present in 40% of patients with PE. T-wave inversions and Qr pattern in the anterior precordial leads might indicate right ventricular (RV) enlargement. Right bundle branch block was present in 16%, and atrial fibrillation in 14%. Although ECG is of low sensitivity, it helps to exclude other causes of the acute symptoms, and might improve pre-test probability prior to other procedures [7, 12, 36, 41].

Laboratory tests D-Dimer.

The use of d-dimer in the diagnosis of acute PE is the subject of ongoing debate. Increased d-dimer levels are found in nearly all patients with PE and VTE, but also in several other acute and chronic medical conditions [1–3]. Currently, 139


d-dimer levels are used in the exclusion of PE in nonhospitalised patients with a negative predictive value of 85–97% [42]. It should not be used in hospitalised patients. False negative values might occur on subsequent PE due to small primary thrombi [43]. A higher rate of PE exclusion can be obtained by use of specific ddimer tests with regard to clinical probability, which might subsequently avoid additional diagnostic procedures [44]. Ongoing studies will clarify the value of the currently available d-dimer test with respect to the clinical circumstances [1]. In patients with positive d-dimer test results, a d-dimer/fibrinogen ratio of w16103 might further indicate an acute thromboembolic process [45].

Blood gas analysis. Arterial blood gas levels are of limited value in patients with suspected PE. A recent study showed a slightly increased percentage of hypoxaemia in patient with PE; however, this difference reached significance only in combination with the d-dimer test, compared to patients without PE [35]. Also, a decreased alveolar–arterial oxygen tension difference provides no further diagnostic accuracy [46]. The presence of metabolic acidosis might indicate an adverse outcome [39].

Cardiac biomarkers. Cardiac biomarkers have been introduced in the assessment of severity of acute PE. Currently, troponins and natriuretic peptides have been suggested for evaluation for risk stratification. Troponins are a sensitive marker of myocardial damage. In acute PE, RV pressure is increased due to elevated pulmonary vascular resistance, resulting in RV overload. This leads to RV microinfarctions with disruption of myofibrils and subsequent release of troponins. An increase in troponin levels is found in 11–50% of patients with acute PE, and levels correlate with the degree of RV dysfunction. However, troponin results might only become positive 6–12 h after the acute event, and the increases are minor and of shorter duration than in myocardial ischaemia. A negative troponin test indicates a favourable outcome after PE, with a negative predictive value of 90–99% with regard to complications and mortality [47, 48]. The exact cut-off level depends upon the manufacturer of the test kit used [49]. Natriuretic peptides originate from cardiac myocytes, and are released by mechanical stretching. In acute PE, RV overload results in RV dysfunction and dilatation, with subsequent stimulation of natriuretic peptides [50]. Brain natriuretic peptide (BNP) is derived from the ventricular musculature. It is secreted as pro-BNP and then activated by metabolism to the biologically active BNP and the remaining N-terminal-pro-BNP (NTproBNP). Both metabolites can be measured by immunoassay and are used in the assessment and follow-up of cardiac failure [51, 52]. However, increases in serum BNP levels take several hours, since pro-BNP is not stored in the myocyte but rather myocardial stretching induces de novo synthesis [53]. When measured within 6 h after onset of symptoms, an initially increased BNP level might point to a pre-existing cardiac condition with impaired left or right heart function. For assessment of severity of PE, a second test 6–12 h after onset of symptoms might be considered [49]. Both BNP and NTproBNP show an excellent negative predictive value of nearly 100% with respect to mortality and complication in acute PE. The currently published cut-off level for BNP is 50 pg?mL-1.

Diagnostic imaging Chest radiography. Albeit nonspecific, only a third of patients with an acute PE show normal chest radiography results. Signs suggestive of PE on chest radiography include peripheral parenchymal changes (e.g. infiltrates due to lung infarction) and vascular 140


changes, such as focal oligaemia (Westermark sign), hilar amputation and distension of the proximal pulmonary artery. Furthermore, an elevated hemidiaphragm and pleural effusion might be present. Chest radiography mainly serves as an adjunctive method, excluding other diseases which might imitate PE and providing information about probable underlying cardiopulmonary disease [1–3, 35]. However, it is also used in clinical assessment scores [38].

Ventilation/perfusion scan. The ventilation/perfusion (V’/Q’) scan has long been the mainstay of diagnosis of PE. A normal V’/Q’ scan virtually excludes a diagnosis of PE, even in the peripheral pulmonary vasculature, and a high-probability scan generally confirms the diagnosis of PE in cases with a high clinical probability [54], even in patients with co-existing chronic obstructive pulmonary disease [55]. Several studies have confirmed that the majority of patients with proven PE do not exhibit a high-probability V’/Q’ scan, and many patients without PE show an abnormal V’/Q’ scan, especially in the presence of underlying cardiopulmonary disorders [1, 54, 56]. Also, the integrated interpretation of V’/Q’ scans (Gestalt), in combination with chest radiography and clinical information, does not, in the main, affect diagnostic accuracy and overall outcome [57]. However, Gestalt criteria might help to differentiate between newly occurring and persistent perfusions deficits (fig. 1). Currently, the V’/Q’ scan is used in conjunction with clinical probability. In 25% of cases, a high probability V’/Q’ test and a high clinical probability confirm the diagnosis. In 25% of cases, with a normal V’/Q’ scan and a low clinical probability, PE can be regarded as excluded and anticoagulation therapy can be safely withheld. However, in y50% of patients, additional tests are required [1–3].

Computed tomographic pulmonary angiography. Computed tomographic (CT) pulmonary angiography (CTPA), as a noninvasive test, has had a major impact on the diagnosis of PE. It is currently the most widely used imaging tool in the diagnosis of acute PE in the outpatient setting, and also in hospitalised patients. Its accuracy has been constantly improving with the introduction of more advanced CT technology [4]. After early enthusiasm, single-detector spiral CTPA, with a sensitivity of 61% and specificity of 84%, has not been able to exclude PE sufficiently [58, 59]. Multi-slice CT scanners are able to detect PE down to the subsegmental level, equivalent to conventional pulmonary angiography. The current generation of four-detector CT scanners identify PE with a specificity of 91% and a sensitivity of 95%. Further improvements will be obtained with the introduction of 16- and 64-detector multi-slice or electron-beam CT [60]. Compared to conventional pulmonary angiography, multi-slice CTPA shows much a)

b)

Fig. 1. – Perfusion scintigraphy of: a) acute pulmonary embolism (PE) with wedge-shaped perfusion deficits; and b) chronic PE with round perfusion deficits.

141


Table 5. – Criteria for the spiral computed tomographic pulmonary angiographic diagnosis of pulmonary embolism Acute

Subacute

Chronic

Filling defect

Central, eccentric, intraluminal Wall adherent (acute angle), Wall adherent (obtuse angle), convex concave, intraluminal webs, signs of thrombus recanalisation, calcification Intrapulmonary Dilated or normal Dilated or normal Small, distal tapering, variable size vessels of segmental vessels, complete retraction of segmental vessels (cut-off), irregular wall thickening Parenchyma Infiltration (haemorrhage), Wedge-shaped pleurally Translobular lines, plate-like round or wedge-shaped based consolidation atelectasis, mosaic perfusion, pleurally based consolidation bronchial dilatation in abnormal areas Pleura Pleural effusion Pleural effusion Pleural effusion Pulmonary Right heart enlargement, Right heart enlargement, Right heart enlargement with hypertension normal wall thickness interventricular septal shift, thickening of the wall (w5 mm), (v5 mm) dilation of central PA changed axis of interventricular septum, dilated central PA, dilated and tortuous bronchial arteries, pericardial effusion, ascites

PA: pulmonary artery. Modified from [61].

better interobserver reproducibility and is much less invasive. The morphological appearance of thrombotic lesions might differentiate between acute and chronic processes (table 5; fig. 2a–c). A further advantage of CTPA is the additional assessment of intrathoracic organs. It can visualise pulmonary parenchymal changes associated with PE, e.g. pulmonary infarction and alterations of the RV contributing to risk stratification [61]. CTPA sufficiently excludes PE, even in the presence of coexisting cardiopulmonary disease or malignant disease with a high risk of thromboembolic events. Under these circumstances, CTPA might reveal the alternative diagnosis [62, 63]. The disadvantage of CTPA is the need for contrast material and exposure to radiation. Reliable high-quality results can only be achieved by precise attention to technique and investigative protocol and the use of advanced CT technology, which might not be universally available. Withholding of anticoagulation therapy is safe in low and intermediate clinical probability cases with no signs of PE on CTPA. The remaining risk of recurrent thromboembolism within 3 months is y0.4% and comparable to conventional pulmonary angiography [1, 64].

Magnetic resonance pulmonary angiography. The advantage of radiation-free imaging, without use of nephrotoxic contrast agents, is especially attractive in pregnancy, known iodinated contrast agent allergy or renal failure, present in approximately a quarter of PE patients [10]. The use of magnetic resonance imaging in the assessment of acute PE has been complicated by long acquisition periods for thoracic examinations, particularly a problem in dyspnoeic patients [1]. This might be overcome by introduction of advanced technology and contrast agents. Currently published studies report a sensitivity of 70–100% and specificity of 95–98% for magnetic resonance pulmonary angiography (MRPA) [65]. The pulmonary vasculature can be visualised down to subsegmental level and even beyond. MRPA also permits precise assessment of RV function and intravascular flow profiles, and might, therefore, 142


a)

d) d)

b)

c)

e)

Fig. 2. – Computed tomographic (CT) pulmonary angiography of acute pulmonary embolism (PE). Four-detector row CT scan of: a) segmental acute PE without right-heart compromise; b) acute PE with mildly dilated rightsided heart chambers, indicating acute cor pulmonale; and c) multi-slice image of a central PE, or so-called saddle thrombus. d, e) Sixteen-detector scan with three-dimensional reconstruction visualising the extent of the thromboembolic process. d) and e) reproduced with permission from [4].

contribute to risk stratification. The major disadvantages are the limited availability of the technology and procedure-related difficulties, which might be overcome with technical progress [1, 66].

Conventional pulmonary angiography. Pulmonary angiography was considered the gold standard for diagnosis of PE until the introduction of CTPA with its advanced technology [1–4]. Both pulmonary angiography and CTPA can visualise PE down to subsegmental level; however, pulmonary angiography exhibits a higher interobserver variability. Pulmonary angiography is an invasive test, requiring contrast agent, and has a procedure-related mortality of 0.5% [67]. Therefore, pulmonary angiography, although rarely used in the routine clinical setting, is the method of choice for all patients for whom noninvasive tests are either inconclusive or not available. Pulmonary angiography is also employed under specific clinical circumstances, such as a combined approach with therapeutic interventions (e.g. catheter fragmentation) [68, 69]. However, pulmonary angiography still has a role to play in assessment and therapeutic decision-making in long-term complications following PE, which are discussed below [70].

Venous examination of lower limbs. Approximately 50–70% of PEs originate from the lower leg veins. Therefore, assessment of DVT has been introduced into diagnostic 143


algorithms for PE [1–3]. Detection of DVT indicates additional thrombotic material for potential further embolisations, and evaluation of the lower limb venous system also contributes to the risk assessment for recurrent PE. In 25–60% of patients with proven PE, DVT is found using ultrasonography or venography [71, 72]. This might be due either to false negative results, especially in thrombosis of the calf veins, or previous embolisation of the entire thrombus [73]. Using ultrasonography, reliable negative results with therapeutic implications can only be achieved with serial measurements [37, 38, 74]. However, both tests have a high specificity of w90%. False positive results could be obtained by the existence of residual changes due to a previous thrombosis. The diagnosis of PE should only be established in cases with a high clinical probability and definite diagnosis of DVT [1, 3, 37]. The use of venography in combination with CTPA or MRPA has been proposed in order to assess the risk of recurrent PE. CT- and MR-venographies show a sensitivity and specificity of w90%, and are, therefore, comparable to venous sonography [75, 76]. However, the disadvantages include a longer examination time and greater irradiation of the gonadal area during CT.

Transthoracic sonography. Although already described in the mid-1970s, transthoracic ultrasonography is not widely used in the diagnosis of PE [77]. Detection of hypoechogenic wedge-shaped pleurally based lesions with effusion and an altered perfusion pattern in atelectatic lung areas have been described in acute PE, but these changes are easy to miss. Furthermore, the differential diagnosis includes atelectasis and pleural effusion of other origin. Bedside availability is the advantage of the method; however, appropriate use requires an experienced examiner. A recent multicentric study found a sensitivity and specificity of 74% and 97%, respectively [78]. To date, it is regarded an adjunctive method (fig. 3).

Transthoracic echocardiography. Since the mid-1980s, echocardiography has emerged as a frequently used tool in the initial assessment of acute PE [12, 79]. As a noninvasive test

Fig. 3. – Transthoracic sonography of a peripheral pulmonary embolism proven by computed tomography. Sonography reveals a triangular hypoechogenic pleurally based parenchymal lesion of 24626 mm. Reproduced from [78].

144


available at the bedside, it can visualise cardiac and haemodynamic consequences of the acute event, detect thromboembolic material in the right-sided heart chambers and central pulmonary artery, and assess coexisting cardiac disorders. In massive PE with cardiogenic shock, it might be the only diagnostic technique immediately available [36, 80]. Although echocardiographic results are mostly normal in acute PE, as there are no signs of acute RV dysfunction in nonmassive PE, it exhibits a high sensitivity and specificity in submassive and massive PE. Relevant RV dilatation is expected whenw30% of the pulmonary vascular bed is obstructed [26, 81]. The presence of RV dysfunction is a bad prognostic parameter in acute PE, and related to an early mortality of 12–23%, whereas patients with an acute PE and normal echocardiographic results show a mortality of 0–1%, and, therefore, a favourable prognosis [12, 39, 82]. Several echocardiographic signs have been described in the assessment of acute RV dysfunction in acute PE [80, 83]. 1) RV dilatation is best assessed in apical four-chamber view in comparison with the size of the left ventricle (LV). In RV dilatation, the RV diastolic area isw60% of the LV diastolic area [39, 84]. 2) RV hypokinesia of the free RV or RV dyskinesia with hypercontraction pattern of the apical part of the RV wall (McConnell sign) shows a high specificity and a negative predictive value of 94–96% in acute PE [39, 85]. 3) RV wall thickness is important for the assessment of the acuity of the process. Free RV wall thickness of w5 mm indicates a pre-existing cardiopulmonary condition with RV overload and pulmonary hypertension [86]. 4) Paradoxical septal motion is characterised by bulging of the interventricular septum towards the LV during systole and early diastole due to pressure overload of the RV leading to LV diastolic dysfunction [11, 83]. An increase in systolic pulmonary artery pressure (Ppa,sys) can be measured via tricuspid regurgitation. In acute PE, Ppa,sys can reach y40–50 mmHg; a much higher Ppa,sys indicates pre-existing pulmonary vascular disease. Furthermore, a change in the flow profile in the RV outflow tract is found in PE. Typically, the acceleration time is shortened and the ratio of acceleration time to ejection time decreased [35, 82, 87]. Intracardiac thromboemboli can be found in the right-sided heart chambers (clot in transit) or in the central pulmonary artery; however, these changes are better visualised using transoesophageal echocardiography (TOE) [88]. A patent foramen ovale (PFO) is a bad prognostic sign due to risk of paradoxical emboli in the systemic circulation. A PFO with significant right-to-left shunt due to increased Ppa,sys is accompanied by significant hypoxia [86, 89]. At the time of echocardiography, coexisting cardiac diseases can be assessed and might provide a differential diagnosis. Impaired LV function, pericardial or valvular heart disease, or pre-existing pulmonary hypertension, particularly, contributes to risk assessment in acute PE (fig. 4) [35, 80].

Transoesophageal echocardiography. In addition to transthoracic echocardiography, TOE can visualise centrally or proximally situated thromboemboli, found in 50–90% of patients with acute PE and RV dysfunction. Therefore, in submassive/massive PE, TOE has a good sensitivity of 80–97% and a specificity of 84–100%, comparable to CTPA. However, the sensitivity decreases considerably when thromboemboli are situated further than the proximal pulmonary arteries [90, 91]. TOE has been suggested for use in unconscious critically ill patients presenting with unexplained sudden cardiac arrest [92]. However, use of TOE might be difficult in conscious dyspnoeic patients. 145


a)

c)

b)

d)

Fig. 4. – Echocardiography of right ventricle and pulmonary vasculature. a) Normal echocardiogram with normal right-sided heart chambers in a healthy subject; and b) corresponding normal flow pattern in right ventricular outflow tract (RVOT). c) Severely dilated right-sided heart chambers with displacement of the intraventricular septum and compressed left-sided heart chambers in a patient; and d) corresponding severely impaired RVOT flow pattern, with shortened acceleration time and typical W-shaped flow curve.

Acute cor pulmonale The development of acute cor pulmonale is of prognostic importance in acute PE. Right heart failure, including haemodynamic instability, cardiogenic shock and cardiopulmonary resuscitation due to PE, are associated with a mortality rate of w50% [11]. In most patients with PE, there are no clinical signs of RV dysfunction; however, an increase in troponin level is found in up to 50% after PE, indicating myocardial involvement [47, 48]. An acute reduction in pulmonary perfusion induces an acute increase in the afterload of the RV [35]. In acute PE, obstruction of the pulmonary vascular bed and subsequent release of pulmonary vasoconstrictive mediators (serotonin and thromboxane) lead to increasing pulmonary vascular resistance [93]; however, there is a hyperbolic relationship between the degree of vascular obstruction and the increase in pulmonary vascular resistance [94]. The thin-walled RV as low-pressure pump cannot immediately adapt to a suddenly increased afterload. Therefore acute cor pulmonale is characterised by RV dilatation and RV failure rather than a massive increase in Ppa [94]. Mean Ppa rises to a 146


maximum of 30–40 mmHg in patients with acute PE without pre-existing cardiopulmonary disease [95]. RV dilatation leads to compression of the right coronary artery, leading to myocardial ischaemia and myocardial necrosis, with an increase in troponin levels [46, 96]. Arterial hypoxaemia due to pulmonary V’/Q’ mismatch or right-to-left shunting may worsen myocardial ischaemia. Furthermore, RV dilatation leads to displacement of the intraventricular septum, with reduced diastolic filling and subsequent impairment of LV function. These processes may result in reduced cardiac output and cardiogenic shock [97]. The haemodynamic consequences of acute PE might not be present initially, but develop within the first 12–48 h; therefore, risk stratification is important in the management of acute PE [1, 3, 35].

Risk assessment for acute pulmonary embolism Acute PE cases can present ranging from an asymptomatic to a life-threatening disease requiring different therapeutic strategies. The outcome of acute PE is closely related to the initial clinical assessment and degree of RV dysfunction [1, 10, 12, 98]. Thus the consequences of acute PE are less dependent on the size of the thrombus than on clinical presentation, additional medical conditions and pre-existing cardiopulmonary disease (fig. 5) [35]. Most patients with acute PE feature a nonmassive event without signs of RV dysfunction and show a favourable outcome on treatment with anticoagulants [12]. Only a minority of patients present with massive PE including right heart failure, haemodynamic instability with cardiogenic shock and the need for cardiopulmonary resuscitation. These patients require immediate therapeutic intervention including thrombolysis and embolectomy, as outlined below. Despite emergency treatment, massive PE is associated with a mortality rate of 30% [1–3]. Risk assessment is required to identify patients with a submassive PE. These patients might deteriorate within the next 12–48 h despite standard treatment, or are at risk of a worse outcome prognosis or early mortality. Stratification includes assessment of

Mortality %

24 22 20 18 16 14 12 10 8 6 4 2 0

0

10

20

30 40 50 60 70 Time from diagnosis days

80

90

Fig. 5. – Association between severity and outcome of pulmonary embolism (–––––: right ventricular hypokinesis; ??????: no right ventricular hypokinesis). Cumulative mortality is associated with right ventricular dysfunction, as shown in the International Cooperative Pulmonary Embolism Registry. Reproduced with permission from [12].

147


Table 6. – Geneva Prognostic Index for adverse outcome# after acute pulmonary embolism (PE) Score Malignancy Systemic hypotension; systolic BP v100 mmHg Heart failure Hypoxaemia; Pa,O2 v8 kPa Previous DVT Current DVT on ultrasonography Risk of adverse outcome High Low

2 2 1 1 1 1 i3} ƒ2}

BP: blood pressure; Pa,O2: arterial oxygen tension; DVT: deep venous thrombosis. # : recurrent PE, major bleeding and death; }: score sum. Data taken from [99].

clinical severity and RV performance, as one of the main prognostic parameters in acute PE. For clinical risk assessment, the Geneva Prognostic Index is an easy-to-use score (table 6) [99]. Clinical signs of major PE with RV dysfunction include syncope, hypotension, cyanosis, severe dyspnoea, tachycardia, congested jugular veins, loud and split second heart sound, and pansystolic murmur. Signs of RV dysfunction and dilatation can be detected on ECG and CTPA [61, 97]. Echocardiography can visualise RV performance and assess the pre-existing cardiopulmonary situation, which might contribute to the haemodynamic instability of the acute event. Cardiac biomarkers, such as troponins and BNPs, have been proposed for the assessment of RV involvement as regards myocardial damage and RV dilatation in acute PE [47, 82, 100]. The presence of RV dysfunction on, for example, echocardiography and/or an increase in levels of cardiac biomarkers identifies a group of patients, at risk of early complications and a worse prognosis, who might benefit from more aggressive therapy, e.g. thrombolysis [101]. Although proposed in current reviews, the concept of aggressive treatment with thrombolysis in patients with submassive PE has not been shown to improve the overall survival of acute PE cases in previous registries, and in a recent randomised controlled trial (MAPPET-3) [7, 11, 12, 102].

Acute therapy Initial anticoagulation therapy Early anticoagulation treatment is the main therapeutic goal in acute PE. It should be started as soon as possible, even in clinical probability situations during the diagnostic work-up, assuming no contraindications are present. Initially, unfractionated heparin (UFH) should be used, with a bolus of 80 U?kg body weight-1 and a continuous infusion of y18 U?kg body weight-1?h-1, to increase the activated partial thromboplastin time to 60–80 s (table 7) [103]. The anticoagulative effects subside on discontinuation of the infusion if other treatment options are indicated, such as embolectomy or thrombolysis [40]. A longer duration of UFH requires frequent control of coagulation and bears the risk of heparin-induced thrombocytopenia (HIT) and osteoporosis. Therefore, in stable patients, subcutaneous use of low-molecular-weight heparin (LMWH) might be an alternative option. It is easier to handle, and carries a lower risk of bleeding and HIT [9, 104]. In a recent meta-analysis, LMWH was better than UFH as regards treatmentrelated mortality and recurrent thromboembolic events [105]. On therapy with LMWH, 148


Table 7. – Weight-based nomogram for anticoagulant therapy Infusion rate increase U?kg-1?h-1

aPTT s

Immediate

Initial v35 (v1.2MN) 35–45 (1.2–1.5MN) 46–70 (1.5–2.3MN) 71–90 (2.3–3.0MN) w90 (w3.0MN)

80 U?kg-1 bolus 80 U?kg-1 bolus 40 U?kg-1 bolus No change No change Stop infusion 1 h

18 4 2 0 -2 -3

aPTT: activated partial thromboplastin time; MN: mean normal. Adapted from [103].

it is recommendable to control thrombocyte count within the first weeks. Furthermore, anti-Xa activity should be measured in patients with impaired renal function, elevated body weight and receiving therapy for w14 days. Several LMWH compounds are licensed for PE therapy, depending on country. Further developments will include the anti-Xa agent fondaparinux, a synthetic pentasaccharide recently approved for DVT prophylaxis in orthopaedic surgery. This compound has been shown to be at least as safe and effective as UFH in the therapy of acute haemodynamically stable PE in a once daily subcutaneous application of 7.5 mg [106]. Newer oral thrombin inhibitors, such as ximelgatran and argatroban, have not yet been evaluated for PE. To date, these compounds have been evaluated for the postoperative prophylaxis of VTE. The advantages of oral formulation and the absence of a requirement for coagulation control are so far countered by the risk of hepatic sideeffects [18, 107].

Thrombolysis Although only limited data are available, thombolysis is an established therapy in massive PE. Compared to heparin therapy, thrombolysis produces a significant haemodynamic improvement, with a 40% reduction in Ppa and 80% increase in cardiac output within the first days, and more rapid resolution of pulmonary vascular obstructions [108, 109]. However, the haemodynamic effects of heparin and thrombolysis equalise after 7 days’ therapy [110]. In haemodynamic instability or patients with circulatory collapse, thrombolysis should be initiated as soon as possible, even during cardiopulmonary resuscitation [111, 112]. The evidence for this is based mainly on uncontrolled case series. In one prematurely terminated randomised controlled trial of thombolysis versus heparin, four patients receiving thrombolysis survived, whereas four patients receiving heparin died [113–115]. In addition, patients with an RV thrombus show a considerably decreased mortality of 30% when receiving thrombolytic therapy [116]. Thombolysis in haemodynamically stable patients with signs of RV dysfunction (submassive PE) is a subject of debate. Several multicentric registries on PE reported a frequency of 22–42% of patients with submassive PE having undergone thrombolysis. However, the risk of intracranial haemorrhage is doubled compared with heparin [1]. In the ICOPER registry, an intracranial haemorrhage rate of 3% has been observed on thrombolytic therapy [12]. Two randomised controlled trials assessed recombinant tissue plasminogen activator (rt-PA) thrombolysis in haemodynamically stable submassive PE. In the multicentric USA study, there were less recurrent thromboembolic and fatal events within 14 days in the rt-PA group compared to the heparin group [117]. The recently performed MAPPET3, comparing rt-PA and heparin versus heparin alone in patients with submassive PE and 149


RV dysfunction found a significant reduction in emergency interventions (e.g. thrombolysis, intubation, resuscitation and embolectomy) in the thrombolysis group (10%) compared to the heparin group (25%). However, a survival benefit could not be demonstrated [102]. Currently, the use of thrombolysis in submassive PE should be based on the individual benefits and risk profile for side-effects. To date, data on the long-term benefit of thrombolytic therapy are sparse. Although a small study indicated a benefit of thrombolytic therapy in the prevention of pulmonary hypertension, another study did not show any benefit regarding survival or persistent pulmonary hypertension [118, 119]. Several schemes for thombolysis have been developed. Besides streptokinase and urokinase, the use of rt-PA is recommended in most guidelines [1–3]. In Germany, recommendations include an initial bolus of 10 mg rt-PA followed by a 2-hourly infusion of 90 mg in combination. In case of emergency, an intravenous bolus of 0.6 mg?kg body weight-1 over 2 min can be administered. The British Thoracic Society recommend, in stable patients with massive PE, intravenous infusion of 100 mg rt-PA over 90 min. Immediate intravenous injection of 50 mg rt-PA is suggested in cardiac arrest in hospital and clinically highly suspected massive PE [1]. The Food and Drug Administration-approved scheme consists of infusion of 100 mg rt-PA over 2 h [120]. UFH should be continued after a 3-h break, or when the activated partial thromboplastin time is less than twice the mean normal. Contraindications for thrombolysis should be adapted to the clinical situation. They are certainly valid for submassive PE. Absolute contraindications are active intraabdominal or cerebral bleeding. Relative contraindication include previous surgery, organ biopsy, spinal anaesthesia, severe trauma or childbirth within the previous 10– 14 days, neurosurgical intervention within the previous 4 weeks, stroke within the previous 2 months, uncontrolled systemic hypertension, current pregnancy, infective endocarditis, aortic aneurysmm, thrombocytopenia and disturbed coagulation [1–3].

Pulmonary embolectomy Embolectomy should be considered in patients at high risk of adverse outcome, or with contraindications for, or nonsuccessful, thrombolysis [121, 122]. Interventional radiological techniques include catheter-based clot fragmentation, rheolytic thrombectomy and clot aspiration using a Greenfield catheter. Successful percutaneous mechanical thrombectomy (hydrolysis and Oasis catheter), in conjunction with thrombolysis, has even been described during cardiopulmonary resuscitation [69, 123]. Surgical emergency embolectomy (Trendelenburg procedure) has been known since the 1920s. Until the 1990s, it had rarely been used because of an almost 100% mortality rate. Since the 1990s, surgical embolectomy has been used more frequently because of improved risk stratification and surgical technique. By enabling operation on the beating heart, improvements in surgical instrumentation and avoiding aortic cross-clamping, a survival rate of 89% has been reported, especially in patients with subtotal obstruction of the main pulmonary arteries without significant pre-existing cardiopulmonary disease [121, 122]. The use of either interventional or surgically based embolectomy depends on individual expertise and the continuous availability of a specialised interdisciplinary team.

Inferior vena cava filter The inferior vena cava (IVC) filter should mechanically prevent recurrent thromboembolic events. However, it might also act as focus for new clot formation, 150


with the risk of blockage of the IVC filter [1, 3]. In a randomised trial, IVC filters showed a proven effect over 12 days; however, they increased the recurrent DVT rate over 2 yrs without affecting mortality [124]. The currently used retractable filters carry a lower risk of injury to the vessel wall and can be removed after short-term use [125]. The insertion of an IVC filter should be considered when anticoagulation therapy is absolutely contraindicated or in recurrent thromboembolism despite adequate anticoagulation therapy. In some centres, it is also used in patients undergoing pulmonary thromboendarterectomy [70].

Additional therapy Basic therapy includes supplemental oxygen to preserve adequate oxygenation. Low-dose morphine might be beneficial for the alleviation of dyspnoea, and, additionally, has vasodilatory effects on the pulmonary circulation. Many clinicians empirically use nitrates to improve PE-related chest pain in haemodynamically stable conditions. Diuretics should be used cautiously in order to avoid a rapid decrease in preload. Conversely, infusion of 500 mL free fluid might have small beneficial effects on cardiac function, but the results are controversial, and fluid challenge might even be harmful in severe RV dysfunction [126]. Use of b-blockers, e.g. for frequency control during atrial fibrillation, should be avoided due to their pulmonary vasoconstrictive activity. In haemodynamically compromised patients, use of dopamine and dobutamine leads to improved cardiac function, with minor effects on pulmonary vascular resistance [127]. If inotropic support is required, adrenalin might be more beneficial than noradrenalin, with its pulmonary vasoconstrictive activity [128]. However, use is dependent on the individual clinical situation. In respiratory failure, noninvasive ventilation should be preferred. Mechanical ventilation with positive intrathoracic pressures might have detrimental effects on RV function, by reduction of venous return and increase of cardiac afterload [35, 129]. There is only limited experience with the use of pulmonary vasoactive medication in acute PE. Inhaled nitric oxide has been shown to improve haemodynamic parameters and gas exchange in a small case series [130]. Use of other pulmonary vasoactive compounds has not been reported to date.

Long-term anticoagulation therapy After establishing a definite diagnosis of PE and initiation of parenteral anticoagulation therapy, oral anticoagulation therapy can be started in stable patients with nonmassive PE, using vitamin K antagonists, such as warfarin or phenprocoumon. Heparin therapy should be continued until an international normalised ratio (INR) of 2– 3 is reached for 2–3 days in order to bridge the hypercoagulable state during initiation of vitamin K antagonist therapy. This is due to the shorter half-life of proteins C and S compared to factors II, VII, IX and X [131]. Repeat testing of the INR is necessary to adjust the dose of vitamin K antagonist. Excessively high INRs are managed by temporarily omitting oral anticoagulant and administration of vitamin K1. In cases of bleeding due to high INR, administration of fresh frozen plasma, concentrate of coagulation factors II, VII, IX and X, and also factor VIIa can reverse anticoagulation treatment rapidly [132]. Early bleeding complications might reveal an underlying organ disorder. Rarely, warfarin-induced skin necrosis develops, which has been associated with deficiency of proteins C and S and malignancy [3, 133]. 151


In recurrent PE, oral anticoagulation therapy should be adjusted to an INR of 2.5–3.5. In recurrent venous and arterial thromboembolic events due to antiphospholipid syndrome, additional therapy with aspirin should be considered [134]. The duration of oral anticoagulation therapy is the subject of ongoing debate. It depends upon the origin and circumstances of the acute PE, and also individual risk factors for recurrent thromboembolism or bleeding complications. In uncomplicated PE due to a known cause, e.g. operation or trauma, without significant comorbid conditions, 4–6 weeks of anticoagulation therapy are supposed to be sufficient. For patients with a first idiopathic PE without an underlying thrombophilic risk factor, an anticoagulation treatment period of 3–6 months is proposed; however, this is still the subject of debate [135, 136]. Individual risk of recurrent thromboembolism can be estimated by d-dimer levels after cessation of anticoagulation therapy [137]. In patients with recurrent thromboembolic events and underlying thrombophilia, such as protein S, protein C and antithrombin III deficiency, and also a strong family history of thromboembolic events, indefinite anticoagulation therapy might be necessary. However, the indication for long-term anticoagulation therapy should always be discussed in an individual setting, as indefinite anticoagulation therapy is associated with an increased risk of bleeding, but a reduced mortality has not yet been proven [29, 138]. A lowered warfarin target dose is not associated with reduced bleeding complications but with a higher recurrence rate of VTE [139]. Use of vitamin K antagonists is contraindicated during pregnancy and the breastfeeding period. Under these circumstances, long-term therapy with heparin is indicated, either therapeutic doses of LMWH or subcutaneous calcium heparin [140]. In Germany, LMWH is not officially licensed for therapy during pregnancy. Therapy should be changed to intravenous UFH prior to delivery for better dose adjustment, and stopped or reduced during labour. After delivery, anticoagulation therapy should be continued for i6 weeks. In total, a 3-month anticoagulation treatment period should be completed after the acute PE [141, 142]. Cancer patients develop a three-fold higher risk of recurrent PE despite adequate anticoagulation therapy and a six-fold higher risk of bleeding compared to other patients [143]. Therefore, an individual strategy should be used. In recurrent thromboembolic events despite sufficient anticoagulation therapy, the target INR might be increased to 3.0–3.5 and the insertion of an IVC filter might be discussed. Use of LMWH for longterm anticoagulation therapy is an alternative, but still expensive, option. LMWH seems also to have positive effects on cancer treatment, especially on metastasis formation [144, 145]. There is no recommendation for duration of anticoagulation therapy under these circumstances.

Long-term complication: chronic thromboembolic pulmonary hypertension Long-term complications after PE include persistent perfusion deficit and the development of chronic thromboembolic pulmonary hypertension (CTEPH). Perfusion deficits on repeat V’/Q’ scan have been found in 15–25% of patients after PE, resulting in prolonged anticoagulation therapy [110]. In most cases, the functional impairment due to chronic vascular obstruction is compensated for by the pulmonary vascular flow reserve. However, obstruction of the pulmonary vascular bed might progress due to expansion of the sessile thrombotic lesions, in situ thrombosis on the injured vessel wall, and symptomatic or silent recurrent embolism even on long-term anticoagulation therapy [146, 147]. An increase in pulmonary vascular resistance and pulmonary hypertension is usually present if w40% of the vascular bed is obstructed [35, 70]. 152


The pulmonary vascular changes lead to cardiac compromise with dilatation of right-sided heart chambers, RV hypertrophy and inadequate adaptation of RV function during exercise [147]. RV hypertrophy and reduced RV function also impede adequate LV performance by paradoxical septal motion leading to impaired LV compliance and underfilling of the LV. Advanced stages are characterised by RV failure and low cardiac output with secondary organ failure [148]. CTEPH is a serious complication that leads to severe functional impairment with a high morbidity and mortality if untreated; however, long-term follow-up data after acute PE are sparse [118, 119]. The previously described incidence of 0.1–0.5% seems to represent a great underestimate according to a recent Italian study, in which manifest pulmonary hypertension was found in up to 4% of patients suffering from persistent dyspnoea following PE [149, 150]. CTEPH develops over months and even years following PE, but patients without typical episodes of acute PE can also be affected due to chronic silent embolisations. To date, there is no clinical risk profile for the development of CTEPH, but a higher rate of CTEPH has been described in patients with additional inflammatory bowel disease, after splenectomy or with a ventriculo-atrial shunt. Coagulation studies might reveal positive anticardiolipin antibody results in 10% of patients, and an increased factor VIII concentration [151]. Patients suffer from gradually decreasing exercise capacity and exertional dyspnoea, but may also not return to normal exercise levels after an acute thromboembolic event. Further signs are cyanosis, syncope and peripheral oedema due to right-heart failure [152]. Diagnosis of CTEPH requires a high level of clinical suspicion. Echocardiography is the most valuable screening test for chronic pulmonary hypertension. The typical findings are dilatation of right-sided heart chambers, increased thickness of free RV wall (w5 mm), paradoxical septal motion with impairment of diastolic LV function, and an increase in Ppa,sys mainly beyond 50 mmHg considering central venous pressure. Typically, in chronic pulmonary hypertension, a change in flow profile in the RV outflow tract can be detected. The presence of pericardial effusion might indicate severe RV functional impairment. A sensitive marker for RV function is the global RV performance index according to Tei, which also has prognostic implications in pulmonary hypertension [153]. Further diagnostic work-up concentrates on differential diagnosis from other forms of pulmonary hypertension and assessment of therapeutic options in CTEPH. A major issue is differentiation between proximal thromboembolic obstructions down to segmental level that are amenable for surgical intervention and inoperable disease due to peripheral vascular obstructions requiring medical therapy. The diagnostic methods used for assessment are similar to those used in acute PE. 1) CTPA is a very sensitive means of recognising intravascular obstructions down to the subsegmental level and other signs of pulmonary hypertension presenting as web-shaped narrowing of the pulmonary vessels. The presence of hypoperfused (hypodense) and hyperperfused (hyperdense) areas in conjunction with pulmonary hypertension, so-called mosaic perfusion, is very characteristic of chronic thromboembolism. Magnetic resonance imaging is increasingly being used in assessment of pulmonary vasculature and cardiac function in pulmonary hypertension [154–156]. 2) Perfusion scintigraphy reveals chronic perfusion defects even in the smallest pulmonary vessels. Gestalt criteria may help to differentiate between acute and chronic vascular obstruction and pulmonary scarring [57, 157]. 3) Pulmonary angiography is still regarded as the gold standard for the exact localisation of the vascular obstruction required for assessment and planning of surgical therapy [158]. 4) Although echocardiography is established in the evaluation of RV function and Ppa, right-heart catheterisation is still inevitable for the exact assessment of altered pulmonary circulation and subsequent RV impairment. Some groups use special catheter techniques for differentiating between more central and 153


peripheral vascular obstruction by partitioning of pulmonary vascular resistance [159, 160]. Also angioscopy has been used for assessment of surgical options (figs 1b and 6) [161]. Therapy for CTEPH is based on sufficient anticoagulation therapy with a target INR of 2.5–3.5, oxygen therapy, diuretics, if required, and physical rest. Specific interventions involving the pulmonary circulation include surgical options and pulmonary vasoactive medication [70, 159]. When proximal pulmonary vascular obstructions are present, pulmonary thromboendarterectomy with removal of the obstructing fibrotic thromboembolic material and the surrounding endothelial layer might be an option. This procedure requires medial sternotomy and is carried out under conditions of cardiopulmonary bypass, hypothermia a)

b)

d)

c)

Fig. 6. – Imaging of chronic thromboembolic pulmonary hypertension (CTEPH). Four-detector row computed tomographic scan showing: a) a central chronic pulmonary embolism with bilateral pleural effusion; and b) severe dilatation of right-sided heart chambers with right ventricular hypertrophy, septal displacement and bilateral pleural effusion, indicating severe CTEPH. c) Pulmonary angiogram showing CTEPH with total obstruction and web-shaped narrowing of segmental vessels (arrows); and d) magnetic resonance pulmonary angiogram showing CTEPH with total obstruction of segmental vessels (arrow). Reproduced with permission from [156].

154


and intermittent complete circulatory arrest. Further details are described elsewhere [71, 149, 159, 162]. The reported peri-operative mortality ranges 5–10% in centres with a specialised and dedicated surgical team [162, 163]. In severely compromised patients, the pre-operative situation should be improved by initiation of pulmonary vasoactive therapy [164, 165]. In special situations with proximal obstruction of a single vessel or a high surgical risk, interventional therapy with balloon angioplasty has been reported [166]. In patients with CTEPH due to peripheral vascular obstructions, or in cases in whom surgical therapy is not feasible, alternative treatment is warranted. Until recently, therapy consisted of anticoagulation, oxygen supplementation, diuretics, digoxin and prevention of adverse medical conditions, e.g. infections [71, 159]. The development of pulmonary vasoactive substances, including prostanoids, endothelin antagonists and phosphodiesterase inhibitors, enabled specific pulmonary vasoactive medical treatment in patients with pulmonary arterial hypertension of different origin [167]. However, CTEPH is regarded as a distinct entity according to the recent classification of pulmonary hypertension [168]. Patients with CTEPH have been explicitly excluded from most of the recent randomised controlled trials for treatment of pulmonary hypertension, but not the randomised placebo-controlled trial with inhaled iloprost [169]. In the Aerosolized Iloprost Randomized study, a significant improvement in functional capacity and haemodynamic parameters on treatment with inhaled iloprost compared to placebo has been found in 203 patients, among them 57 patients with CTEPH not amenable to surgery [170]. Based on this study, inhaled iloprost is licensed for treatment of CTEPH with distal vascular obstruction in Australia. Uncontrolled trials have reported the successful use of intravenous or inhaled prostanoids and sildenafil for the long-term treatment of CTEPH. The largest experience with favourable longer-term results has reported use of sildenafil either as monotherapy or in combination with inhaled iloprost [171–173]. Experiences with the endothelin antagonist bosentan have also been reported recently [174]. The diagnostic assessment of CTEPH and therapeutic decisions require an interdisciplinary approach from an experienced medical, surgical and radiological team familiar with pulmonary hypertension. Therefore, patients with known or highly suspected CTEPH should be referred to a specialised centre [71, 159].

Conclusion Considerable progress has been made in the diagnosis and management of acute pulmonary embolism since the early 1990s. Diagnostic strategies and risk assessment have been improved by the introduction of new CT technology and cardiac biomarkers. Therefore, diagnostic algorithms are changing rapidly in conjunction with national guidelines and the local availability of diagnostic investigations [1–4, 175, 176]. Development of acute cor pulmonale has emerged as a risk factor for adverse outcome in PE. Current diagnostic strategies include risk assessment of cardiac compromise that might affect therapeutic decisions. Therapeutic options are expanding, with new anticoagulation strategies, including LMWHs and heparinoids, increased use of thrombolysis and the improvement of embolectomy techniques. These therapeutic advances will influence the overall outcome and the frequency of early and late complications. CTEPH, as a long-term complication after PE, develops more often than previously suspected. This potentially life-threatening condition is characterised by the development of chronic cor pulmonale and chronic right heart failure when untreated. 155


Management has improved greatly since the 1990s, and includes surgical and medical options. Diagnostic and therapeutic assessment should be performed in specialised centres experienced in caring for patients with pulmonary hypertension.

Keynote messages 1) Pulmonary embolism occurs frequently and is frequently underdiagnosed. 2) Diagnosis depends mainly upon clinical probability, the d-dimer test and CTPA scan. 3) Risk stratification is based upon clinical assessment, echocardiography and newly discovered biomarkers. 4) Rapid initiation of anticoagulation therapy improves outcome. 5) The indications for thrombolysis seem to have expanded; however, further studies are required concerning outcome. 6) Interventional therapy and surgical embolectomy should be considered according to clinical setting and local availability. 7) The duration of secondary prophylaxis depends upon individual risk factors. 8) Follow-up with clinical assessment and echocardiography is recommended. 9) Long-term complications, with the development of pulmonary hypertension, occur more frequently than previously suspected. 10) Patients with signs of CTEPH should be referred to specialised centres for further assessment. 11) Treatment for CTEPH includes surgical and medical options.

Summary Pulmonary embolism (PE) remains a frequent but often overlooked disease, despite improvements in diagnostic strategies, including clinical probability scores, the d-dimer test, and computed tomography or perfusion scintigraphy. Development of acute cor pulmonale has emerged as a risk factor for adverse outcome in PE. Therefore, risk evaluation has been attempted, based on clinical assessment, echocardiography and newly discovered biomarkers, in order to improve therapeutic decisions. The main therapeutic goal is still the rapid initiation of anticoagulation therapy, including unfractionated heparin, low-molecular-weight-heparins and heparinoids, which also improves overall outcome. Several studies have encouraged the expanded use of thrombolysis; however, further studies concerning short- and long-term outcome are required. Interventional and surgical embolectomy should be considered in precarious situations according to the clinical setting and local availability. The duration of anticoagulation therapy as secondary prophylaxis depends upon individual risk factors. Therefore, follow-up with clinical assessment and echocardiography is recommended for the early detection of long-term complications. The development of chronic thromboembolic pulmonary hypertension is observed more frequently than previously expected. The treatment of chronic thromboembolic pulmonary hypertension includes surgical and medical options; however, this should be assessed in specialised centres. Keywords: Chronic thromboembolic pulmonary hypertension, diagnosis, pulmonary embolism, risk assessment, therapy. 156


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CHAPTER 11

Pneumothorax and bronchopleural fistula M. Noppen Correspondence: M. Noppen, Interventional Endoscopy Clinic, Respiratory Division, University Hospital AZ-VUB, Laarbeeklaan 101, B-1090 Brussels, Belgium. Fax: 32 24776840; E-mail: marc.noppen@az. vub.ac.be

Pneumothorax represents a common problem to the pulmonologist, surgeon or emergency care physician. Although the symptoms can be alarming, spontaneous pneumothorax is rarely life-threatening at presentation, allowing for a rational, algorithmic therapeutic approach. It is important to note that spontaneous pneumothoraces in patients with severe underlying disease, tension pneumothorax, spontaneous haemopneumothorax and traumatic noniatrogenic pneumothorax can be life threatening at presentation, requiring immediate intervention. Bronchopleural fistula can be considered a special case of complicated persistent pneumothorax, representing a challenging management problem associated with significant morbidity and even mortality. In this chapter, emphasis is given to evidence-based management strategies, and on the importance of multidisciplinary collaboration in the management of these disorders.

Pneumothorax Pneumothorax is defined as the presence of air in the pleural space. From a clinical point of view, pneumothorax is classified as spontaneous, traumatic or iatrogenic (table 1) [1, 2]. Spontaneous pneumothorax occurs without preceding trauma or other obvious precipitating causes and is subclassified as primary, secondary and catamenial. Primary spontaneous pneumothorax (PSP) arises in patients without clinically apparent lung disease and typically occurs in smoking ectomorphic males aged 20–40yrs. PSP occurs quite often, with a reported incidence of 7.4–28/100,000?yr-1 in males and 1.2–6/100,000?yr-1 in females [3, 4]. Catamenial pneumothorax occurs in relation to menstruation, typically in 30–40-yrold females. It usually affects the right lung and occurs within 24–72 h after the onset of menstruation [5]. Secondary spontaneous pneumothorax (SSP) is associated with known underlying lung disease (table 2). Although almost every lung disease has been associated with spontaneous pneumothorax, the most frequent causes of SSP are chronic obstructive pulmonary disease (COPD), cystic fibrosis, AIDS-related Pneumocystis carinii pneumonia and tuberculosis [6]. The incidence of SSP is similar to that of PSP. The symptoms are more severe than those of PSP, and may even be life threatening because of an already compromised lung function [7].

Eur Respir Mon, 2006, 36, 165–176. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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Table 1. – Clinical classification of pneumothorax Spontaneous Primary: no apparent underlying lung disease Secondary: known underlying lung disease Catamenial: in conjunction with menstruation (Neonatal) Traumatic Penetrating chest injury Blunt chest injury Iatrogenic Secondary to diagnostic or therapeutic procedures

Table 2. – Disorders complicated by secondary spontaneous pneumothorax Airway disorders COPD (bullous emphysema) Cystic fibrosis Acute severe asthma Infectious lung diseases Pneumocystis carinii pneumonia Tuberculosis Necrotising pneumonia Interstitial lung diseases Sarcoidosis Idiopathic pulmonary fibrosis Histiocytosis X Lymphangioleiomyomatosis Connective tissue diseases Rheumatoid arthritis Ankylosing spondylitis Polymyositis/dermatomyositis Sclerodermia Marfan’s syndrome Ehlers–Danlos syndrome Cancer Lung cancer Sarcoma

COPD: chronic obstructive pulmonary disease.

Primary spontaneous pneumothorax Clinical evaluation and diagnosis Most patients suffering from PSP present with ipsilateral chest pain, which may be minimal or severe, and with some degree of dyspnoea [1, 2]. Typically, symptoms decrease spontaneously within 48 h [7]. Therefore, many patients do not seek medical advice for several days, with 46% waiting w2 days [8]. Physical examination may be normal in small pneumothoraces. In patients with a large pneumothorax, examination may reveal ipsilateral absence of breath sounds, absence of tactile fremitus, and hyper-resonant percussion. Tachypnoea and tachycardia may be present [2]. The diagnosis is confirmed by the demonstration of a thin visceral pleural line on upright postero-anterior chest radiography. Radiographs taken at expiration do not help in the diagnosis, even in the case of small pneumothoraces, and are not indicated as a routine investigation [9]. As the mediastinum is not a fixed structure in the thorax, even relatively small pneumothoraces may be accompanied by a contralateral shift of the trachea, heart and mediastinum. This 166

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contralateral mediastinal shift is not ominous or pathognomonic for tension pneumothorax, and should not alter the treatment strategy. In very small pneumothoraces, lateral decubitus radiographs or computed tomography (CT) scans of the thorax are more sensitive. Routine CT scanning of the lung is not indicated in uncomplicated first episodes of PSP. Arterial blood gas measurements frequently show some degree of decreased oxygenation. Clinical examination and postero-anterior chest radiography are sufficient for the diagnostic work-up of PSP.

Management In most treatment guidelines, quantification of the size of a pneumothorax is one of the determinants of treatment choice [10, 11]. Although no agreement exists on the definition of "small" or "large", the following practical classification can be proposed: a "small" pneumothorax is defined as a partial (most often apical) collapse of the lung, or as a complete collapse causing a pneumothorax volumev20% of the hemithorax as estimated by the Light index (fig. 1; light index=((1–DL3)6100)?(DHT3)-1, where DL is the distance from the mediastinal line to the visceral line of the lung and DHT is the distance from the mediastinal line to the parietal pleura, both measured at hilar level) [12]. Other parameters directing patient management are: 1) the severity of symptoms; 2) whether the pneumothorax is a first episode or a recurrence; 3) patient preference; and 4) medico-legal requirements [1, 10–13].

Should every patient presenting with a primary spontaneous pneumothorax be treated? As described previously, most patients with a PSP will present with chest pain and dyspnoea of varying severity, which will decrease or even resolve in most patients within

DHT DL

Fig. 1. – Quantification of the size of a pneumothorax. DHT: distance from the mediastinal line to the parietal pleura; DL: distance from the mediastinal line to the visceral line of the lung.

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a few days. In general, PSP should not be considered dangerous, rather it is a nuisance. Spontaneous air absorption from the pleural space occurs at a rate ofy1.25–1.8% of the volume of the hemithorax per day, a process which can be accelerated up to four times with oxygen supplementation [14]. As a consequence, in small pneumothoraces without significant symptoms, simple observation should be the treatment of choice [1, 10, 11, 13]. Patients should not be hospitalised, but can be discharged with easy outpatient review, and with clear, written advice to return in the event of worsening symptoms. In the case of significant dyspnoea at presentation, however, treatment should be initiated, irrespective of pneumothorax size.

Should treatment choice depend upon whether primary spontaneous pneumothorax is a first or recurrent episode? A first episode of PSP that is treated by observation or air removal only shows a tendency to recur; recurrence rates range 16–57%, probably averaging y30% [15]. The question of whether patients should be treated with a (more invasive) recurrenceprevention treatment rather than with air evacuation alone remains unresolved. Costeffectiveness studies [16–18] suggest that immediate recurrence-prevention treatment after a first episode is the most cost-effective approach; however, about two-thirds of patients will receive unnecessary invasive treatment [1, 13]. Nevertheless, some patients will demand recurrence-prevention treatment after a first episode, and in some professions (e.g. flying personnel), this is a requirement before patients can resume their professional activities. The treatment of a first episode of PSP should, therefore, be tailored to the individual patient, taking into account the following facts: 1) the majority of patients will never have recurrences; 2) no predictive tests for recurrence exist; and 3) the possible psychological patient preference for an immediate, invasive but conclusive recurrence-prevention treatment versus not having to undergo an invasive treatment unnecessarily. A first episode of PSP should not be treated by recurrence-prevention techniques, unless the patient requests it, or unless there are medico-legal reasons.

Air-evacuation treatments In clinically stable first-episode PSP patients with large pneumothoraces, and/or in patients who are symptomatic and who choose not to undergo immediate recurrence prevention, an air-evacuation procedure should be performed [1, 2, 10, 11]. Treatment options include simple manual aspiration with immediate catheter removal after confirmed re-expansion of the lung, aspiration through a small-bore catheter (v14 F), which can remain in place if necessary, or placement of a small-to-medium-sized chest tube. The catheter and the chest tube can be attached to a Heimlich valve or to a waterseal device [1, 11]. Simple manual aspiration has been shown to be successful in 59–83% of cases. Due to its very low morbidity, cost saving (decreased hospitalisation as it enables outpatient-based treatment if successful) and proven safety (no urgent re-admissions have been reported), this technique probably represents the best first-line treatment approach in uncomplicated first episodes of PSP requiring air evacuation [1, 10, 19–22]. Aspiration can be performed using various types of small-calibre catheters (e.g. central intravenous catheters), which can be removed immediately after successful aspiration, Alternatively, dedicated (but more expensive) small-bore catheter aspiration kits are commercially available. The latter can be left in place until full re-expansion of the lung is confirmed. In case of immediate recollapse of the lung, repeat aspiration or connection to an underwater-seal system is facilitated through these indwelling catheters. A repeat aspiration can be successful in up to one-third of cases [19], although this has not been 168


observed by others [21]. If simple aspiration or catheter aspiration drainage is unsuccessful, then an intercostal tube should be inserted. There is no evidence that large tubes (i20–24 Ch) are any better than small tubes in the management of pneumothoraces. The initial use of large intercostal tubes is therefore not recommended, although it sporadically becomes necessary to replace a small chest tube with a larger one in case of persistent air leakage. The presence of associated pleural fluid or of a haemopneumothorax would favour the immediate choice of a larger tube. Although Henry et al. [10] propose that chest tubes should be the initial treatment in pneumothoraces of i50%, Noppen et al. [21] have found manual aspiration to be similarly successful irrespective of the size of the pneumothorax. There is no evidence to support the routine initial use of suction [23], because it does not shorten drainage time and it may be a risk factor for the development of re-expansion pulmonary oedema [10]. On the contrary, in pneumothoraces after pulmonary resection, the initial application of a water seal has been shown to shorten chest-drainage time compared with immediate active suction [24, 25]. In cases where there is persistent air leak for 48 h, or a failure of lung re-expansion, suction can be applied (-10– -20 cmH2O using a high-volume (i15–20 L?min-1) system) [26]. The chest tube can safely be removed when there is complete lung re-expansion and absence of bubbling for i12 h. There is no consensus about whether the tube should be clamped before removal, since this manoeuvre has not been shown to make a significant difference to the recollapse rate [23]. Drain clamping (to detect small air leaks not obvious at bedside) is therefore not generally recommended (for safety reasons), but is acceptable under close clinical supervision [10].

Recurrence-prevention treatment Observation and air evacuation treatments (aspiration or chest tube drainage) have no impact on the recurrence of pneumothorax [10]. Recurrence prevention can be achieved by treatment of the lung leak, by inducing pleurodesis, or by a combination of the two [1]. There is no consensus on the optimal recurrence-prevention technique in view of the controversies regarding the exact cause of the air leak in PSP (rupture of a bleb or bulla; pleural positivity elsewhere at the visceral lung surface; alveolar rupture at the bronchovascular interstitial level leading to an air leak via the mediastinal pleura; or a combination of these [1, 2]). Therapeutic options include: 1) chemical pleurodesis via a chest tube (using talc slurry or tetracycline); 2) so-called "medical" thoracoscopic talc poudrage performed by a pulmonologist; 3) video-assisted thoracic surgery (VATS) with bleb/bulla treatment (stapling, coagulation, ligation) and/or pleurodesis (partial pleurectomy, pleural abrasion, talc insufflation); 4) and thoracotomy (muscle sparing or axillar thoracotomy). No prospective, randomised studies comparing these approaches have been published; analysis of the abundant, largely uncontrolled, studies in the literature suggests that the more invasive the procedure, the lower the recurrence rate. Of the above techniques, medical thoracoscopic talc poudrage and VATS show recurrence rates v10%, and thoracotomy v5%. These are considered the best options [1, 2, 10, 11]. Finally, thoracoscopy (medical or VATS) is indicated within 3–5 days in cases with a persistent air leak or failure of lung re-expansion (see later).

Secondary spontaneous pneumothorax Clinical evaluation and diagnosis In general, the clinical symptoms associated with SSP are more severe than those associated with PSP [6]. Due to the underlying lung disease, hypoxaemia is more 169

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pronounced. Although arterial blood gas measurements are indicated in SSP, pulmonary function tests are too insensitive and are, therefore, not recommended [10]. As is the case with PSP, the diagnosis of a SSP is made on a standard postero-anterior chest radiograph. In SSP, however, CT scanning can be useful, e.g. to differentiate emphysematous bullae from pneumothoraces, or to evaluate the type and severity of the underlying lung disease process.

Management In SSP, observation alone is recommended only in patients with small pneumothoraces of v1 cm depth, or isolated apical pneumothoraces in asymptomatic patients [10]. However, hospitalisation (with oxygen supplementation) is recommended in any case. All other cases require active intervention. In contrast with PSP, most patients with SSP should receive recurrence-prevention treatment after a first episode, because of the more dramatic impact, morbidity and even mortality in SSP. Therefore, simple aspiration is probably not the best initial treatment in SSP; not only is it less likely to succeed in SSP (33–67% of cases), but it does not allow for recurrence-prevention therapy. Therefore, simple aspiration in SSP is recommended only as an initial treatment in small pneumothoraces in minimally symptomatic patients aged v50 yrs [10]. Patients with SSP who are treated successfully with simple aspiration should be admitted to hospital and observed for i24 h [10]. Therefore, most authors recommend chest tube drainage as an initial treatment in most cases of SSP [9–11]. Unless subsequent mechanical ventilation is probable, small tubes (ƒ14 F) will suffice [10]. The recommendations on suction and clamping made for PSP are valid in SSP. When a chest tube is in place, and complete lung re-expansion has been achieved, chemical pleurodesis by instillation of substances into the pleural space can be considered. However, because of the technique’s significantly lower efficacy compared with thoracoscopic procedures, chemical pleurodesis through the chest tube is recommended only in patients who are unwilling or otherwise unable to undergo thoracoscopy [10, 11]. As for PSP, thoracoscopic procedures include treatment of the lung abnormality (closure of visible air leak), bleb/bulla treatment if indicated, and a pleurodesis procedure. In selected cases of SSP (e.g. patients with cystic fibrosis or relatively young patients with severe emphysema), pleurodesis should be performed in close collaboration with a possible future lung transplant surgical team (some, but not all, transplant surgeons prefer to avoid intrapleural instillation of talc).

Tension pneumothorax Tension pneumothorax (which can occur in both PSP and SSP) is rare in spontaneous pneumothorax. It occurs when intrapleural pressure exceeds the atmospheric pressure throughout inspiration and expiration, owing to a check-valve mechanism at the level of the air leak. Tension pneumothorax is a clinical, not a radiological diagnosis. Patients typically experience a rapid (over seconds or minutes) deterioration in their cardiopulmonary status (hypotension, tachycardia, tachypnoea, severe dyspnoea, hypoxaemia and cyanosis, diaphoresis), which, if left untreated, may result in death. There are no predictive features (e.g. pneumothorax size at presentation, underlying lung disease). When tension pneumothorax is suspected, high-flow (10 L?min-1) oxygen should be given, and a cannula or needle should be introduced into the pleural space, usually at the second or third anterior intercostal space, mid-clavicular. 170


Air should be allowed to escape until the patient is no longer compromised, followed by chest tube insertion.

Special situations Further accepted indications for immediate recurrence-prevention treatment (preferably using thoracoscopy/VATS) are a first episode of contralateral spontaneous pneumothorax, a bilateral spontaneous pneumothorax, and a spontaneous haemopneumothorax [10].

Traumatic non-iatrogenic pneumothorax A traumatic, non-iatrogenic pneumothorax can result from either penetrating or nonpenetrating (blunt) chest trauma [27]. Traumatic pneumothorax should be considered in every patient suffering significant trauma. Overall,y5% of multiple trauma patients have a pneumothorax, whereas ƒ40% of blunt chest trauma patients have a pneumothorax (half of whom have a haematopneumothorax) [28, 29]. In penetrating trauma, air can enter the pleural space directly through the chest wall, and additionally from the tracheobronchial tree if the visceral pleura is also penetrated. In blunt chest trauma, the visceral pleura may be lacerated secondary to a rib fracture or dislocation. More frequently, however, there are no associated rib features. In these cases, it is thought that sudden chest compression, with an ensuing sudden increase in alveolar pressure, may lead to alveolar rupture. Air may be forced into the interstitial space towards the visceral pleura and mediastinum. A pneumothorax then occurs if pleural ruptures are present. The diagnosis of traumatic pneumothorax can be made on the supine or semi-erect chest radiography films frequently used in trauma patients. However, the radiological presentation of a pneumothorax may be different from that seen on a standard upright postero-anterior study: air may accumulate in the anterior-medial hemithorax (producing a medial pneumothorax), over the hemidiaphragm (producing the deep sulcus sign), or in the anterior costophrenic sulcus (producing a basilar pneumothorax). Since these signs can be missed in ƒ40% of cases, especially in small pneumothoraces, a chest CT scan is recommended for every chest trauma patient [28].

Management Traumatic (haemo)pneumothorax should be treated with chest tube placement, preferably i20 Ch. If a haemopneumothorax is present, a second chest tube can be placed, directed caudally, to remove the blood. In most cases, lung re-expansion and airleak closure can be achieved in ƒ72 h. In every patient with traumatic pneumothorax, two diagnoses should be considered. The first is fracture or rupture of the trachea or major bronchus, especially in patients with a large pneumothorax with continued air leakage after chest tube placement, a fracture of one or more of the first three ribs, or haemoptysis. In these situations, bronchoscopy is indicated. Treatment usually consists of primary surgical repair. The second diagnosis that should be considered is traumatic rupture of the oesophagus. This condition is typically associated with a hydropneumothorax. A reliable screening test for oesophageal rupture is measurement of the pleural fluid amylase concentration. If this is elevated, contrast radiographic studies and/or oesophagoscopy should be performed. Small tears can be treated conservatively (no oral intake of food or liquid, total parenteral nutrition, proximal (oesophageal) and 171

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distal (gastric) aspiration catheter placement, antibiotic coverage). Larger tears usually require primary surgical closure.

Traumatic iatrogenic pneumothorax Iatrogenic pneumothorax results from a complication of a diagnostic or therapeutic intervention. Its incidence is higher than that of spontaneous pneumothorax, and is likely to increase as the use of invasive procedures increases [2]. Leading causes are transthoracic needle aspiration (15–37%; y10% requiring treatment), central venous puncture, especially subclavian (1–22%), thoracocentesis (5–20%), blind pleural biopsy (8–10%) and mechanical ventilation (5–15%). The clinical manifestation of iatrogenic pneumothorax varies from almost complete absence of symptoms (e.g. after thoracocentesis) to a sudden and severe tension pneumothorax (e.g. during mechanical ventilation). The diagnosis is made by chest radiography. Here also, supine radiographs may be underdiagnostic, and a CT scan is often necessary to confirm the diagnosis [2]. The majority of iatrogenic pneumothoraces will resolve with observation (with or without oxygen supplementation) alone. If required, treatment should be simple aspiration, which is successful in ƒ90% of cases [10]. The exceptions are patients with COPD who develop an iatrogenic pneumothorax (these patients are more likely to require chest tube drainage) and patients who develop a pneumothorax while on mechanical ventilation (requiring large-bore chest tube drainage).

Bronchopleural fistulas Bronchopleural fistulas (BPFs) are communications between the bronchial tree and the pleural space. Although relatively rare, they represent a challenging management problem and are associated with significant morbidity and even mortality [30]. Sound scientific evidence for the management of BPFs is lacking; treatment strategies vary from conservative management to aggressive surgical procedures. No guidelines or consensus statements have been established.

Aetiologies The most common aetiology of BPFs is pulmonary resection, followed by lung necrosis complicating infection, chemo- or radiotherapy, persistent spontaneous pneumothorax, and tuberculoses [31]. Pre-operative risk factors for the development of BPFs after pulmonary resection are fever, steroid use, Haemophilus influenzae in sputum, elevated sedimentation rate and anaemia. Post-operative risk factors that have been implicated are fever, steroid use, pre-operative chemo- or radiotherapy, leukocytosis, tracheostomy, and bronchoscopy for mucus plugging. Other risk factors for post-operative fistulisation include residual tumour at the resection margins, long bronchial stump, tightness of sutures, excessive peribronchial and paratracheal dissection, adult respiratory distress syndrome, invasive chest procedures and underlying debilitating disorders (diabetes, malnutrition, pneumonia, lung abscess and severe COPD with bullous disease). The incidence of BPFs following pulmonary resection averages 2–5% (ƒ1% after lobectomy; ƒ12.5% after pneumectomy). BPFs almost always occur within 3 months after surgery [32]. 172


Clinical presentation The acute presentation of BPFs is often dramatic and can be life threatening because of tension pneumothorax or pulmonary flooding; signs and symptoms include sudden dyspnoea, hypotension, subcutaneous emphysema, cough with expectoration of purulent material or fluid, persistent air leak and decrease or disappearance of pleural effusion on chest radiography (in post-operative cases). Subacute presentation is more insidious and is characterised by wasting, malaise, fever, and cough. In the chronic form (which is usually associated with an infectious process), there is fibrosis of the pleural space and mediastinum, typically preventing mediastinal shift [33]. The diagnosis can be confirmed by direct visualisation at bronchoscopy, or by using selective bronchography or instillation of methylene blue. CT scanning is proposed in suspicious BPFs, to guide management by identifying underlying causes, especially in nonsurgical BPFs and in persistent pneumothorax.

Management The first principle of management is to address any immediate, life-threatening conditions (e.g. pulmonary flooding, tension pneumothorax), by placing the patient with the affected side down and performing adequate pleural drainage [33]. Air leaks through BPFs may range v1–16 L?min-1, and a chest tube with an adequate diameter to convey these airflows must be chosen (e.g. a 32 F tube), especially in cases where the patient is undergoing mechanical ventilation. In these cases, specific ventilator settings and ventilation modes may be required [34]. In general, care should be taken to decrease the pressure gradient between the airways and the pleural space: mean airway pressure should be minimal and, if the lung remains fully inflated, suction on the chest tube(s) should be minimised. In case of a major stump dehiscence (usually within the first week after lung resection) immediate resuture and reinforcement of the bronchial stump is recommended [35]. When infectious aetiologies are present or empyema is suspected, adequate drainage of the pleural space is mandatory along with proper antimicrobial coverage. Proper nutrition is required, frequently requiring enteral and/or parenteral feeding. In cases with a more subacute clinical presentation, the patient’s status should first be optimised by means of drainage and reduction of the pleural space, antibiotic therapy, nutritional supplementation and adequate ventilator management, when ventilated [31, 34]. After 1–3 weeks, surgical re-intervention can be attempted. The success of surgical closure of BPFs has been reported to be 80–95%, but is associated with the risk of open thoracotomy (although reported mortality has been as low as zero) [33]. Surgical techniques include chronic open drainage, direct stump closure with intercostal muscle reinforcement, omental flap, trans-sternal bronchial closure, and thoracoplasty with or without extrathoracic chest wall muscle transposition. Some of these may be performed using VATS techniques. If the patient’s general condition is too poor for surgery, or when only a small fistula (v3 mm diameter) is present, bronchoscopic treatment appears to be an effective alternative, with fistula closure achieved in more than one-third of patients [31, 33]. Various sealing compounds or devices have been applied through the bronchoscope. These include lead shot, absolute ethanol, polyethylene glycol, cyano-acrylate glue, fibrin glue, blood clot, antibiotics (tetracycline, doxycycline), albumin glutaraldehyde tissue adhesive, cellulose, gel foam, balloon catheter occlusion, silver nitrate, calf bone, silicon spigots and stents [33]. 173

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There are no controlled studies comparing the effectiveness of the different sealants or comparing surgical and endoscopic therapy; treatment is generally tailored to the individual patient, using available or personally preferred techniques. In cases of spontaneous primary or secondary pneumothorax with persistent air leak (a specific type of BPF presentation), observation for 4 days is allowed to assess for spontaneous closure of the fistula [1, 2, 10, 11]. If the air leak persists for i4 days, the patient should be evaluated for surgical closure of the air leak (using thoracoscopic or open surgical approaches) and to perform pleurodesis to prevent pneumothorax recurrence. Use of an additional chest tube or increase of the suction pressure are not indicated. Except in special cases where surgery is contraindicated or a patient refuses surgery, chemical pleurodesis should not be used in the management of most patients. If chemical pleurodesis is performed, tetracycline (doxycycline) or talc slurry is the preferred sclerosing agent.

Summary Spontaneous pneumothorax is frequently encountered in clinical practice. A distinction is made between primary (i.e. no known underlying lung disease, occurring in adolescents and young adults, in particular tall thin smoking males) and secondary disease (i.e. occurring in patients with underlying lung disease such as chronic obstructive pulmonary disease, tuberculosis, lymphangioleiomyomatosis and numerous others). Nevertheless, better and new visualisation techniques have shown that the underlying lung and/or visceral pleura are also diffusely damaged in primary spontaneous pneumothorax, and blebs and bullae are not always the cause or localisation of the air leak. Observation only is indicated in small, asymptomatic, first episodes. Manual aspiration is the established first-line treatment in first episodes of large and/or symptomatic disease. In cases of recurrence or persistence of pneumothorax, medical thoracoscopic talc poudrage (which has also been proven to be safe) and video-assisted thoracoscopic surgery are equally effective. The cornerstone of both treatments is effective pleurodesis. In secondary spontaneous pneumothorax, which is potentially more dangerous owing to the extent and type of underlying disease, a more aggressive approach is suggested, including a pleurodesis technique after the first episode. A bronchopleural fistula is a persistent communication between the bronchial tree and the pleural space. Thus, persistent spontaneous or traumatic pneumothorax can be considered a specific cause of bronchopleural fistula. However, complication of pulmonary resection is the most common cause by far. Bronchopleural fistulas are associated with significant morbidity and mortality, and represent a challenging management problem. Treatment includes various surgical and bronchoscopic techniques, the choice of which depends upon the underlying cause, the localisation and the size of the fistula. In high-risk surgical patients, bronchoscopic procedures may serve as a temporary bridge to definitive surgical treatment, while in others they may be the only treatment option. There are no prospective randomised trials comparing various approaches. Current treatment options seem to be complementary, and treatment should be individualised. Keywords: Bronchopleural fistula, chest tube drainage, pneumothorax, thoracoscopy, treatment. 174


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Noppen M, Baumann MH. Pathogenesis and treatment of primary spontaneous pneumothorax: an overview. Respiration 2003; 70: 431–438. Noppen M, Schramel F. Pneumothorax. In: Loddenkemper R, Antony VB, eds. Pleural Diseases. Eur Respir Mon 2002; 7: No. 22, pp. 279–296. Melton LJ, Hepper NG, Offord KP. Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974. Am Rev Respir Dis 1979; 120: 1379–1382. Bense L, Wiman LG, Hedenstierna G. Onset of symptoms in spontaneous pneumothorax: correlations to physical activity. Eur J Respir Dis 1987; 71: 181–186. Joseph J, Sahn SA. Thoracic endometriosis syndrome: new observations from an analysis of 110 cases. Am J Med 1996; 100: 164–170. Tanaka F, Hoh M, Esaki M. Secondary spontaneous pneumothorax. Ann Thorac Surg 1993; 55: 372–376. Sahn SA, Heffner JE. Spontaneous pneumothorax. N Engl J Med 2000; 342: 868–874. O’Hara VS. Spontaneous pneumothorax. Milit Med 1978; 143: 32–35. Schramel FM, Golding RP, Haakman CD, Sutedja TG, de Jong KA, Postmus PE. Expiratory chest radiographs do not improve visibility of small apical pneumothoraces by enhanced contrast. Eur Respir J 1996; 9: 406–409. Henry M, Arnold T, Harvey J. BTS guidelines for the management of spontaneous pneumothorax. Thorax 2003; 55: Suppl. 11, ii39–ii52. Baumann MH, Strange C, Heffner JE, et al. Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001; 119: 590–602. Noppen M, Alexander P, Driesen P, Slabbynck H, Verstraeten A. Quantification of the size of primary spontaneous pneumothorax: accuracy of the Light index. Respiration 2001; 68: 396– 399. Baumann MH, Noppen M. Pneumothorax. Respirology 2004; 9: 157–164. Northfield TC. Oxygen therapy for spontaneous pneumothorax. BMJ 1971; 4: 86–88. Schramel JFMN, Postmus PE, Vanderschueren RG. Current aspects of spontaneous pneumothorax. Eur Respir J 1997; 10: 1372–1379. Torresini G, Vaccarili M, Divisi D, Crisci R. Is video-assisted thoracic surgery justified at first spontaneous pneumothorax? Eur J Cardiothorac Surg 2001; 20: 42–45. Schramel FM, Sutedja TG, Braber JC, van Mourik JC, Postmus PE. Cost-effectiveness of videoassisted thoracoscopic surgery versus conservative treatment for first time or recurrent spontaneous pneumothorax. Eur Respir J 1996; 9: 1821–1825. Morimoto T, Shimbo T, Noguchi Y, et al. Effects of timing of thoracoscopic surgery for primary spontaneous pneumothorax on prognosis and costs. Am J Surg 2004; 187: 767–774. Archer GJ, Hamilton AA, Upadhyay R, Finlay M, Grace PM. Results of simple aspiration of pneumothoraces. Br J Dis Chest 1985; 79: 177–182. Andrivet P, Djedaini K, Teboul JL, Brochard L, Dreyfuss D. Spontaneous pneumothorax. Comparison of thoracic drainage vs immediate or delayed needle aspiration. Chest 1995; 108: 335– 339. Noppen M, Alexander P, Driesen P, Slabbynck H, Verstraeten A. Manual aspiration versus chest tube drainage in first episodes of primary spontaneous pneumothorax: a multicenter, prospective, randomized pilot study. Am J Respir Crit Care Med 2002; 165: 1240–1244. Light RW. Manual aspiration: the preferred method for managing primary spontaneous pneumothorax? Am J Respir Crit Care Med 2002; 165: 1202–1203. So SY, Yu DY. Catheter drainage of spontaneous pneumothorax: suction or no suction, early or late removal? Thorax 1982; 37: 46–48. Marshall MB, Deeb ME, Bleier JI, et al. Suction vs water seal after pulmonary resection: a randomized prospective study. Chest 2002; 121: 831–835.

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CHAPTER 12

Emergencies in interstitial and immunological lung disease M. Kolb, G. Cox Dept of Medicine, Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. Correspondence: FIRH T2123, St. Joseph’s Healthcare, McMaster University, 50 Charlton Ave East, Hamilton, ON, L8N 4A6, Canada. Fax: 1 9055216132; E-mail: [email protected]

The group of interstitial and immunological lung diseases is a complex mixture of a wide variety of disorders. One of the features that most of these conditions have in common is that they usually do not present as respiratory emergencies, at least not emergencies related to the underlying immune process. However, usually does not mean exclusively, considering that pulmonary haemorrhage syndromes can be a rather dramatic presentation requiring immediate intervention. Nevertheless, it is much more common that the diagnosis of these diseases is made in nonemergency situations. Patients with interstitial lung disease can present with the entire spectrum of respiratory symptoms, none of those being disease specific. Once a definite or likely diagnosis is established, treatment may be initiated or the clinical course may be observed for months to years without anything else but symptomatic therapy. Even patients with severe and eventually fatal interstitial lung disease (ILD), such as usual interstitial pneumonia (UIP), are often stable for a long period of time before they suddenly deteriorate and then present as an emergency. In this chapter, a number of scenarios are presented that are representative of emergency situations for patients with ILD.

Scenario 1: acute deterioration of pulmonary fibrosis A 62-yr-old patient with UIP and a moderate restrictive pattern on pulmonary function test (PFT) with vital capacity (VC) and total lung capacity ranging 50–60% predicted has been clinically stable for w1 yr after initial presentation. Immunosuppressive therapy was not initiated because of rather mild symptoms and reportedly bad response rates. The patient reports a rapid increase in dyspnoea over a period of 1–2 weeks. There are no symptoms of a viral disease or respiratory tract infection, no fever, no increase in sputum volume or change of colour. Repeat PFT shows a minor decrease of VC by 6% compared with the previous result. The oxygen saturation on room air is only 91% and drops to 86% during a 6-minute walk test. There are no new marked changes on the chest radiograph, and no increase of peripheral blood leukocyte counts. There is also no indication of right ventricular failure, although recent echocardiography showed a mild increase in mean pulmonary arterial pressure to 35 mmHg. This patient is unlikely to have an infection causing the deterioration of respiratory symptoms. However, the decrease of resting oxygen saturation suggests that there is a progressive pathological process in the lungs. A recent analysis of 168 patients assigned to placebo in the interferon-c trial [1] showed minimal physiological deterioration as measured by forced vital capacity, diffusion capacity of the lung for carbon monoxide, and alveolar–arterial oxygen gradient over 72 weeks of follow-up. However, almost half Eur Respir Mon, 2006, 36, 177–182. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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of the patients demonstrated rapid progression of their disease. Respiratory failure developed rapidly in the absence of infection or other complicating problems, such as pneumothorax, ischaemic cardiac injury, or left or right ventricular failure. One very important finding in the study by Martinez et al. [1] was that half of the deaths that were directly related to IPF (and not secondary complications) occurred acutely within a 4week period of deterioration. This is much higher than previously recognised. Another analysis examining the reasons for deterioration and clinical course of IPF patients admitted to an intensive care unit (ICU) showed that progression of the underlying disease was responsible for the decline in y50% of these patients [2]. Continuous fibroproliferation in the lung tissue leading to further destruction of the lung parenchyma with eventual failure of compensatory mechanisms is one potential explanation of such acute exacerbation of IPF. Pathological examination can show acute alveolar injury with or without hyaline membrane formation [3]. Little information is available about how to effectively treat these episodes of rapid decline in IPF. The usefulness of immunosuppressive drugs, such as high-dose corticosteroids, azathioprine and cyclophosphamide, has not been analysed systematically in this context, but, considering their limited efficacy in slowly progressive UIP, it is questionable that they would significantly improve outcomes. The acute deterioration and lack of efficient drug therapy will frequently lead to consideration of ICU admission and mechanical ventilation in UIP patients. The majority of patients, especially the younger ones and those listed for lung transplantation, will probably be admitted to the ICU even if there is strong evidence for rapidly progressive IPF and no potentially treatable factor identified. However, several studies have demonstrated the extraordinarily poor prognosis of UIP patients once they have been admitted to the ICU, regardless of the precipitating condition leading to initiation of mechanical ventilation [2, 4]. Stern et al. [4] reported that 22 out of 23 IPF patients requiring mechanical ventilation died with a median survival of 3 days; the only survivor received a single-lung transplant. This study, [4], similar to others, suggested that the most common cause for acute respiratory failure was progression of IPF. A retrospective analysis from the Mayo Clinic (Rochester, MN, USA) described the clinical course of 38 IPF patients admitted to ICU, half of whom required mechanical ventilation. Only 15 of these patients were discharged from hospital, and 13 of them died within 2 months of discharge [2]. All these studies and reports show the poor outcome of ICU treatment in IPF patients who develop acute or subacute respiratory failure without evidence of a treatable complication. Physicians have to be aware of this prognosis, and patients and their families should be informed about the overall outcome when they are asked to make decisions about life support.

Scenario 2: respiratory tract infection in patients with advanced lung fibrosis The same clinical situation as Scenario 1, plus fever, malaise, diaphoresis and new onset of a productive cough with yellow–green sputum strongly suggests a respiratory tract infection as complicating issue for the patient with known pulmonary fibrosis, which may easily present as emergency. It has been repeatedly reported that patients with advanced interstitial and fibrotic lung disease have a higher incidence and mortality from respiratory tract infections. Most clinicians with a special interest in treating these patients will agree with this observation. However, no study has been performed, to date, addressing this question, and publications on this subject are mostly review articles or textbook contributions, 178

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reflecting expert opinions but not confirmed scientific evidence [5, 6]. Valuable information can be drawn from the latest trials in IPF, investigating the efficacy of interferon-c and N-acetylcysteine [7, 8]. The interferon trial [7] reported that 68% of patients assigned to the interferon arm developed respiratory tract infections (upper and lower), with 15% of them suffering from pneumonia compared with 56 and 8%, respectively, amongst placebo-treated patients; no comment is made in this study on the use of antibiotic therapy. The other study [8] reported that 39% of patients receiving Nacetylcysteine and 49% of placebo-treated patients had upper or lower respiratory tract infections, with 25 and 32%, respectively, developing pneumonia. The clinical management of pulmonary infections should take into account that patients with advanced lung fibrosis are usually immunocompromised due to both the underlying disease and immunosuppressive treatment. Hence, numerous opportunistic infections, such as Pneumocystis carinii, fungi and cytomegalovirus must be considered. Furthermore, advanced fibrotic lungs have a high incidence of (clinically unapparent) bronchiectasis, possibly colonised with Gram-negative bacteria and Pseudomonas [9]. Pulmonary infections in patients with fibrotic lung disease have to be viewed as emergencies, and multidrug-resistant pathogens are often involved. For a detailed review of the best drugs and therapeutic regimen, please refer to the appropriate guidelines, e.g. the American Thoracic Society (ATS) 2005 guidelines on the management of complicated pneumonia [10]. At the current authors’ centre, a broad spectrum antipseudomonal cephalosporin (e.g. ceftazidime), plus an aminoglycoside or flouroquinolone, is used as empirical therapy. It is very difficult to respond to the question of ventilator support for patients with an apparent respiratory tract infection and underlying advanced lung fibrosis. The poor outcome of the patients mentioned above may not apply to this group suffering from a usually treatable and reversible complication. The current authors’ experience would support the use of short-term noninvasive ventilation, in cooperative patients to help bridge the poor respiratory reserves from an emergency situation to a more stable condition, unless significant sputum production is present as part of the infection.

Scenario 3: acute alveolitis Induction chemotherapy for a 19-yr-old patient with acute lymphoblastic leukaemia included prednisolone, vincristine and daunorubicin, and was performed uneventfully. Thereafter, central nervous system prophylaxis was scheduled with cranial irradiation and intrathecal administration of methotrexate (MTX) twice weekly. After the fourth dose of MTX, the patient developed fever, nonproductive cough and shortness of breath. Basal coarse crackles were noted bilaterally on chest examination. The patient was severely hypoxaemic, and chest radiograph revealed diffuse interstitial infiltration of both lung fields. Antibiotic treatment was initiated but the clinical course deteriorated rapidly. Mechanical ventilation was required. An open lung biopsy disclosed acute diffuse alveolar damage with septal oedematous thickening, inflammatory cell infiltration, and hyaline membrane formation along the alveolar walls. The patient was treated with methylprednisolone (160 mg?day-1) for MTX-induced lung injury. A dramatic resolution of pulmonary infiltrates was shown on chest radiograph within 2 days. The patient was successfully weaned from the ventilator 4 days after the administration of corticosteroids [11]. Acute alveolitis and interstitial pneumonitis can develop as a response to numerous agents. Cases of acute respiratory failure after intrathecal administration of MTX are fortunately rare events. By the year 2000, 123 cases of MTX lung were recorded in the literature [12]. The onset of symptoms is usually insidious, with dry cough, fever, dyspnoea and hypoxaemia. The ILD can rapidly progress and acute respiratory failure 179

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with an adult respiratory distress syndrome-like picture can develop; this is more frequently seen after intrathecal administration of the drug. The pneumonitis can occur hours after the initial dose, or after years of chronic treatment. There is no dosedependent response. Nitrofurantoin, b-blockers, carbamazepine, docetaxel and anorectic drugs (fenfluramine) are amongst other drugs that are known to cause acute pneumonitis (detailed information can be obtained through www.pneumotox.com). The histological findings are variable, ranging from interstitial inflammation (sometimes with eosinophilia), interstitial fibrosis, granuloma formation, and type-II cell hyperplasia to acute alveolar damage with hyaline membranes. No randomised clinical trials reporting treatment of these episodes of acute ILD are available, but withdrawal of the causative drug is crucial and initiation of intravenous corticosteroid therapy appears to be beneficial in many cases. Another potential cause for acute ILD is hypersensitivity pneumonitis (HP) in response to an inhaled antigen (extrinsic allergic alveolitis). A large variety of causative antigens have been identified, and a careful history including occupational exposure is crucial in recognising them [13]. However, even if HP presents acutely, it is rarely a respiratory emergency. Symptoms include fever, chills, cough and dyspnoea with hypoxaemia; withdrawal of the patient from the offending environment and, occasionally, prednisone treatment is required to improve the respiratory problems. There is not much literature to be found investigating the outcome of patients with acute HP. One study following 24 patients with pigeon breeders’ lung disease did not report any deaths related to HP [14].

Scenario 4: diffuse alveolar haemorrhage A 53-yr-old male developed diffuse alveolar haemorrhage 3 weeks after a viral illness, with anti-neutrophil cytoplasmic autoantibody (ANCA)-positive microscopic polyangiitis. Progressive anaemia and hypoxia prompted intubation within 24 h of admission, despite two plasma exchanges, i.v. methylprednisolone and cyclophosphamide. The patient was severely hypoxic, and recombinant activated factor VII (FVIIa), 120 mg?kg-1 of bodyweight, was administered, and repeated twice at 3-h intervals. Within minutes of the first dose, oxygenation improved. The patient was eventually discharged on room air with normal renal function [15]. Diffuse alveolar haemorrhage (DAH) is in most cases caused by pulmonary small vessel vasculitis [16]. The most common diseases in this group are Wegener’s granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome, frequently associated with ANCA. Medium and large vessel vasculitis (e.g. polyarteriitis nodosa), primary immune complex-mediated vasculitis (Goodpasture’s syndrome) and idiopathic pulmonary haemorrhage, can cause similar clinical emergencies requiring rapid diagnostic work-up and treatment. Any DAH associated with the need for ventilator support has to be considered as generalised acute or severe disease according to the European Vasculitis Study Group (EUVAS) prompting aggressive immunosuppressive therapy with intravenous corticosteroids and cyclophosphamide, possibly with the addition of plasmapheresis or intravenous immunoglobulin (as reviewed in [16]). The mortality of patients such as in this scenario is as high as 30% [15]. Even if aggressive therapy halts the progression of vasculitis, side-effects are considerable [17]. It is still a matter of debate whether cyclophosphamide should be given intravenously as a highdose bolus of 0.75 g?m-2 (with a possible reduction of side-effects), or orally daily at a dose of up to 2 mg?kg-1 [18]. Sometimes additional interventions like administration of recombinant FVIIa might be helpful to stop progressive pulmonary haemorrhage and improve outcome as described in the case [15]. There are no specific protocols for 180

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ventilator support, although many centres use relatively high positive end-expiratory pressure settings to "tamponade" the alveoli and prevent further bleeding into the lumen.

Summary Acute presentation as a respiratory emergency is very uncommon for interstitial and immunological lung diseases, unless severe diffuse pulmonary or alveolar haemorrhage is involved. However, patients with chronic interstitial and fibrotic lung diseases may have low respiratory reserves so that even a seemingly mild respiratory tract infection or minor subsegmental pulmonary embolism can be too much for these patients to tolerate. Abrupt changes in the clinical state of these patients should trigger an emergency awareness in their care. Keywords: Acute alveolitis, infection, pulmonary fibrosis, pulmonary haemorrhage.

References 1. 2.

3.

4. 5. 6. 7. 8. 9.

10.

11.

12. 13.

Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142: 963–967. Saydain G, Islam A, Afessa B, Ryu JH, Scott JP, Peters SG. Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit. Am J Respir Crit Care Med 2002; 166: 839– 842. Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K. Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases. Chest 2001; 103: 1808–1812. Stern JB, Mal H, Groussard O, et al. Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for acute respiratory failure. Chest 2001; 120: 213–219. Meyer-Sydow J, Weiss SM, Buhl R, Rust M, Raghu G. Idiopathic pulmonary fibrosis: current clinical concepts and challenges in management. Semin Respir Crit Care Med 1994; 15: 77–96. Panos RJ. Therapy and management of idiopathic pulmonary fibrosis. Compr Ther 1994; 20: 289– 293. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004; 350: 125–133. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353: 2229–2242. Desai SR, Wells AU, Rubens MB, du Bois RM, Hansell DM. Traction bronchiectasis in cryptogenic fibrosing alveolitis: associated computed tomographic features and physiological significance. Eur Radiol 2003; 13: 1801–1808. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388–416. Dai MS, Ho CL, Chen YC, Kao WY, Chao TY. Acute respiratory distress syndrome following intrathecal methotrexate administration: a case report and review of literature. Ann Hematol 2000; 79: 696–699. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000; 15: 373–381. Mohr LC. Hypersensitivity pneumonitis. Curr Opin Pulm Med 2004; 10: 401–411.

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14. 15. 16. 17.

18.

Bourke SJ, Banham SW, Carter R, Lynch P, Boyd G. Longitudinal course of extrinsic allergic alveolitis in pigeon breeders. Thorax 1989; 44: 415–418. Henke D, Falk RJ, Gabriel DA. Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 2004; 140: 493–494. Frankel SK, Cosgrove GP, Fischer A, Meehan RT, Brown KK. Update in the diagnosis and management of pulmonary vasculitis. Chest 2006; 129: 452–465. Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 2003; 42: 1149–1153. de Groot K, Adu D, Savage CO. The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16: 2018–2027.

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Emergency treatment of communityacquired pneumonia M. Valencia, J. Sellares, A. Torres Dept of Pulmonology and Respiratory Critical Care Medicine, Hospital Clı´nic de Barcelona, Universitat de Barcelona, Barcelona, Spain. Correspondence: A. Torres, UVIR Hospital Clinic Servei de Pneumologia, Villarroel 170, 8036 Barcelona, Spain. Fax: 34 932279813; E-mail: [email protected]

Community-acquired pneumonia (CAP) is a frequent cause of emergency room (ER) visits, and, although its diagnosis is usually straightforward, certain aspects, such as the evaluation of severity and choice of antibiotic treatment, influence the progress of the patient. Other factors of great importance in CAP treatment are respiratory insufficiency and the associated sepsis treatment. In this chapter, the authors discuss some new and/or controversial aspects of CAP.

Diagnostic methods The diagnosis of CAP is not usually difficult. Patients generally present acute manifestations of general malaise, dyspnoea, cough with purulent expectoration and compatible auscultatory findings. Posteroanterior and lateral chest radiography is a valuable tool in the diagnostic approach of patients with CAP and aids in establishing a definitive diagnosis, as well as in determining the extent of parenchymatous involvement, and other possible coexisting conditions, such as pleural effusion or bronchial obstruction. Some patients may be admitted to hospital with a diagnosis of CAP but with normal chest radiographs. Basi et al. [1] evaluated 2,706 patients with CAP. Onethird of the patients suspected of having pneumonia and admitted to hospital did not have pneumonia. The characteristics were similar among admitted patients irrespective of radiographic findings, although patients without pneumonia on chest radiograph were older and had greater pneumonia-specific severity-of-illness scores. Patients without radiographic images had similar rates of positive sputum and blood cultures. In-hospital mortality was similar to that of patients with infiltrates. The authors concluded that the absence of radiographic findings should not supercede clinical judgment and empirical treatment in these patients. The usefulness of sputum culture in guiding microbiological diagnosis of CAP is controversial as they have poor sensitivity and specificity. However, in a cohort of 1,669 patients with CAP, Garcia-Vazquez et al. [2] found an acceptable diagnostic yield for the identification of Gram-positive diplococci in the sputum culture to predict Streptococcus pneumoniae. The sensitivity, specificity, positive predictive value and negative predictive value were 60%, 98%, 91% and 85%, respectively. It is important to note that good quality sputum could be obtained in only 14% of patients. In summary, chest radiography, blood cultures, Gram and sputum cultures and, when available, Legionella and pneumococci urinary antigen tests should be performed in all patients admitted to hospital. This diagnostic approach should be carried out in patients Eur Respir Mon, 2006, 36, 183–199. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2006; European Respiratory Monograph; ISSN 1025-448x.

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in whom a microbiological study is performed due to suspicion of infection by multiresistant bacteria and who may be treated on an outpatient basis.

Severity evaluation of the patient Once the patient has been diagnosed with CAP, the next step is to evaluate its severity and the risk of a poor outcome, which has implications about where the patient must receive treatment, the diagnostic tests to be performed and the initial, empirical treatment. The choice of location where the patient is going to be treated (ambulatory or inhospital) is the first and most important decision in the initial evaluation of a pneumonia patient. The consequences derived from this evaluation are significant and determine the thoroughness of the subsequent examinations, the antibiotic treatment, the cost of the treatment, and the monitoring and security of the patient. This decision must be based upon the identification of diverse risk factors (clinical, analytical and radiological) that are associated with a poor prognosis or increase in the mortality rate for pneumonia and that necessitate treatment in a hospital setting. A recently published trial by Sin et al. [3] demonstrated among patients with CAP that in-hospital mortality was greater in those with hypocapnia or hypercapnia (adjusted odds ratio (AOR) 1.8–2.6). Thus, the measurement of arterial carbon dioxide tension provides prognostic information and may be used for clinical purposes to stratify the risk. Table 1 shows risk factors for a complicated course according to the American Thoracic Society (ATS). The

Table 1. – Factors for a poor prognosis in community-acquired pneumonia Epidemiological and comorbid factors Age w65 yrs COPD or other pulmonary disease Cardiac insufficiency Chronic renal insufficiency Liver disease Diabetes mellitus Alcoholism Malnutrition Immunosuppression (including systemic corticosteroids) Suspicion of aspiration Hospitalisation in the last year Previous splenectomy Findings from the physical examination Temperature w38.3uC Respiration rate w30?min-1 Systolic pressure v90 mmHg or diastolic v60 mmHg Mental status altered Extrapulmonary compromise (septic arthritis, meningitis, etc.) Radiological findings Multiple or bilateral lobes affected Cavitation Pleural effusion Laboratory findings Leukocytosis w306109?L-1 or leukopenia v46109?L-1 Haematocrit v30% or haemoglobin v9 g?dL-1 Pa,O2 v60 mmHg or Sa,O2 v90% breathing air at atmospheric pressure Creatinine w1–2 mg?dL-1; BUN w20 mg?dL-1

COPD: chronic obstructive pulmonary disease; Pa,O2: arterial oxygen tension; Sa,O2: arterial oxygen saturation; BUN: blood urea nitrogen. 184

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recommendations of the ATS advise the admission of patients with multiple risk factors. Since the clinical evaluation of the severity of the patient depends on the experience of the physician (the seriousness of the pneumonia is typically overestimated), diverse predictive models have been developed which, although not designed specifically to define the need for hospitalisation, can help the clinician to identify patients with a poor prognosis early. The purpose of these rules is to support the decision of the clinician and should not be used to substitute them.

The PORT Study The Pneumonia Outcomes Research Team (PORT) study, published by Fine et al. [4], developed the Pneumonia Severity Index (PSI), the main objective of which is the identification of patients with CAP who are at low risk for mortality within 30 days and whose treatment can be performed on a outpatient basis or with a short period of observation in the ER (table 2). Additionally, it separates patients into five groups according to risk of death. Initially, patients with the lowest risk of death (Group I) are identified, based solely on the information provided by their clinical history and physical examination, including: 1) patients aged v50 yrs; 2) without comorbidity (neoplasia, cardiac insufficiency, renal insufficiency, hepatic insufficiency or cerebral-vascular disease); and 3) no clinical indications of severity (alterations in consciousness, pulse rate Table 2. – Pneumonia Outcomes Research Team risk scale# Risk characteristics

Points assigned

Age Males yrs Females yrs Nursing home residence Neoplastic disease Hepatic disease Congestive cardiac insufficiency Cerebrovascular disease Renal disease Reduction in level of consciousness Respiratory rate w30?min-1 Systolic pressure v90 mmHg Temperature v35uC or w40uC Pulse w125?min-1 Arterial pH v7.35 BUN w30 mg?dL-1 Naz v130 mmol?L-1 Glucose w250 mg?dL-1 Haematocrit v30% Pa,O2 v60 mmHg Pleural effusion #

-10 z10 z30 z20 z10 z10 z10 z20 z20 z20 z15 z10 z30 z20 z20 z10 z10 z10 z10

: The final score of each patient is the total sum obtained according to the scale. Patients are assigned to the following: Group I: patients aged v50 yrs, without comorbidity and no clinical indications of severity; Group II: score 70, clinical treatment; Group III: score 71–90, brief admission for observation; Group IV: score 91–130, hospital admission; Group V: score w130, hospital admission. BUN: blood urea nitrogen; Pa,O2: arterial oxygen tension. 185

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i125?min-1, respiratory rate i30?min-1, systolic blood pressure v90 mmHg, and temperature v35uC or i40uC). In this group of patients (risk class I) the risk of death is between 0.1 and 0.4%, and treatment as an outpatient is recommended. In the second step, the patient is classified into categories II through V depending on whether the patient is aged w50 yrs, has comorbidities or has abnormal findings in the physical examination or laboratory tests. In-hospital treatment is recommended for groups IV and V (risk of mortality 9% and 27%, respectively), while patients in category III are candidates for a brief admission to an observation unit given that the risk of deterioration is greater in the first few hours of the initiation of the disease. Patients in group II can be treated on an outpatient basis. Among the limitations of the index is the great weight placed on the patient’s age in the final scoring, which could hide important risks in younger patients and vice versa. The clinician should also value the importance of the psychosocial conditions of the patient, which can limit outpatient treatment despite a low-risk score. In regard to social comorbidities influencing hospital admission, Goss et al. [5] evaluated the clinical characteristics, healthcare costs and resource utilisation of patients with low-risk CAP at an urban hospital. Of 425 patients, 253 (60%) were classified as PSI class I–III. Of these patients, only four died during admission and 138 patients (55%) could potentially have been treated as outpatients. However, 49% of these patients had a history of alcoholism, 20% had blood alcohol levels w50 mg?dL-1 and 44% were homeless. All patients with hypoxaemia (defined as an arterial oxygen saturationv90% or an arterial oxygen partial pressure of v60 mmHg in a patient breathing room air) or severe haemodynamic instability should be admitted no matter what PSI group they belong to. Other indications for admission are metastatic or suppurative complications of the infection, such as empyema or bacterial endocarditis. High fever, tachycardia, female sex, AfricanAmerican race and medical insurance coverage were determinants for admission among low-risk CAP patients in another study [6]. All these data demonstrate that although the PSI is useful in the decision of whether a patient should be admitted to hospital, other factors, which may affect the outcome of the patient, should be taken into account. Campbell et al. [7] assessed the safety of discharging patients with CAP according to clinical guidelines based on the PSI. Of 685 patients with a PSI of v91, 1.9% were readmitted and 0.76% died within 30 days of the ER visit. The current study corroborates the utility of PSI to safely discharge patients in risk classes II or I.

British Thoracic Society algorithm Although the PSI has been validated by multiple studies, its application is very complex and it is impractical at most levels of care. Moreover, it prioritises the identification of low-risk patients. Therefore, the British Thoracic Society (BTS) has derived and validated various rules [8] for the prediction of the severity and identification of patients with severe pneumonia. Based on the original rules (BTS I and II), the modified BTS rules have been derived. Also known as CURB, it is based on the following variables: 1) confusion; 2) urea concentration (w7 mmol?L-1); 3) respiratory rate (i30?min-1); and 4) blood pressure: systolic pressure ƒ90 mmHg. The mortality risk is based on the number of variables present in the patient, being 1.4% for patients with none of the above variables (score 0) and 5.4, 14.2, 32.9 and 14.3% for patients with 1, 2, 3, or all variables, respectively. Besides CURB, another predictive rule named CURB-65 has been validated which simply adds age to the previous list (i65 yrs) [9]. The mortality risk of these patients varies from 0.7% (score 0) to 40% (score 4). It allows the categorising of patients with pneumonia into three groups: Group 1, score 0 or 1, low mortality (1.5%); Group 2, score 2, 186

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Prognostic factors: Confusion Urea concentration >7 mmol·L-1 Respiratory rate >30·min-1 Blood pressure (systolic 500 200500

Bacterial pneumonia Kaposi's sarcoma Tuberculosis

100200

PCP Cryptococcosis Aspergillosis CMV MAC

50100 6 months

CMV EBV, VZV, adenovirus Pyogenic pneumonia Nocardia, Listeria

Fungi Candida Parasites

Mycobacteria Pneumocystis jiroveci Aspergillus Toxoplasma gondii

Fig. 3. – Time-dependent course of infections in patients after transplantation. HSV: Herpes simplex virus; CMV: cytomegalovirus; EBV: Epstein–Barr virus; VZV: varicella–zoster virus; HBV: hepatitis B virus; HCV: hepatitis C virus.

cytomegalovirus (CMV) infection, which is a major threat for the transplant patient. The classical period for the manifestation of CMV disease is the second phase after transplantation (3–6 months), particularly in high-risk patients with CMV "mismatch" (donor seropositive/recipient seronegative), if no prophylaxis regimens are used. Since many patients now receive chemoprophylaxis with ganciclovir during the first few months, the manifestation of CMV disease has become increasingly postponed to later periods (w6 months) post-transplant [13, 14]. In addition, rejection episodes requiring intensified immunosuppression play a permissive role. Although CMV is still the most important virus affecting immunocompromised patients, recent studies using molecularbased diagnostic tools show that respiratory viruses are also the cause of high morbidity and mortality [15]. In patients with haematological malignancies, the duration of neutropenia is the key point for calculating the risk of opportunistic pathogens, especially with regard to aspergillus infections (fig. 4). The incidence of invasive fungal infections has increased in most studies during the past two decades. Clinical and microbiological factors have been characterised by the European Organization for Research and Treatment of Cancer/ Mycoses Study Group in an attempt to better graduate the risk of invasive pulmonary aspergillosis [16]. Again, this risk is modulated by antifungal prophylaxis [17] and exposure of the host to increased concentrations of moulds in the ambient air. In addition, other fungal infections have to be increasingly considered in the differential diagnosis of pulmonary infiltrates [18].

Radiographic presentation The chest radiograph is undoubtedly the most important screening method for pneumonia in the immunocompromised host. However, chest radiography has several shortcomings in this context. First, the specificity of radiographic patterns is low due to 202

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100

Risk of infection %

80 Aspergillus spp.

60 40 20 0

Yeast 0

10

20

30

40

Duration of neutropenia days Fig. 4. – Incidence of invasive fungal infection during neutropenia.

the unusual presentation of infections observed in this patient population. In general, focal consolidations are more frequently seen in bacterial and fungal infections, whereas diffuse bilateral infiltrates are more characteristic for CMV pneumonia, PCP or druginduced pneumonitis [19, 20]. However, these findings are not at all specific and should not lead to presumptive radiological diagnoses without an effort for pathogen detection. In a study by experienced radiologists evaluating how often opportunistic infections were correctly predicted from the radiographic pattern, disappointing results emerged ranging from 25% (CMV infection) to 38% (aspergillosis) with the single exception being PCP in AIDS patients, which was correctly classified in most cases [21]. Secondly, and more importantly, the sensitivity of the chest radiograph is decreased in the early phase of disease. Thus, 8–20% of pneumocystis pneumonias in AIDS patients are not detected on chest radiographs in spite of clinical symptoms and positive bronchoalveolar lavage (BAL) findings [22, 23]. Delayed radiographic manifestations are also observed in invasive pulmonary aspergillosis in neutropenic patients. Timely diagnosis and treatment is of paramount importance for the prognosis of this disease. The advantages of computed tomography (CT) scanning in this respect have been demonstrated previously [24, 25]. A large clinical study comparing chest radiography to CT scanning showed that 60% of CT scans performed in patients with negative radiographs had already revealed pulmonary infiltrates suggestive of fungal infection. Thus, the time gain for the diagnosis of pneumonia by performing CT was 4 days when compared with plain radiography [26].

Pathogen-detection methods Is sputum detection worthwhile in pneumonia in the immunocompromised host? In a large mixed population of HIV-negative immunocompromised patients, Rano et al. [6] showed that the sensitivity of distal respiratory sampling by bronchoscopic and nonbronchoscopic techniques (the latter mainly conducted in intubated patients) had a favourable diagnostic yield of 50–62% compared with noninvasive methods (fig. 5). However, sputum analysis can be helpful if microorganisms are isolated which do not normally colonise the oropharynx, such as Mycobacterium tuberculosis or Legionella spp. In particular, induced sputum is successfully used for the diagnosis of PCP, mainly in 203

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70 60 Sensitivity %

50 40 30 20 10 0

BC

Sputum CMV-Ag TBAS

FBAS

BAL

PSB

Fig. 5. – Sensitivity of diagnostic techniques in non-HIV patients (modified from RANO et al. [6]). BC: blood cultures; CMV: cytomegalovirus; Ag: antigen; TBAS: tracheobronchial aspirate; FBAS: fibrobronchial aspirate; BAL: bronchoalveolar lavage; PSB: protected specimen brush.

HIV care centres, before proceeding to bronchoscopy. In a recent meta-analysis, Cruciani et al. [27] concluded that in developed countries some invasive procedures may be avoided by starting with sputum induction for the diagnosis of PCP. However, in patients under chemoprophylaxis, the probability of PCP decreases and the sensitivity of sputum is considerably lower resulting in more modest outcomes [28]. Bronchoscopy has the additional advantage of clarifying the differential diagnosis with respect to disorders not accessible to sputum evaluation (e.g. CMV infection, drug-induced pneumonitis, cryptogenic organising pneumonia) and to polymicrobial infections, which are frequent in immunocompromised patients [7, 13].

Bronchoscopy: BAL versus transbronchial biopsy or both? In a population consisting mainly of patients under chemotherapy for malignancy or rheumatological diseases, fibreoptic bronchoscopy showed a diagnostic yield of 56.2% [8]. In HIV infection and transplant patients, the diagnostic yield of BAL has been shown to be in a similar range [14, 29, 30]. In neutropenic patients who are frequently heavily pre-treated, pathogen detection rates may be considerably lower [31, 32]. The decision whether BAL is sufficient for diagnostic purposes or whether transbronchial biopsy (TBB) should be additionally performed has to be made in the light of the radiographic distribution of infiltrates, pre-existing prophylaxis regimens, and calculation of the microorganisms expected. BAL alone has an excellent yield for Pneumocystis jiroveci in AIDS, approaching 90% in patients without PCP prophylaxis [33, 34]. This rate drops significantly in patients undergoing chemoprophylaxis [35, 36] or in HIV-negative patients; in the latter, this is due to the lower number of pathogens present in the alveolar compartment [37]. Under these circumstances, multiple-site BAL [38] or a combination of BAL, preferentially from the upper lobes, and TBB may be the procedure of choice [34, 36]. In contrast, BAL has a low detection rate ofy50% for Aspergillus fumigatus [39, 40] even under optimal conditions. Therefore, TBB should be primarily considered when Aspergillus is a concern [41]. Conversely, the detection of bacterial pathogens in biopsies is problematic regarding the scattered distribution of bacterial foci in the lungs and the possibility of nonspecific fillings. In contrast, a quantitative BAL culture yielding a respiratory pathogen in concentrations i104 colony-forming units (cfu)?mL-1 or a 204


protected specimen brush (PSB) with i103 cfu?mL-1 [20, 42, 43] remain the best standardised evidence for bacterial infection in this patient population. The diagnostic yield is lower in patients who have been pre-treated with antibacterial substances [44]. Sampling error may be the explanation for the comparatively low sensitivity of the PSB for cultivating bacterial pathogens in some studies [6]. In addition, fastidious and slowly growing pathogens, such as Nocardia spp. [45], may be missed if nonsterile materials, such as BAL, are exclusively used for diagnosis, particularly when the transfer to the microbiological laboratory is delayed. Mycobacteria can be easily identified from respiratory samples, including sputum, if sufficient quantities of bacilli are present as is the case in patients with large cavities. However, in immunocompromised patients, atypical presentations with noncavitating or miliary infiltrates are more frequently observed [46], which may result in a lower yield of respiratory culture. Thus, TBB [41] or needle-aspiration biopsy [47] are helpful procedures in patients with smear-negative samples. Regarding herpes viruses, the diagnosis of CMV pneumonia cannot be proven by qualitative detection of the organism in respiratory fluids alone, since virus shedding in immunocompromised patients is a frequent event in the absence of disease [48]. This leads to a low predictive value of BAL for the diagnosis of CMV disease in patients with pulmonary infiltrates, particularly in AIDS patients. Therefore, the clinician has the choice between a specific diagnosis made by TBB demonstrating tissue infection with typical "owl eyes" cells, and a presumptive diagnosis with a positive PCR from blood or BAL in patients at risk after exclusion of relevant differential diagnoses. CMV PCR should be evaluated quantitatively with a threshold for apparent disease clearly defined by the laboratory [49–51]. There is some recent evidence suggesting that PCR detection in BAL may be superior compared with blood, or when quantitative cultures from cell and supernatant fractions of BAL are analysed, but these findings await further confirmation [52–54]. Taken together, in many cases a combined diagnostic approach using bronchoscopy with BAL and TBB may be advisable in an attempt to avoid repeated investigations when considering the need for a rapid clarification of infectious versus noninfectious aetiology and identification of the causative microorganism(s) [6]. Thus, Cadranel et al. [34] were able to classify 26 out of 29 cases of pneumonia in HIV-positive patients correctly by the combined approach with BAL and TBB, whereas eight diagnoses would have been missed by exclusively performing BAL or TBB. Surgical lung biopsy was needed in only three out of 29 cases [34].

A new diagnostic tool: transthoracic CT-guided fine-needle aspiration biopsy in focal lung lesions Before proceeding to surgical biopsy, CT-guided fine-needle aspiration biopsy (FNAB) may be considered as a less invasive option in patients with negative results for bronchoscopy and peripheral focal lung lesions [47, 55]. In a study of 71 cancer patients with peripheral lesions, a definitive diagnosis was reached by this procedure in 71.8%, with 20% of these being of infectious origin. In the majority of these cases, mycobacterial and fungal infections were found, thus highlighting the difficulties of bronchoscopic identification of these aetiologies [47].

What place remains for surgical lung biopsy? Three decades ago, open lung biopsy (OLB) was the diagnostic standard for opportunistic pneumonia. At present, the high yield and technical standard of less 205

H. KOTHE, K. DALHOFF

invasive techniques has led to a sharp decline in the use of OLB for this indication in most centres. However, there remains a group of patients without a clear diagnosis after extensive work-up by bronchoscopy and noninvasive methods. Before proceeding to OLB, the clinician should assess if the results of the procedure can be expected to influence the prognosis of the patient. The decision may be easier if the procedure is associated with a therapeutic benefit, as in neutropenic patients with a suspected diagnosis of aspergilloma [56]. A recent study by White et al. [57] (from a large cancer centre) suggests that a specific diagnosis may be obtained in 62%, with about one-third of these being infections, inflammatory disorders or recurrence of malignancy in the lungs, respectively. The probability of arriving at a useful result was greater in patients with focal infiltrates compared with patients with a diffuse radiographic pattern [57].

Risk/benefit ratio of invasive procedures in immunocompromised patients with pulmonary infiltrates Table 1 shows the average risk of complications from bronchoscopic and transthoracic procedures. The most common adverse event is fever, which occurs in 3–50% of patients and is typically not related to infection [58]. In recent studies, BAL was associated with a transient but significant drop in arterial oxygen saturation (Sa,O2) [59], which had to be supported by short-term ventilation due to respiratory failure in 2% of patients [8, 60]. Minor bleeding was the most common complication during bronchoscopy which was self-limited in most cases [31]. Whereas all procedures have a considerable morbidity, mortality is increased after biopsy, ranging from 0.2% in TBB to 5% in OLB [47, 57]. The risk of OLB has declined with the advent of video-assisted thoracoscopy; however, in this severely compromised patient population, an increased risk of coagulation abnormalities, and of pneumothorax and nosocomial superinfections, has to be anticipated, all of which have been documented in association with invasive diagnostic procedures. In contrast, recent studies demonstrate that a late diagnosis or failure to identify the aetiology is a negative survival factor in immunocompromised patients with pulmonary infiltrates [5]. Moreover, several studies have demonstrated changes in antimicrobial treatment according to the results of invasive testing in a considerable proportion of patients [6, 30, 31, 57]. Therefore, the challenge is to reach a specific diagnosis rapidly with the procedure best tolerated by the individual patient. In patients with febrile neutropenia, a primarily empirical treatment strategy is established [61]. However, in the presence of lung infiltrates, the risk of serious infections (e.g. with fungi) rises [32, 62]; as a result, invasive evaluation should be considered on an individual basis. For the management of non-neutropenic HIV-negative patients (fig. 6), and for HIV-positive persons with pulmonary infiltrates (fig. 7), the following algorithms for the clinical management are proposed. Empirical treatment should be started immediately after invasive testing and should be corrected according to the results. Table 1. – Risk of complications from bronchoscopic and transthoracic procedures

BAL TBB FNAB OLB

Morbidity %

Mortality %

v1–15 2.5–8.1 15–46 8–33

v0.01 v0.2 1.4–3.6 1.6–5

BAL: bronchoalveolar lavage; TBB: transbronchial biopsy; FNAB: fine-needle aspiration biopsy; OLB: open lung biopsy. 206


Pulmonary infiltrate Noninvasive investigations Empirical therapy

-

Bronchoscopy+BAL/TBB

+

-

+ Pathogendirected therapy

No further investigation

Open lung biopsy or FNAB + Pathogen-directed therapy

Fig. 6. – Algorithm for the clinical management of HIV-negative patients with neutropenia with pulmonary infiltrates. z: positive result; -: negative result; BAL: bronchoalveolar lavage; TBB: transbronchial biopsy; FNAB: fine-needle aspiration biopsy.

CD4 cells >200·mm-3

Bacterial pneumonia suspected

Sputum

Empirical therapy -

+ Pathogen-directed therapy

Induced sputum

Mycobacteriosis suspected

CD4 cells

Respiratory Emergencies (Monograph of the European Respiratory Society)

Respiratory Diseases in Infants and Children (European Respiratory Monograph)

Clinical Exercise and Testing (European Respiratory Monograph)

Immunopharmacology of Respiratory System

Respiratory System

Respiratory System

Respiratory Physiology: The Essentials

Respiratory Physiology: The Essentials

Respiratory Critical Care

Pulmonary Respiratory Therapy Secrets

Oxford Handbook of Respiratory Medicine

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