9 Acute respiratory distress syndrome

9 Acute respiratory distress syndrome KLAUS LEWANDOWSKI K O N R A D J. F A L K E

Ashbaugh et al (1967) coined the term 'acute respiratory distress syndrome', or ARDS, for a syndrome they observed in 12 out of 272 consecutive adult patients receiving respiratory support in their intensive care unit. The clinical pattern included severe dyspnoea, tachypnoea, cyanosis that was refractory to oxygen therapy, loss of lung compliance and diffuse alveolar infiltration seen on chest X-ray. The American-European Consensus Conference on ARDS (Bernard et al, 1994) recently decided that the term 'acute' rather than 'adult' should be used. This decision was made in recognition of the fact that ARDS is not limited to adults. Non-uniformity in the use of the term goes back to an article by Petty and Ashbaugh (1971), in which 'adult' was used instead of 'acute' as part of the term. During the past 28 years, ARDS has been defined differently for the purposes of research, epidemiology and individual patient care (Ashbaugh et al, 1967; Bone, 1978; National Heart, Lung and Blood Institute, 1979; Bell et al, 1983; Frikker et al, 1992; Sloane et al, 1992; Lewandowski et al, 1993, 1995a; Hickling et al, 1994). The definition of ARDS should include only the most severe cases of low-pressure permeability pulmonary oedema. As it is crucial to have a uniform definition for all these areas, the above mentioned American-European Consensus Conference on ARDS (Bernard et al, 1994) recommended the use of the following criteria: 1. 2. 3. 4.

acute onset; ratio of arterial oxygen tension to fraction of inspired oxygen (Pao2/Fio2) <26.6 kPa (200 mmHg) regardless of positive end-expiratory pressure (PEEP) level; bilateral infiltrates seen on frontal chest X-ray; pulmonary artery wedge pressure <2.4kPa (18mmHg) when measured, or no clinical evidence of left atrial hypertension.

ARDS develops secondary to a variety of insults, illnesses and risk factors. Some of the non-pulmonary conditions associated with ARDS are shock (Katzenstein et al, 1976), sepsis (Bersten and Sibbald, 1989), nonpulmonary trauma (Pepe et al, 1982; Maunder and Hudson, 1991), drug overdose (Heffner and Sahn, 1981; Vincent et al, 1985), pancreatitis (Hayes et al, 1974; Hudson, 1982; Nicod et al, 1985), eclampsia (Andersen et al, Bailli~re' s Clinical Anaesthesiology-

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1980), central nervous system disease (Ducker, 1968; Colice et al, 1984; Melon et al, 1985), emboli (Collins, 1969; Wolf and Neuhof, 1977; Riska and Myllynen, 1982), burns (Fowler et al, 1983) and massive transfusion (Collins et al, 1978; Hudson, 1982; Fowler et al, 1983). The pulmonary conditions associated with ARDS include aspiration (Shimada et al, 1979), lung contusion (Pepe et al, 1982; Frikker et al, 1992), pneumonia (Ferstenfeld et al, 1975; Fischman et al, 1978; Larsen et al, 1985; Frikker et al, 1992), infection (Hyers and Fowler, 1986), radiation (Dawes, 1979), toxic gases (Everett and Overholt, 1968; Frikker et al, 1992) and neardrowning (Fine et al, 1974; Glauser and Smith, 1975; Modell et al, 1976). Recently, knowledge about the incidence of ARDS has been updated: Whereas the National Heart, Lung, and Blood Institute (1979) estimated that, in the USA, 150 000 patients per year suffered from ARDS, reflecting an incidence of 75 per 100 000 per year, latest studies suggest that this figure is a gross overestimation. Using a computerized search strategy employing ICD-9 codes, Earle et al (1993) found that only 21 000 cases annually (10.5 per 10 000 per year) are to be expected in the USA. Thomsen et al (1993) determined the incidence of the syndrome in Utah, USA, to be 5.3-7.1 per 100 000 per year. Our own group established the incidence of ARDS in Berlin, Germany, a metropolis with 3.4 million inhabitants, to be 3.0 per 100 000 per year (Lewandowski et al, 1995a). A similar incidence of 4.5 per 100 000 per year was derived from a retrospective study in a British health district (Webster et al, 1988). An incidence of 1.5-3.5 per 100 000 per year was reported for the island of Gran Canaria, Spain, by Villar and Slutsky (1989). We recommend that citation of an incidence of 75 per 100 000 per year (or 150 000 cases per year in the USA) from the 1979 Task Force (National Heart, Lung, and Blood Institute, 1979) be abandoned. Since first described in 1967 (Ashbaugh et al, 1967), the syndrome has been associated with a high mortality. Multicentre trials, as well as studies of individual working groups from Europe and the USA, continue to report a mortality in excess of 50%. There are, however, hints in the literature that, during the past decades, survival rates in patients with ARDS may have been improving. Figure 1 presents the trends in reported survival rates of ARDS since 1966 in two treatment groups (conventionally and extracorporeal membrane oxygenation [ECMO]-treated patients). The reported survival rates in conventionally treated ARDS patients, as well as in the ECMO-treated ones, have improved, and the two have converged. Difficulties in evaluating potential improvements in the survival rate of ARDS are related to the heterogeneity and lack of definitions for the underlying disease processes, the lack of a clear-cut definition for ARDS, the various therapies applied and indistinct definitions of study populations (Bernard et al, 1994). PATHOLOGY/PATHOPHYSIOLOGY Macroscopic pathological examination of the ARDS lung shows a dark red and heavy organ. Its consistency can be compared to that of 'wet chamois

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leather'. In contrast to a lung with predominantly intra-alveolar oedema, no foamy fluid can be squeezed out, suggesting predominantly interstitial oedema. Histopathological appearances in ARDS lungs can be divided into acute and subacute or chronic changes (Nunn, 1987). In the acute stage, electron microscopy shows extensive damage to the type ][ alveolar epithelial cells. The basement membrane and the endothelium usually remain morphologically intact, although endothelial permeability is increased. Interstitial oedema is present. Alveoli are filled with protein-rich fluid, erythrocytes, leukocytes and fibrin. The exudate begins to form hyaline membranes. Intravascular coagulation can usually be observed. In the subacute or chronic stage, which develops within a few days of the onset of the syndrome, several morphological changes occur. The endothelium, epithelium and interstitial space thicken, and type I epithelial cells are replaced by type II cells, which proliferate but do not differentiate into type I cells as normal. Oedema fluid, fibres and proliferating cells markedly widen the interstitial space. After the first week, fibrosis and organization of the protein-rich alveolar exudate (hyaline membranes) develop. The hyaline membranes are characteristic of ARDS and destroy the structure of the alveoli. Pathophysiologically, ARDS is characterized by pulmonary oedema owing to injury of the capillary-alveolar membranes and increased pulmonary artery pressure. It is further distinguished by severe hypoxaemia unresponsive to the usual methods of support for respiratory failure. Hypoxaemia is caused by intra-pulmonary right-to-left shunting (Qs/QT) owing to persistent perfusion of non-ventilated alveoli. Another characteristic feature in ARDS is the low thoracopulmonary compliance (Murray et al, 1988; Petty, 1988). The lesions in ARDS lungs are not homogeneously distributed. As has been shown by computed tomography (CT) studies, the lesions are often found in dependent lung regions (Gattinoni et al, 1991b). Gattinoni et al (1992) hypothesized that the inhomogeneous ARDS lung is a mixture of three different zones: healthy (H), recruitable (R) and diseased (D). Gas exchange is accomplished only in zones H and R. Based on this assumption, in adult patients with ARDS, the remaining healthy 'baby' lung (zone H plus zone R), which is 20-30% of a normal adult lung, must provide the body's whole gas exchange. ARDS is characterized not only by a low compliance, but also by high airway and tissue resistance (Broseghini et al, 1988; Wright and Bernard, 1989; Eissa et al, 1991). DIAGNOSIS

The differential diagnosis of ARDS includes extensive pneumonia and cardiac pulmonary oedema. In both ARDS and pneumonia, the pulmonary capillary wedge pressure (PCWP) is normal; in cardiac pulmonary oedema, PCWP is elevated and its measurement can guide diagnosis and therapy. The diagnosis of ARDS rests on the constellation of anamnestic, clinical, radiological, laboratory, lung mechanical and haemodynamic findings and their development and progress over time. Usually a catastrophic event

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(insult, illness or a risk factor) precedes the development of ARDS. Typical findings on physical examination are cyanosis, dyspnoea and tachypnoea. Hyperventilation (with hypocarbia) persisting after the initial injury is one of the first signs of respiratory difficulty. Later in the course, blood gas analysis reveals profound hypoxaemia and hypercapnia. Supplemental oxygen does not result in marked improvement of the arterial oxygen tension. The increased alveolar-arterial oxygen gradient reflects the increased Qs/QT, characteristic for ARDS. Radiological appearance is one of the basic criteria for diagnosis of ARDS. The definitive radiological pattern appears 12-24 hours after the onset of clinical symptoms and is characterized by poorly defined alveolar infiltrations throughout both lung fields. The pattern resembles that of acute pulmonary oedema but without cardiomegaly, pulmonary vascular redistribution or pleural effusion. Subsequently, the alveolar infiltrates increase and melt into one another, giving the typical 'whitening out of the lungs'. Involvement of one lung only has occasionally been described. During the past few years, the CT scan has gained importance in studying ARDS lungs. New insights derived from CT studies of ARDS lungs have led to a reconsideration of the pathophysiology and morphology of the syndrome and have influenced its therapy. In particular, the CT can visualize the inhomogeneity of lung parenchymal lesions. CT studies performed by Gattinoni et al (1991a) and Maunder et al (1986) have demonstrated that the lung densities in ARDS are primarily located in dependent regions. The specific distribution pattern of lung densities cannot be seen by the conventional anterior-posterior chest X-ray, which shows a bilateral diffuse increase of densities ('white lungs'). In addition, the CT scan can help in detecting localized pathological features that are difficult or impossible to detect by anterior-posterior chest X-ray, such as pneumothoraces in either the dorsal or ventral regions of the lung, pleural effusions, abscesses and bullae. In ARDS, the CT scan is of value for the determination of lung weight in vivo. This information helps accurately to determine the severity and distribution of ARDS damage and assists treatment planning. Figures 2 and 3 show synopses of chest X-rays and corresponding lung CTs of two patients with severe ARDS. Central venous pressure (CVP) represents fight atrial pressure or right ventricular filling pressure. Changes in CVP correlate with changes in left ventricular filling pressure in healthy persons. This correlation is no longer valid in patients with pre-existing pulmonary or cardiac disease and in those with polytrauma. Cardiac performance, blood volume, vascular tone, increased intra-abdominal or intrathoracic pressures, as well as vasopressor therapy, may influence the CVP value. In such circumstances, CVP does not correctly reflect volume status. Therefore, measured CVP values must be interpreted cautiously in such severely diseased patients. These observations suggest that the measurement of CVP is of limited value in diagnosing ARDS. Mild pulmonary arterial hypertension usually occurs in ARDS, and the degree of hypertension parallels the severity of the syndrome (Zapol et al, 1992). In ARDS, the PCWP usually is normal, while in hydrostatic

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Figure 2. Concurrent display of a chest X-ray (A) and a thoracic CT scan (B) of a 24-year-old female suffering from severe ARDS secondary to fulminant pneumococcal pneumonia. The chest X-ray was taken 30 minutes prior to the CT scan. It shows nearly complete 'whitening out' of both lungs, typical for advanced ARDS. The experienced reader will have a suspicion of a left-sided pleural effusion. In the CT scan, distinct basal infiltrations can be visualized. Additionally, a large pleural effusion becomes clearly visible. A chest tube was inset-ted and drained 1.5 litre of pleural effusion.

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pulmonary oedema it is elevated. In some ARDS patients, however, PCWP may be elevated. Possible explanations are left ventricular myocardial failure due to pre-existing coronary artery disease or acute myocarditis (Sutherland et al, 1981) or a dilated right ventricle that impedes blood flow from the left atrium into the left ventricle by a shift of the interventricular septum, with consequent elevation of the left atrial pressure (Jardin et al, 1981). Transient elevations of PCWP may go unrecognized before insertion of a pulmonary artery catheter. It is not known whether these transient elevations of PCWP frequently contribute to the development of the syndrome. Hypoxaemia in ARDS is primarily, explained by alveolar oedema and collapse, resulting in an increased Qs/QT (Dantzker et al, 1979; Gerdeaux et al, 1984; Lemaire et al, 1985). The shunt is usually so large (i.e. over 40%) that increasing the Fio 2 alone will not correct the hypoxaemia. An important objective in the diagnosis of ARDS is to assess the degree of pulmonary oedema. Increased extravascular lung water (EVLW) and increased body weight may reflect the increased vascular leak and extravascular accumulation of fluid in these patients. Measurement of EVLW by the double-indicator dilution technique, as described by Lewis et al (1982), may help to assess the degree of pulmonary oedema. Alternatively, the degree of pulmonary oedema can be assessed and quantified by careful analysis of the chest X-ray as proposed by Milne and Pistolesi (1993). Falke et al (1972) reported static lung compliance and pulmonary pressure-volume loops obtained during mechanical ventilation, showing that pulmonary compliance was reduced in ARDS. Other methods of assessing pulmonary compliance have been suggested, such as Suter et al's (1975) calculation of thoracopulmonary quasistatic compliance or determination of pulmonary compliance by Matamis' et al's (1984) method, using Janney's (1959) super-syringe technique. THERAPY

In the past, the therapy of patients with ARDS has involved mechanical ventilation with PEEP and high tidal volumes (VT) of 10-15 ml/kg body weight. Connors et al (1981) recommended a VT even higher than 15 ml/kg body weight. This form of ventilatory support was based on clinical studies by Bendixen et al (1963), who could compensate for the deterioration in oxygenation when ventilating patients with a low VT by intermittently

Figure 3. Radiological findings in the course of a 26-year-old male suffering from severe ARDS secondary to aspiration pneumonia during induction of anaesthesia for cholecystectomy. (A) CT scan taken on admission to our ICU: it shows marked infiltrations, primarily in the basal lung areas, and a pneumothorax in the right anterior pleural cavity. (B) Chest X-ray taken 2 hours later: chest tubes have been placed; the pneumothorax is no longer detectable. The X-ray shows diffuse bilateral infiltrations of the lungs. (C) CT scan taken on the patient's discharge (77 days later): infiltrations have nearly completely resolved. The patient was spontaneously breathing room air. (D) Chest X-ray taken on the patient's discharge (77 days later): the infiltrations in the chest X-ray have completely cleared.

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inflating the lung with a high VT. According to these investigators, this form of ventilatory support counteracted the formation of atelectasis. This idea was supported by a study performed by Suter et al (1978) dealing with the impact of VT on respiratory compliance. This study revealed that a value of VT ranging from 12 to 15 ml/kg body weight produced the maximal respiratory compliance in acute respiratory failure. To accomplish eucapnia, however, it was common practice to apply a high VT at a low respiratory frequency. This approach often led to high peak inspiratory pressures (PIPs). During the past 10 years, there has been strong evidence from laboratory and clinical research that this form of ventilatory support can contribute to the progression of the disease and by itself, produce acute pulmonary damage (Lachmann et al, 1980, 1982; Dreyfuss et al, 1985; Maunder et al, 1986; Kolobow et al, 1987; Dorrington et al, 1989; Dreyfuss and Saumon, 1991). High Fio2 levels have been shown to be harmful to healthy lungs (Barber et al, 1970) and can contribute to the progression of ARDS (Nash et al, 1967, 1971; Gillbe et al, 1980). Several investigators have demonstrated that a high Fio2 can induce clinically manifest lung damage, as well as pathological changes similar to those observed in ARDS (Nash et al, 1967). A correlation, however, between the application of high Fio2 and the development or progression of tung injury has so far only been conclusively demonstrated in animal studies. Studies suggest that the application of a high Fi% generates free oxygen radicals that are responsible for the observed lung injury (Gattinoni et al, 1991a; Risberg et al, 1991). During the past few years, some new and old ventilatory and other adjunctive measures have emerged that have the potential to improve pulmonary gas exchange while minimizing the above-mentioned damage resulting from classical mechanical ventilation techniques. The most promising of them will be discussed. Pressure-controlled ventilation

Pressure-controlled ventilation is a form of controlled mechanical ventilation in which approximately 'square' waves of pressure, with a defined frequency and a specified period of constant pressure, are applied. This represents the basis of several modes of mechanical ventilation recently introduced into the treatment of ARDS: pressure-controlled inverse ratio ventilation (pcCMV-IRV), airway pressure release ventilation (APRV), biphasic positive airway pressure (BIPAP) ventilation and intermittent mandatory pressure release ventilation (IMPRV). pcCMV-IRV is a method of ventilatory support that provides a prolonged inspiratory time for the stabilization of pulmonary units and diffusion of gases. The shortened expiratory phase enables an adequate Vx to escape without allowing alveoli to fall below their closing volume. Gurevitch et al (1986) suggest that because of an early and sustained inflation, IRV results in progressive alveolar recruitment with stabilization of surfactant-deficient regions. It has been known for more than 20 years that the infant respiratory dis-

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tress syndrome (IRDS) can be treated effectively by pcCMV-IRV (Reynolds, 1971). Lachmann et al (1982) demonstrated that pcCMV could improve pulmonary gas exchange in an animal model of ARDS (surfactant-depleted rabbits). Enthusiastic, but largely anecdotal, reports or uncontrolled studies followed in the adult literature (Cole et al, 1984; Gurevitch et al, 1986). In an uncontrolled study, Tharratt et al (1988) reported a mean improvement in oxygenation from 9.2 + 0.5 kPa (69 + 4 mmHg) to 10.6 + 0.6kPa (80 + 4.5 mmHg) in 31 patients with severe ARDS when pcCMV-IRV with low VT and low PEEP was compared with volume-controlled ventilation. Switching from volume-controlled conventional ratio ventilation to pcCMV-IRV resulted in a reduction of minute ventilation, PIR mean airway pressure and PEER Other authors have published similar results using pcCMV-IRV (Andersen, 1986, 1987; Abraham and Yoshihara, 1989). pcCMV-IRV can result in dyssynchrony when the patient breathes spontaneously. To obtain the most beneficial effects of this ventilatory mode in terms of gas distribution and alveolar filling, patients frequently require deep sedation and pharmacological paralysis. Current knowledge of lung mechanics implies that pcCMV-IRV generates elevated shear forces during inspiration, which may contribute to lung tissue injury, especially in the low-compliant ARDS lung. Indeed, clinicians have noted that the application of pcCMV is frequently associated with the occurrence of barotrauma (Tharratt et al, 1988; Marini, 1994; Slutsky, 1994b; Armstrong and Maclntyre, 1995). Tharratt et al (1988) reported 8 incidences of pneumothorax in 35 episodes of pcCMV-IRV; in Armstrong and Maclntyre's (1995) series of 14 ARDS patients ventilated in the pcCMV-IRV mode, 4 patients developed pneumothorax. In patients ventilated in other modes, however, the occurrence rate of barotrauma was similar, i.e. ranging from 0.5 to 20% (Kumar et al, 1973; Zwillich et al, 1974; Rohlfing et al, 1976; De Latorre et al, 1977; Petersen and Baier, 1983; Schnapp et al, 1995). A closer look at several studies using pcCMV-IRV in ARDS patients suggests that the seemingly frequent occurrence of barotrauma can be attributed to the use of high airway pressures exceeding 3.4 kPa (35 cmH20), which are currently believed to promote barotrauma (Gurevitch et al, 1986; Tharratt et al, 1988; Slutsky, 1994a; Armstrong and Maclntyre, 1995). This view is supported by the results of Lain et al's (1989) study in which pcCMV-IRV was applied to 19 patients with acute respiratory failure (12 ARDS patients and seven patients with severe pneumonia). Switching the patients from conventional intermittent positive pressure ventilation (IPPV) to pcCMV-IRV led to a reduction in PIP from a mean of 4.74 + 1.34 to 3.22 + 0.80kPa (48.3 _+ 13.6 to 32.8 + 8.1 cmH20). While several patients had required chest tubes for the drainage of pneumothoraces during IPPV, no pneumothorax occurred during pcCMV-IRV. To date, however, no study has evaluated the impact of pcCMV-IRV on the incidence of pulmonary barotrauma in ARDS patients. In 1987, APRV was added to the armamentarium of mechanical ventilation (Stock et al, 1987). APRV can be described as two levels of continuous positive airway pressure (CPAP) that are applied for fixed time periods.

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Changing between the two levels is technically achieved by a solenoid valve that directs a high fresh gas flow alternately to the positive end-expiratory valves. Spontaneous breathing is possible at both CPAP levels. APRV does not differ from pcCMV-IRV if the patient does not breathe spontaneously. APRV resembles intermittent mandatory ventilation (IMV) in that it allows spontaneous breathing between machine-cycled breaths. APRV, however, generates lower peak airway pressures (Rfis~nen et al, 1991; Valentine et al, 1991) and lower fractional dead space ventilation than does synchronized IMV (SIMV) (Valentine et al, 1991). Baum et al (1989) modified APRV for the weaning of patients fi'om volume-controlled mechanical ventilation. The idea of their so-called BIPAP ventilation was to augment the patients' spontaneous breaths by switching between a high and a low CPAP level in an adjustable time sequence. The characteristic BIPAP allows and requires spontaneous breathing on both CPAP levels. In the course of the weaning process, the phase during which the patient breathes on the lower CPAP level is prolonged stepwise. IMPRV is a combination of pressure support ventilation and APRV (Rouby et al, 1992). The pressure release during APRV occurs at a fixed frequency set by the physician, unrelated to the patient's spontaneous respiratory phase. In contrast, during IMPRV, the airway pressure release takes place in the expiratory phase of a patient-triggered pressure support breath. In patients with respiratory failure, switching from CPAP to IMPRV resulted in an increased minute ventilation and reduction of Pac% and respiratory frequency (Rouby et al, 1992). As APRV and its modifications allow spontaneous breathing, many of the negative side-effects of controlled mechanical ventilation modes, such as reduced venous return and impairment of renal and gastrointestinal tract function, can be prevented. Pharmacological muscle relaxation often is not necessary. It still has to be investigated whether the frequency of barotrauma is less with APRV and its modifications when compared with conventional forms of controlled mechanical ventilation. Patients with vigorous inspiratory efforts may generate markedly negative pleural pressures and thereby develop higher transalveolar pressure gradients than are reflected by the preset pressure levels. APRV and its modifications have been successfully applied to patients with mild-to-moderate respiratory failure (Baum et al, 1989; Rfisfinen et al, 1991; Rouby et al, 1992; Sydow et al, 1994). Recently, Sydow et al (1994) demonstrated in 18 patients with acute lung injury that, during APRV the alveolar-arterial oxygen tension gradient (A-aD%) to Fi% ratio and venous admixture improved significantly with time after more than 8 hours. These changes were not observed during 24 hours of volume-controlled inverse ratio ventilation. Currently, no data are available to explain fully the underlying mechanisms of the observed improvements. It is also unknown whether APRV and its modifications are equal or superior regarding oxygenation, side-effects on organ functions (e.g. kidney, liver and cardiovascular system) and survival when compared with established forms of positive pressure ventilation in patients with ARDS.

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Positive end-expiratory pressure (PEEP) Already in 1964, Btihlmann et al (1964) had observed that mechanical ventilation with PEEP of patients with mitral valve disease led to an increase in mixed venous oxygen saturation. These findings indicated that the application of PEEP could improve oxygen transport. Subsequently, American working groups described the beneficial effects of PEEP on functional residual capacity and arterial oxygenation in patients with acute respiratory failure (ARF) (Ashbaugh et al, 1967; Kumar et al, 1970; Falke et al, 1972). Several mechanisms have been postulated to explain the improvements in pulmonary gas exchange. The most common hypothesis is the recruitment of previously collapsed alveolar units (Ashbaugh et al, 1967; Kumar et al, 1970; Falke et al, 1972) and the reduction of cardiac output (Dantzker et al, 1980). The co-existence of severely and less damaged areas in ARDS lungs can result in further deterioration in lung function when ventilating ARDS patients with PEEP. The mechanically administered breath is distributed preferentially to the more compliant non-dependent regions of the lung (Rehder et al, 1972, 1977), while dependent lung ventilation is reduced owing to airway closure and alveolar collapse (Milic-Emili et al, 1966; Hedenstierna et al, 1976, 1981). On the other hand, perfusion, being determined by gravity, is diverted mainly towards dependent lung regions. General PEEP increases alveolar pressure, which further impedes nondependent lung perfusion (Shapiro, 1990). Gattinoni et al (1988) have visualized the beneficial effects of PEEP by CT scanning of the lung. Increased PEEP in patients with severe ARDS caused progressive clearing of radiographic densities and enlarged the mass of normally inflated tissue, while reducing venous admixture. The PEEP level that provides the greatest benefit while producing the fewest non-beneficial effects is difficult to define but must be determined. The impact of increasing levels of PEEP, beginning with 0.5 kPa (5 cmH20), on haemodynamics, pulmonary gas exchange and respiratory compliance should be tested. Current practice is to choose a PEEP level at or above the lower inflection point on the pressure-volume curve (Benito and Lemaire, 1990). In the early phase of acute lung injury, this is generally a PEEP level of between 0.8 and 1.5 kPa (8 and 15 cmH20). No data exist substantiating the concept that clinically appropriate levels of PEEP should be withheld for fear of producing barotrauma (Pepe et al, 1984; Shapiro, 1990).

Permissive hypercapnia The combination of a peak airway pressure limited to less than 2.9-3.4 kPa (30-35 cmH20) and a PEEP level sufficient to prevent alveolar collapse and airway closure may result in a small VT (5-8 ml/kg body weight). In these patients, Paco2 can often not be maintained within a normal range. A strategy termed 'permissive hypercapnia' (PHC) allows the Pa¢o2 to rise gradually despite concomitant development of a respiratory acidosis (Hickling et al, 1990; Pesenti, 1990). While acute hypercapnia potentially leads to intracellular acidosis, pulmonary hypertension, increased intracerebral blood

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flow and activation of the adrenergic system, a gradual increase in Pac% allows compensatory mechanisms to be activated. We have learned from patients with chronic obstructive lung disease that even marked hypercapnia is well tolerated if it develops gradually. In these patients, hypercapnia has been viewed as a compensatory mechanism allowing carbon dioxide elimination to be maintained on a lower level with reduced work of breathing. Pesenti (1990) suggested that an increase in Paco2 from 5.3 to 10.6 kPa (40 to 80 mmHg) leads to a reduction of required alveolar ventilation of 50%. Experience in patients with severe ARDS has shown that even quite marked hypercapnia is well tolerated if it develops gradually over days (Hickling et al, 1990). There is also a strong suspicion that ventilatory supportive techniques consisting of pressure-limited ventilation with PHC may result in a reduction of mortality in severe ARDS. Since 1984, Hickling et al (1990) have gradually adopted the policy of limiting PIP in patients with severe ARDS by reducing VT, allowing spontaneous breathing with SIMV and tolerating hypercapnia. A retrospective analysis of 50 patients with severe ARDS demonstrated a hospital mortality that was significantly lower than that predicted by the APACHE II score (16% versus 39.6%). The authors confirmed these favourable results in a prospective trial investigating another 53 patients (Hickling et al, 1994). Lewandowski et al (1995b) showed that limitation of PIP to 2.9-3.4 kPa (30-35 cmH20) in 97 ARDS patients was possible by use of a therapeutic strategy that included PHC. This approach resulted in mean maximal Pac% levels ranging from 7.7 to 9.4kPa (58 to 71 mmHg), depending on the treatment group. Recently, Amato et al (1994) demonstrated in a randomized controlled study of PHC that, in the PHC-treated group, oxygenation was improved, lower airway pressures were applied and a higher survival rate was achieved. The obvious benefits and good tolerance of PHC have led to reconsideration of the sequelae of hypercapnia. Concerns regarding hypercapnia focus on the prolonged extracellular acidosis with which it is associated. However, intracellular pH is responsible for most of the effects of acute hypercapnia (Siesj6, 1971). It is now apparent that intracellular pH returns to 90% of normal within 3 hours as a result of intracellular buffering, consumption of organic acids and cell wall proton pumps (Siesj6 et al, 1972; Hickling, 1992), whereas extracellular renal pH correction occurs slowly and remains incomplete after 3 days. The quick intracellular compensation of acid-base disorders may be responsible for the good tolerance of PHC. Consequently, in most ARDS patients treated with PHC, buffering with bicarbonate should be considered only in the presence of marked extracellular acidosis. Generally accepted contra-indications to treatment with PHC are ischaemic heart disease, hypertension and increased intracranial pressure.

Body position changes The advantageous effects of body position changes in intensive care patients have long been known. Lateral and prone positioning in patients with severe ARDS improve pulmonary gas exchange.

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Lateral position Falke et al (1972) noted that in two patients with predominantly unilateral lung disease, a significant rise in Pao2 could only be achieved by applying PEEP with the better lung in the dependent position. Later, Fishman (1981) advocated lateral positioning in patients with asymmetrical bilateral lung injuries: 'Down with the good lung'. Several investigators reported a better oxygenation in patients in the lateral position with the less injured lung down (Remolina et al, 1981; Zack et al, 1984). The likely mechanism of improved gas exchange may be improved ventilation-perfusion matching within the injured lungs. Perfusion being gravity dependent is mainly directed towards the less injured ('healthier') lung, while only a smaller fraction of pulmonary blood flow but the greater portion of V~ is distributed to the other lung.

Prone positioning Lung CTs in patients with ARDS have shown that densities appear primarily in the dependent regions of the lung, while non-dependent regions generally maintain a normal density (Gattinoni et al, 1988). Retrospective and prospective studies have examined the impact of prone positioning on pulmonary gas exchange in ARDS. Piehl and Brown (1976) reported an average improvement in Pao2 of 6.3 _+ 2.1 kPa (47 + 16 mmHg) when turning five patients from the supine to the prone position. The authors attributed the enhancement in oxygenation to an optimized ventilation-perfusion matching, reducing the alveolar-arterial oxygen gradient. Similar findings were obtained by Douglas et al (1977) when investigating the effects of prone positioning in six ARDS patients. A mean increase in Pao2 of 9.2 kPa (69 mmHg) was observed. Langer et al (1988) described a series of 12 patients with ARF in whom gas exchange effects of the prone position were variable. Recently, Gattinoni et al (1991b) conducted a prospective study investigating the effect of a supine-to-prone position change on the CT scan and on pulmonary gas exchange in 10 patients with ARE During prone positioning, dissolution of the posterobasal densities was observed, while at the same time new densities appeared in the anterior region. Although changes in the location of the densities were observed, the average density and the total amount of tissue mass were not altered. No significant changes were noted in gas exchange, or haemodynamics. However, dramatic improvements in Pao2 and Qs/QT were observed in two subjects. The CT scans in Figure 4 show resolution of basal lung densities in an ARDS patient following prone positioning. Pappert et al (1994) reported the effects of pcCMV and the prone position on ventilation-perfusion relationships in ARDS. pcCMV in the prone position resulted in an overall increase in arterial oxygenation in the 12 patients studied. In the responder group (n = 8; greater than 1.3 kPa [10 mmHg] increase in Pao2 after 30 minutes), prone positioning caused a decrease of shunt perfusion of 11 + 5% and a concomitant increase in the perfusion of lung areas with normal ventilation-perfusion ratios by 12 _+ 4% after 30 minutes. No change could be observed within areas with low ventilation-perfusion relationships.

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(A)

(B)

Figure 4. CT lung scans of a patient with severe ARDS. The CT scan displayed in (A) shows significant densities in the posterobasal 'dependent' lung regions when the patient is placed in the supine position. After 30 minutes of prone positioning a subsequent CT scan (B) shows that the densities in the posterobasal lung regions have resolved.

The redistribution of densities with prone positioning may result from alveolar collapse and/or alveolar size reduction in the dependent lung levels and alveolar reopening in non-dependent lung levels in response to variations of gravitational pressure gradients. The observed improvement in oxygenation in some patients may be explained by a redistribution of blood flow from the poorly to the better ventilated areas. Furthermore, the prone position may promote the drainage of tracheobronchial secretions and thereby prevent

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consolidation and superinfection. In spite of the fact that no studies investigating the long-term efficacy of prone positioning exist, we suggest that the prone position be tried in patients suffering from severe ARDS. Increases in Pao2 may allow Fi% and PIP to be decreased below toxic levels.

Reduction of the pulmonary oedema In patients with respiratory failure, accumulation of water in the lung may be caused by (DiCarlo et al, 1990): 1. increased pulmonary capillary pressure; 2. altered permeability of the pulmonary capillary membrane; 3. reduced plasma oncotic pressure; 4. pulmonary lymphatic dysfunction; 5. increased negative interstitial pressure. Minimizing the degree of pulmonary oedema is a mainstay in the treatment of ARDS. A study conducted by Eisenberg et al (1987) revealed that increasing amounts of lung oedema were associated with a higher mortality. Standard clinical practice is to limit left atrial pressure, reflected by the PCWP, as much as possible by limiting intravenous fluid and by the use of diuretics, haemofiltration and/or haemodialysis. Recently, measurement of the superior vena caval pressure (SCVP) has gained attention in guiding the therapy of pulmonary oedema. It has been reported that an elevated SCVP may impair the lymphatic drainage from the lungs as lymphatic vessels must pump against the SCVP. The slowed removal of interstitial fluid may contribute to the development or progression of lung oedema (Laine et al, 1986; Allen et al, 1987). In patients with severe ARDS, crystalloid solutions may result in increased EVLW, a phenomenon that occurs to a greater extent in the presence of endothelial damage. Administration of colloids is a potential hazard to the injured lung, as it may lead to an increased filtration of water and protein into the interstitium and is therefore inherently deleterious to the lung with ARDS (Shapiro, 1990). However, when applied in combination with diuretics, the administration of colloids may result in an improved A-aDo 2. Skillman et al (1970) treated patients with acute respiratory failure with concentrated human salt-poor albumin and ethacrynic acid. A strong correlation between A-aDo 2 and urine output was observed, A-aDo2 decreasing with increased urine output. Because of the high incidence of ototoxicity from ethacrynic acid, the authors proposed fmsemide as a substitute. Fmsemide has been shown to achieve a negative fluid balance, which consecutively led to an improvement in oxygenation and an increase in static compliance of the respiratory system (Bone, 1978). Although achieving negative fluid balance with frusemide is widely practised, we are not aware of any studies demonstrating its impact on the reduction of pulmonary oedema associated with an improvement in gas exchange. If this dehydration regimen fails to establish a negative fluid balance, institution of haemofiltration and/or haemodialysis should not be delayed. Several

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authors have reported the beneficial effects of this management (Bone, 1978; Barckow and Schirop, 1983; DiCarlo et al, 1990). As all these therapeutic measures bear the inherent risk of compromising renal and other organ function, they should only be established when they lead to a definite reduction of the interstitial pulmonary oedema. Regular measurements of EVLW, as well as close-meshed chest X-rays, are imperative to guide further treatment. In order to avoid hypovolaemia and to maintain adequate organ perfusion, careful fluid replacement therapy is essential. We favour the initial use of red blood cells up to haemoglobin values of 14-15 g/dl followed by an empirically based, combined application of small amounts of crystalloid and colloid solutions. A similar fluid resuscitation management is proposed by Petty (1990). There is some rationale from experimental work by Prewitt et al (1981) that the application of intravenous nitroprusside at a dosage of 5 btg/kg per minute is able to block pulmonary vasoconstriction occurring in severe lung injury and reduce the extent of pulmonary oedema. Up to now, however, no clinical studies have been available demonstrating a reduction in EVLW with this approach. The issue of fluid management in ARDS needs continued study before definitive recommendations can be made.

Differential lung ventilation (DLV) Ventilation of each lung via a double-lumen endotracheal tube can provide superior treatment in selected ARDS patients when compared with more conventional ventilation modes via a single-lumen endotracheal tube. The rationale for the use of differential lung ventilation (DLV) in patients with pronounced one-sided distribution of the lung lesions is the presence of regional differences in compliance and airway resistance (Baehrendtz et al, 1983). Being stiffer, the more diseased lung is less prone to expand during inspiration while the 'healthier' or less diseased lung is more compliant and hence better ventilated or even relatively overinflated. General PEEP increases alveolar pressure, which further decreases lung perfusion of the less diseased lung and thereby worsens the ventilation-perfusion mismatch (West et al, 1964). DVL decreases ventilation of the poorly perfused overinflated 'healthier' lung, while it increases ventilation of the poorly inflated, but better perfused 'diseased' one. There is a decline in venous admixture and a rise in arterial oxygenation, indicating an overall improvement of the ventilation- perfusion mismatch (Baehrendtz and Hedenstierna, 1984). Pulmonary lesions in severe ARDS, however, are mostly dishomogeneously distributed within both lungs: more or less healthy and compliant regions co-exist with regions of alveolar oedema and consolidation, which are possibly recruitable. In these patients with symmetrical distribution of pulmonary lesions, application of differential ventilation combined with PEEP and the lateral decubitus posture resulted in a decrease of venous admixture and an improvement in arterial oxygenation without a concomitant negative impact on cardiac output (Baehrendtz and Hedenstierna, 1984). In order to define the role of differential ventilation, Scherer (1989) reviewed the published data on the limited number of patients treated with

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this mode of artificial ventilation. The survey showed an improvement in oxygenation in 53, with survival in 33, out of 61 patients. Differential ventilation via a double-lumen tube is particularly useful in ARDS patients with asymmetrical lung lesions, especially bronchopleural fistula.

Extracorporeal respiratorysupport The first artificial device that was able to oxygenate blood and perfuse isolated organs was developed by yon Frey and Gruber (1885). Gas exchange was achieved by a continuous flow of oxygen through an inclined rotating cylinder whose inner surface was covered with a thin film of blood. Gibbon (1937) began developing the heart-lung machine in 1937 to permit open heart surgery. To substitute for the lung, he devised a system in which anticoagulated blood was directly exposed to oxygen ('film-' or 'bubble oxygenators'). However, owing to the direct contact between the blood and the gaseous phase, severe haemolysis, thrombocytopenia, haemorrhage and organ failure occurred and limited the use of this device to a few hours (Lee et al, 1961). Clowes et al (1956) developed an artificial lung that separated the gaseous and liquid phases with a membrane. This 'membrane oxygenator' provided faster and more efficient blood oxygenation with fewer complications, and became practical for cardiopulmonary bypass for more than a few hours (Kolobow and Bowman, 1963). In 1972, clinical application of membrane oxygenators in respiratory failure of newborns and adults was attempted. In that year, Hill et al (1972) reported successful so-called extracorporeal membrane oxygenation (ECMO) in a 24-year-old polytraumatized patient with ARDS. Four years later, Bartlett et al described the survival of baby Esperanza, the first newborn successfully treated with ECMO (Bartlett et al, 1976). A multicentre randomized trial in 1977 (Zapol et al, 1979) showed that venoarterial extracorporeal gas exchange with artificial lungs was ineffective in acute respiratory distress in adults (90% mortality). In contrast, venoarterial perfusion for newborns with persistent pulmonary hypertension and meconium aspiration has proved to be quite successful (Toomasian et al, 1988). The ECMO study of the National Heart, Lung and Blood Institute (1979) dampened the previous enthusiasm for extracorporeal respiratory support in adult patients, and the technique was abandoned by most groups. However, the concept of supporting impaired lung function with extracorporeal gas exchange in adults was pursued by Kolobow et al (1977). The rationale of their technique was to prevent further damage to the diseased lungs by reducing motion (pulmonary rest). Consequently, they applied only a few ventilator breaths with low VT and low PIP (lowfrequency, positive pressure ventilation: LFPPV) (Gattinoni et al, 1986). With this method, oxygen uptake and carbon dioxide removal were dissociated: oxygenation was primarily accomplished through the motionless lung (apnoeic oxygenation), while carbon dioxide was cleared through the artificial lung (extracorporeal carbon dioxide removal: ECCO2-R). The so-called LFPPV-ECCO2-R was performed at lower extracorporeal blood flows (20-30% of cardiac output), so that now a venovenous bypass

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technique sufficed, which turned out to be less harmful to blood cells, coagulation and internal organs than did venoarterial perfusion. Using this technique, Gattinoni et al (1986) reported survival rates of up to 49%. Again, there was the necessity to test the altered ECMO technique against 'advanced standard treatment'. In 1994, Morris et al published results of a randomized clinical trial. The purpose of their study was to compare pcCMV-IRV followed by LFPPV-ECCO2-R with controlled positive pressure ventilation (CPPV) in patients with ARDS. They reported that survival was not significantly different in either group (42% with conventional versus 33% with new therapy), although the overall survival rate had improved significantly when compared with results from the original US ECMO Study (National Heart, Lung, and Blood Institute, 1979). The authors recommend that the use of ECMO in the treatment of adult ARDS be abandoned. Continuous success of ECMO in Europe, however, reflected by a 51% survival rate (Table 1) raises the question of why improved gas exchange with the new therapy did not produce better survival rates in the trial by Morris et al (1994). One possible explanation is that Morris et al reported 22 bleeding complications in the patients treated with LFPPV and ECMO; ECMO had to be terminated in 7 out of 21 patients because of problems of bleeding. Table 1. Current survival of patients with ARDS managed with extracorporeal gas exchange in nine European centres (fax survey). Centre

Principal investigator

Milan and Monza/Italy Marburg/Germany 13erlin/Germany Paris/France Stockholm/Sweden Freiburg/Germany Munich/Germany Mannheim/Germany Kuopio/Finland

Gattinoni, Pesenti Lennartz Falke 13runet Bindslev Geiger Forst Quintel Takala

As of (mouth/year)

Patients (n)

Survivors (n)

Survivors (%)

12/94 12/94 12/94 12•93 12/94" 12194 12/94 12/94 12/94

98 165 49 64 26 31 21 9 6

43 97 27 27 9 15 17 4 1

44 56 55 42 35 48 81 44 17

469

240

51

Total * ECMO treatment has ceased since summer 1993.

Other authors have reported bleeding owing to anticoagulation as the major complication during extracorporeal respiratory support (Uziel et al, 1990; Anderson et al, 1993; Brunet et al, 1993). In 1983, Larm et al developed a technique in which the heparin molecule is covalently attached to synthetic surfaces, so that all blood-contacting surfaces of the extracorporeal gas exchange device can be treated. Bindslev et al (1987) reported the first long-term application of a surface-heparinized extracorporeal circuit in a 44-year-old woman with severe ARDS. Since that time, other centres have reported successful clinical application of surfaceheparinized extracorporeal circulation with no or minimal systemic heparinization (Bindslev et al, 1991; Lewandowski et al, 1994). In most

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European centres, the use of heparin-coated extracorporeal equipment has led to a clear reduction of problems with bleeding. The outcome of Morris et al's patients treated with LFPPV and ECMO might have been more favourable with the use of heparinized equipment. All studies on ECMO published during the past 27 years used various criteria for initiating extracorporeal respiratory support. However, in all the studies, the criteria used for the application of ECMO defined a state of great severity of ARDS, which may have contributed to the low survival rates in patients treated with ECMO. The improved survival rates within the last decade may be partly attributed to advanced ECMO technology and experience. As a randomized controlled trial considering these aspects is unlikely to be established in the near future, we advocate the use of prospective observational studies to further elucidate the efficacy of ECMO. Inhalation of nitric oxide (NO) Pulmonary arterial hypertension frequently accompanies the increase in vascular permeability in ARDS (Zapol et al, 1985) and is the result of a combination of three major factors: vascular obstruction, obliteration and vasoconstriction. The vasoconstrictive element in ARDS may represent a basic alteration of pulmonary vasoreactivity. In the presence of acute lung injury, attenuation of hypoxic pulmonary vasoconstriction may produce a maldistfibution of ventilation relative to perfusion, an increase in Qs/Qv and a deterioration in oxygenation. Inhalational anaesthetics, nitrates, nitro= prusside, calcium-channel blockers and bronchodilators have been shown to attenuate hypoxic pulmonary vasoconstriction (Cutaia and Rounds, 1990). In 1987, NO was reported to be an important endothelium-defived relaxing factor of vascular smooth muscle (Ignarro et al, 1987; Palmer et al, 1987). Animal studies have shown that the inhalation of NO reversed acute pulmonary vasoconstriction within 3 minutes. The systemic vascular resistance, cardiac output, left atrial and central venous pressures were unaltered by NO inhalation. No significant adverse effects were reported (Frostell et al, 1991). In patients with ARDS, the agent enables a selectively improved perfusion of ventilated pulmonary areas, making it possible significantly to improve oxygenation, thus lowering inspiratory pressure and oxygen concentrations to less dangerous levels (Rossaint et al, 1993). In our institution (Rossaint et al, 1993), 9 out of 10 consecutive patients with severe ARDS inhaled NO in two concentrations for 40 minutes each. Inhalation of NO in a concentration of 18 parts per million (p.p.m.) significantly reduced the mean pulmonary artery pressure from 4.9 kPa (37 mmHg) to 4.0 kPa (30 mmHg) and decreased Qs/QT from 36 to 31%. Mean arterial pressure and cardiac output remained unchanged. Recently, BigateIlo et al (1993) reported similar results in seven ARDS patients. Inhaling NO in concentrations ranging from 2 to 20 p.p.m, significantly reduced mean pulmonary artery pressure and increased oxygenation. Systemic haemodynamics remained unaffected. As there remains concern about tile toxic effects of NO (Norman and Keith, 1965; Stevens et al, 1972; England and Corcoran, 1974; Chiodi and Mohler, 1985; Ripple et al, 1989; Stavert and Lehnert, 1990), it is crucial

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to apply the lowest possible dose to achieve the desired effect. Gerlach et al (1993b) have shown that, in ARDS patients, effective doses for the improvement of oxygenation can be low, with a median effective dose (EDs0) of 100 parts per billion (p.p.b.). The ED50 for a reduction of mean pulmonary artery pressure was 2-3 p.p.m. Oxygenation improved at a much lower concentration than that needed to decrease mean pulmonary artery pressure. These data also suggest that individual dose-response curves are helpful to determine the dose for either improvement in oxygenation and/or decrease in mean pulmonary artery pressure in a given patient. In another study in three consecutive ARDS patients (Gerlach et al, 1993a), the authors found that the lowest effective NO dose, i.e. the dose that increased the Pao2 Fi% ratio by 30%, was 60, 100 and 230 p.p.b. respectively. Changes in mean pulmonary artery pressure were not observed. The authors concluded that improvement in oxygenation by NO inhalation in ARDS does not necessarily require the reduction of pulmonary vascular resistance. NO will have to prove its safety and effectiveness in ongoing clinical trials. Frostell et al (1991) enthusiastically expect 'a new era in the selective treatment of pulmonary vascular disease'.

OUR EXPERIENCE WITH ARDS Advanced treatment of ARDS currently consists of: 1. 2. 3. 4.

ventilatory techniques aiming at the re-establishment of impaired gas exchange, such as pcCMV, PEEP and permissive hypercapnia; adjunctive supportive measures that seek to improve the ventilationperfusion mismatch and reduce the extent of the pulmonary oedema, such as positioning manoeuvres and dehydration; inhalation of NO; establishment of ECMO for the maintenance of adequate oxygenation and gas exchange until the lungs recover sufficiently.

Each of these treatments has shown its clinical efficacy in selected populations of ARDS patients. Combined application of all these measures may be the best treatment for all ARDS patients. However, any one therapy may be beneficial in a given patient but result in further deterioration in another. No data exist substantiating the view that combined application of the cited therapeutic measures is superior to the application of selected options in a defined patient population. Challenged by this lack of information, we began in 1989 to develop a step-by-step approach that amalgamated the most promising of the above-mentioned therapeutic measures into an 'algorithm for the treatment of severe ARDS'.

Application of the algorithm (Figure 5) After admission and rejection criteria for advanced treatment have been checked, patients are transferred to our intensive care unit. Immediately

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I Rejection:

It • • • • •

Incurable disease Immunosuppression CNS-damage Chron, pulm. disease PCWP_> 2.4 kPa ( > 18 mmHg)

Admission: • ARDS as defined by Ashbaugh et al, (1967) • PaO2 -< 10.7 kPa (< 80 mmHg) at FiO2 ~ 0.6 and PEEP >- 1.0 kPa (> 10 cmH20) for 48 h Fast entry - criteria fulfilled: • PaO2/FiO2 < 6.7 kPa (< 50 mmHg), • PEEP>_ 1,0 kPa(> 10 cmH20) for _>2 h

I

Evaluation period: 24 - 120 h

1 NoImprovement

1 Improvement

I

I

~low entry - criteria fulfilled: • PaO2/FiO2 < 20.0 kPa (< 150 mmHg) • PEEP >- 1.0 kPa (_>10 cmH20) • Qs/QT_>30% • E V L W > 1 5 m I / k g B W • CTs~t-< 306 ml / kPa (-< 30 ml / cmH20) or recurrent barotrauma

Weaning

t

UnsuccessfulIq I

I

1

Successful[

I

Figure 5. Algorithm for the treatment of ARDS. For explanation, see text.

after arrival, a pulmonary artery catheter, a multilumen catheter and a femoral artery catheter for the measurement of EVLW and arterial blood pressure are inserted. A chest X-ray and, if the patient's condition is stable, a CT with special emphasis on the lungs (high-resolution CT) are obtained. We then proceed with treatment according to the algorithm. In patients meeting fast-entry ECMO criteria, venovenous ECMO (vvECMO) with heparin-coated internal surfaces is immediately instituted.

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K. LEWANDOWSKI AND K. J. FALKE Table 2. Therapeutic measures for the treatment of ARDS.

Pressure controlled mechanical ventilation

(pcCMV)

Respirator setting (Servo-ventilator 300 C or 900 C): • Pressure-controlled mode • PIP: 2.9-3.4 kPa (30-35 cmH20) * Fioz: aim at Pao: of 7.3-8.0 kPa (55-60 mmHg) • Respirator rate: 12-16/min Inspiration to expiration ratio: • Initial: 1:1 • 2:1 if no improvement in oxygenation is achieved • (consider 'auto-PEEP', reduce PEEP accordingly)

PEEP

Determination of 'best PEEP' (analysis of pressure-volume curves, results of lung CT) Avoid baro- and volutrauma

Permissive hypereapnia

Reduce PIP to 2.9-3.4 kPa (30-35 cmH20) and V T (5-6 ml/kg body weight) Allow Paco: to rise to 9.3-10.7 kPa (70-80 mmHg) arterial pH not below 7.28

Positional manoeuvres

Lateral position when asymmetrical distribution of lung lesions is present Prone position in all ARDS patients for a test period If Pao~ 1" and Qs/Qr $, positional manoeuvres should be performed twice daily for 4 hours

Reduction of pulmonary oedema

Therapeutic goals: • Haemoglobin level 14-15 g/100ml • PCWP < 1.3 kPa (< 10 mmHg) • CVP 0.7-1.1 kPa (5-8 mmHg) • Colloid osmotic pressure 3.3-3.9 kPa (25-29 mmHg) • Urine output per hour: 1 ml/kg body weight Assure success by Decrease of X-ray signs of pulmonary oedema Pao: "1",Qs/QT, ,1, Sao 2 $, extra-vascular lung water $

• Fluid restriction • Pharmacological dehydration • Haemofiltration

Special ventilatory measures

Indication for DLV: • Asymmetrical distribution of lung lesions • Bronchopleural fistula with large air-leak flow

VV-ECMO

Indication for vv-ECMO (see Figure 3) Use of heparin-coated ECMO circuit Only minimal systemic anticoagulation required: activated clotting time 130-150 seconds Extracorporal blood flow is adjusted to reduce respirator Fio~ to 0.5 Respirator setting during vv-ECMO: • PIP: 2.9-3.4 kPa (30-35 cmH20), 'best PEEP', respirator rate 6-8 per minute • Inspiration to expiration ratio: 1:1

Inhalation of NO

NO selectively improves perfusion in ventilated lung areas Dosage: 0.1-20 p.p.m. Significant improvement of oxygenation

Advanced conservative measures without vv-ECMO (Table 2) are applied to those patients not fulfilling fast-entry criteria. If the combined application of these measures does not prove to be successful, i.e. slowentry criteria are fulfilled within a timespan of 24-120 hours, vv-ECMO is established.

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Results During the time period from April 1989 to February 1995, 124 patients with severe ARDS have been transferred to our intensive care unit for advanced treatment, including vv-ECMO. The expected mortality rate in these patients was estimated to be at least 70%. We derive this figure from the European Collaborative ARDS Study (Artigas et al, 1992), which evaluates patients fulfilling entry criteria for group B (Pao2 less than 10.0kPa [75 mmHg] at an Fio2 of over 0.5 plus PEEP of 0.5 kPa [5 cmH2o]). The aetiology of ARDS in 124 patients according to mode of treatment and survival rates is shown in Table 3. Table 4 gives the number of patients treated and their survival rates according to treatment groups. With the use of our algorithm, we achieved an overall survival rate of 77% in 124 patients with severe ARDS. All of the survivors were discharged from hospital without the need for any further respiratory support. The results of our ARDS treatment suggest that higher survival rates in ARDS could be achieved by use of a clinical algorithm including ECMO. Table 3. Aetiology of ARDS in 124 patients according to mode of treatment and survival rates. Advanced treatment Without vv-ECMO

Aetiology

Total

with vv-ECMO

n"

S*

n

S

n

s

% survival

Polytrauma Pneumonia Sepsis Aspiration Pancreatitis Following major surgery Others

33 20 8 4 2 -6

32 18 6 4 1 -5

13 20 5 7 1 3 2

9 I1 1 4 1 2 1

46 40 13 11 3 3 8

41 29 7 8 2 2 6

89 73 54 73 67 67 75

Total

73

66

51

29

124

95

77

* n=number of patients treated; s=number of survivors. Table 4. Treatment of ARDS: outcome (4/89-2/95; mean age 31 _+ 15 years). Patients (n)

Survivors (n)

Survival rate (%)

Advanced treatment without vv-ECMO* vv-ECMO fast-entry vv-ECMO slow-entry

73 24 27

66 14 15

90 58 56

Total

124

95

77

* This group includes 4 patients who fulfilled slow-entry criteria but developed contra-indications to vv-ECMO. None of these 4 patients survived.

CONCLUSION ARDS is rare but carries a high mortality rate. Despite more than 25 years of research, our knowledge of the syndrome is still fragmentary, and we know little about the usefulness of our therapeutic practice in this field. It

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has never been proven beyond doubt that our currently applied therapeutic options produce more good than harm. A number of therapeutic approaches discussed in this chapter, however, suggest the potential positively to affect pathophysiological features of the syndrome and may reduce mortality rates. Specifically, pcCMV with PEEP and permissive hypercapnia, positioning manoeuvres, dehydration, inhalation of NO and ECMO have demonstrated efficacy, mostly in uncontrolled clinical studies. Clinical algorithms that include these therapeutic measures may be advantageous. Studies demonstrate a trend towards higher survival rates, and algorithms like the one described here may further improve survival.

SUMMARY

The ARDS is characterized by the presence of an acute direct or indirect damage to the lungs followed within 24-72 hours by respiratory distress, arterial hypoxaemia, reduced pulmonary compliance and diffuse bilateral infiltrates visible on chest X-ray. The incidence is low, i.e. between 3 and 10 cases per 100 000 population, but the syndrome has a high mortality of about 50-80%. Within the last years, a trend towards higher survival rates has been observed. Ventilation and other adjunctive strategies in ARDS have changed from the conventional approach aiming at normalization of physiological ventilatory parameters to an elaborated approach that attempts to protect the ventilated lung, prevent oxygen toxicity, recruit the infiltrated, atelectatic and consolidated lung, and reduce the anatomical and alveolar dead space. This new approach consists of different forms of pressure-controlled mechanical ventilation with PEEP and permissive hypercapnia, body position changes, reduction of pulmonary oedema and inhalation of NO. Should these procedures fail to improve impaired gas exchange, extracorporeal respiratory support is an additional therapeutic option. Clinical algorithms that include these therapeutic measures may help to put this new approach into clinical practice. Introduction of such an algorithm into our intensive care practice has been followed by a 77% survival rate in severe ARDS.

REFERENCES Abraham E & Yoshihara G (1989) Cardiorespiratory effects of pressure controlled inverse ratio ventilation in severe respiratory failure. Chest 96: 1356-1359. Allen SJ, Drake RE, Williams JP et al (1987) Recent advances in pulmonary edema. Critical Care Medicine 15: 963-970. Amato MBP, Barbas CSV, Medeiros DM et al (1994) Hemodynamic effects of permissive hypercarbia with high PEEP and low tidal volume in ARDS. American Journal of Respiratory and Critical Care Medicine 149: A75. Andersen HF, Lynch JP & Johnson TRB (1980) Adult respiratory distress syndrome in obstetrics and gynecology. Obstetrics and Gynecology 55: 291-295. Andersen JB (1986) Changing ventilatory strategy may alter outcome in catastrophic lung disease. Intensive Care Medicine 12 (supplement): 200A.

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