Ventilatory Support in Patients with ARDS

Symposium on Critical Care

Ventilatory Support in Patients with

ARDS Scott H. Norwood, M.D.,* and joseph M. Civetta, M.D.t

Mortality rates in patients who develop the adult respiratory distress syndrome (ARDS) remain 50 to 60 per cent in most reported series despite a decade of advancement in critical care management and respiratory therapy. This article reviews the most recent literature concerning risk factors leading to development of the syndrome and discusses current pathophysiologic theories. A survey of the various ventilatory and pharmacologic therapeutic maneuvers will be presented, emphasizing the differences between standard forms of therapy in clinical use today and other possible interventions, which, at present, must be considered for use only in experimental protocols. The adult respiratory distress syndrome-acute respiratory failure caused by diffuse alveolar injury--can be considered a final common pathway for multiple insults resulting in direct or indirect damage to the alveolocapillary interface. 26 Acute respiratory failure after trauma was reported as early as World War I, 65 but the syndrome, as it is recognized today, was not described until 1967. 1 The name "adult respiratory distress syndrome" was chosen because of the apparent clinical and pathologic similarities to infant respiratory distress syndrome. 23 Whereas the etiology of infant respiratory distress syndrome is due to inadequate surfactant production in the premature lungs of infants, the etiology of ARDS is not clearly understood. The criteria for diagnosing ARDS were described in 1967 by Ashbaugh1 and reviewed more recently by Petty. 65 The syndrome is usually preceded by a catastrophic event, such as multiple trauma, occurring in a patient with previously normal pulmonary function. Increased intrapulmonary shunting and loss of functional residual capacity because of decreased pulmonary compliance leads to hypoxemia refractory to increased *Major, United States Air Force, Medical Corps, and Surgical Director, Intensive Care Unit, Department of Surgery, United States Air Force Medical Center, Keesler Air Force Base, Mississippi tProfessor and Chief, Division of Emergency Surgical Services, University of Miami School of Medicine, Jackson Memorial Hospital, Miami, Florida All opinions stated are those of the authors and are not necessarily those of the United States Air Force.

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inspired oxygen concentrations. The diagnosis is confirmed when diffuse bilateral infiltrates are present on chest roentgenogram. Hypoxemia, tachypnea, and decreased pulmonary compliance commonly occur in trauma and surgical patients in sepsis before any signs of pulmonary abnormalities develop on chest roentgenogram. In those patients who develop these clinical signs, the syndrome might better be defined as acute respiratory insufficiency rather than "early ARDS." Because the mortality rate from ARDS is still reported to be 50 to 60 per cent2• Bl and because it is estimated that 150,000 people a year in the United States are afflicted with ARDS,68 it remains one of the leading causes of death in this country. It is not clear, however, whether all patients with ARDS die because of it or whether the primary condition (such as sepsis) should be implicated as the cause of death, with ARDS merely a complicating factor. In the early 1970s, more patients seem to have died because of progressive hypoxemia; today, patients receiving ventilatory support yet maintaining normal oxygen delivery die from a single overwhelming cause-multiple organ system failure or an untoward event (pulmonary embolus, head injury, cardiac arrhythmia, or technical complications related to a surgical procedure or intensive care monitoring or treatment). This distinction is important because many changes have been introduced in the last decade, and the apparent decrease in the number of deaths from hypoxemia may well be related to overall improvements in the intensive care unit (ICU)-new therapeutic measures, better and more available monitoring, and increased knowledge and experience. In this new era of cost containment, it will be necessary to scrutinize carefully the resources utilized in parochial therapy. When no important differences exist, the most efficient and least costly method should be preferred. Use of nursing time, the number of monitoring devices and laboratory tests, the duration of hospitalization, and outcome must all be balanced to provide effective and efficient care. Goals of therapy must be evaluated from this perspective in addition to desirability and ease of attaining objectives.

RISK FACTORS

Long lists of apparent causes and associated syndromes have previously been reported. 32, 45 • ss, 92 Many of these factors have been discussed in isolated case reports, in which a temporal relationships with ARDS has been mistaken for a cause-and-effect one. Others, such as disseminated intravascular coagulopathy, multiple blood transfusions, and various forms of nonseptic shock, may represent a constellation of related phenomena that all result from the severity of illness rather than true etiologic risk factors. Several clinical states may be classified as direct and indirect causes of pulmonary injury. The most common causes of direct injury are aspiration of gastric contents, near drowning, and inhalation of smoke or other toxic substances. Diffuse pneumonia of viral,2s mycoplasma, 29 and rickettsial71 origin have also been associated with ARDS.

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The most common indirect risk factor is systemic sepsis. 64 In a retrospective study, Fein27 showed that 18 per cent of all patients admitted to the hospital with septicemia, documented by at least two blood cultures, developed ARDS. The incidence may be even higher in patients with trauma who develop a clinical picture of sepsis, regardless of the results of blood cultures. Several studies identify sepsis as the most common factor identified leading to the development of ARDS.l 4• 33• 44 · 48, 65 This risk factor also appears to be the most ominous because the pulmonary abnormalities usually cannot be reversed unless the source for systemic sepsis can be identified and eliminated.3, 5, 21 Hypovolemic shock after trauma often occurs before the development of acute respiratory failure, but its importance as an etiologic risk factor is doubtful. In the absence of other risk factors, hypovolemic shock is rarely associated with the development of ARDS either in clinical data44 or in animal models. 45 Fat embolism secondary to release of neutral fat from long-bone fractures and subsequent conversion to free fatty acids in the lung is a definite but rare cause of acute respiratory failure after trauma. 63 Axillary, conjunctival, or retinal petechiae support this diagnosis. Severe pancreatitis and ARDS are commonly associated. In animal studies, this type of respiratory insufficiency may result from release of free fatty acids by the action of pulmonary lipoprotein lipase. 51 Pepe and coworkers64 prospectively studied 136 patients who were placed on mechanical ventilation and had at least one. of eight preselected conditions usually considered to be risk factors for development of ARDS. These risk factors were sepsis, aspiration, pulmonary contusion, multiple emergency blood transfusions, multiple major fractures, near drowning, pancreatitis, and prolonged hypotension. ARDS developed in 25 per cent of patients with only one condition, 42 per cent with two conditions and 85 per cent with three conditions. In regard to single conditions as risk factors, 38 per cent of patients with sepsis, 30 per cent with aspiration, and 17 per cent with pulmonary contusion developed ARDS. The number of emergency blood transfusions received in a 12-hour period also correlated with increased risk. Twenty-four per cent of patients who had no other predisposing factors and who received at least 22 units of blood in 12 hours or less developed ARDS in Pepe' s study. A similar study by Fowler31 showed that aspiration, disseminated intravascular coagulopathy, and diffuse pneumonia increased the risk for ARDS, whereas bacteremia alone did not. In summary, patients with systemic sepsis and direct pulmonary injury from aspiration, near drowning, and pulmonary contusion are probably at increased risk for developing ARDS. In addition, patients with severe pancreatitis and, possibly, those having multiple emergency blood transfusions should be monitored closely for early signs of respiratory insufficiency. PATHOPHYSIOLOGY

A brief review of normal pulmonary physiology should help us to understand the pathophysiology of ARDS. Normally, there are many forces

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governing the egress of water from the capillaries to the interstitium. 69· 82 Since the alveolocapillary membrane is permeable to water, the gradient of hydrostatic pressure tends to drive water out of the capillary and into the interstitium. This gradient is the difference in pressures between the pulmonary capillary and the pulmonary interstitium, which has a slightly negative pressure under normal conditions. 86 The hydrostatic pressure gradient is partially balanced by a gradient in the oncotic pressures between the blood and the interstitial fluid. Because the hydrostatic pressure gradient exceeds the gradient of oncotic pressures, the net effect is a slight flux of water from the capillaries into the interstitial space under normal conditions. Water leaves the capillaries to reach the interstitium through small clefts, approximately 40 A in diameter, located at the junction of the endothelial cells lining the capillary walls. 86 The diameter of these clefts affects the permeability coefficient of Starling's equation. An increase in pore diameter will result in an increased flux of fluid and protein from the capillaries into the interstitium. 86 What prevents a constant state of pulmonary edema? Three safety factors tend to prevent the accumulation of fluid when the flux of fluid increases86: the "washout" of interstitial protein, which lowers the oncotic pressure; elevation of the interstitial pressure toward atmospheric pressure without a significant increase in interstitial volume; and increased lymphatic flow carrying filtered fluid away from the interstitial space. These factors counteract rising pulmonary microvascular pressure (PMVP) and can prevent pulmonary edema until PMVP rises more than 20 torr. The washout of interstitial protein accounts for 50 per cent of this effect. Normally, the serum oncotic pressure is approximately 20 torr, interstitial oncotic pressure is 16 torr, and the gradient is 4 torr. If water-without protein-enters the interstitium, the protein-rich fluid there will be "diluted." The interstitial oncotic pressure will decrease, and the oncotic gradient will increase. If the interstitial oncotic pressure fell to 10 torr, the gradient would rise to 10 torr, and this elevated gradient could counteract an increase of 6 torr in the PMVP. Elevation of the interstitial pressure functions in this fashion: If PMVP were approximately 4 torr, and interstital pressure -6 torr, the hydrostatic gradient would be 4- (- 6), or 10, torr. If hydrostatic and interstitial pressures both were elevated by 6 torr, the gradient would be 10- (0), or 10, torr. The rise in hydrostatic pressure would not cause an increase in the "force imbalance"86 in the Starling forces. Finally, if PMVP rises and there is an increase in fluid flux, greater evacuation of this fluid through the lymphatics can prevent interstitial edema. This last-named factor represents 25 per cent of the margin of safety. Increased lung water can result from elevations in PMVP that exceed the capability of the safety factors, as in congestive heart failure, or from disruption of the alveolocapillary membrane, resulting in altered capillary permeability, which occurs in acute respiratory failure caused by aspiration or sepsis. Altered capillary permeability is the end result of most initiating agents of ARDS. The scenario may be as follows: The risk factors initiate poorly understood events, ultimately increasing capillary permeability.

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Enlargement of pre-existing endothelial clefts has been suggested by Brigham 9 ; animal studies of Pseudomonas sepsis suggest that the initial event is due to the action of endotoxin9 ; the release of free oxygen radicals by complement-activated polymorphonuclear leukocytes is also a popular hypothesis (see further on). As the capacity of the lymphatics for removal of filtered fluid is exceeded, interstitial hydrostatic pressure simultaneously increases. When the safety factors are overcome, interstitial fluid first accumulates in the peribronchial areas. 82 Although this fluid does not directly interfere with gas exchange, this area of the interstitium also contains the terminal bronchioles. In its earliest stages, this interstitial edema does not interfere with gas exchange either directly or indirectly. The interstitium surrounding the alveoli is much thinner, allowing for gas exchange in the normal situation. 53 If the cause for the increased permeability is not corrected, fluid continues to collect and the pressure continues to rise. The first event that creates a decrease in gas exchange is increasing peribronchiolar edema, which causes narrowing and collapse of the terminal airways. At this point, alveolar architecture and gas exchange are normal. 21 The terminal airways lie in juxtaposition to small branches of the pulmonary artery and, unlike the alveoli, lack the support of loose connective tissue. Therefore, any rise in pulmonary artery or interstitial pressure will first cause collapse of the terminal airways. As flooding of the interstitial space progresses and the ability of the lymphatics to remove the excess fluid and protein is overcome, the alveoli become flooded.I 7 Flooding of the alveoli occurs late in the disease process and should not be considered a mechanism to account for the early hypoxemia that is seen clinically. The exact mechanism that causes migration of fluid from the interstitium to the alveoli is not known.I7 Fluid in the alveoli decreases surfactant activity and destruction of Type I alveolar cells, which causes lowered alveolar surface tension and leads to alveolar collapse. Loss of alveolar volume is measured clinically as a reduced functional residual capacity. Lesser degrees of peribronchiolar edema narrow the terminal airways and restrict ventilation to their alveoli. This results in an increased number of areas with ventilationto-perfusion ('V/Q) mismatch. In other words, a large number of alveoli are perfused but poorly ventilated. This condition is expressed clinically as increased pulmonary venous admixture, or physiologic right-to-left shunt (Q,/Q 1), and hypoxemia. . Decreasing pulmonary compliance occurs early in the course of ARDS and progresses as hyaline membranes are formed from the proteinaceous exudate in the final stages. This sequence describes the physical events believed to occur at the alveolocapillary level in patients with ARDS. It is not at all clear what precipitates this chain of events, and it has been the subject of numerous investigations over the past few years. Research into a number of possible biochemical and cellular mediators of lung injury has provided a basis for several theories concerning the etiology of ARDS. Thrombocytopenia, increased Factor VIIJI 0 and Factor XIII56 activity, and complement activation have all been documented in patients with ARDS. These findings, however, may only reflect the severity of illness and not be causally linked to the lung injury itself. Many in vitro and animal studies have shown that activated granulo-

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cytes damage endothelial cells. 41 · 61 · 72, 85, 92. 93 Granulocytes can be activated by the complement system (especially C 5a), which results in peripheral leukopenia and pulmonary leukostasis. 8, 16 Endotoxins of gram-negative bacteria are also known to activate complement and produce leukopenia. 7 Pulmonary leukostasis has been demonstrated in patients with ARDS using indium-labeled granulocytes. 7 In experimental models, the damage caused by granulocytes occurs only when these cells are closely approximated to the endothelial surface of the pulmonary capillaries. The destruction is inhibited by superoxide dismutase and catalase. These enzymes are known to destroy free oxygen radicals. Thus, it has been inferred that superoxide radicals or hydroxyl ions may be involved in mediating endothelial injury. 87 In a small series of patients, Schneider73 has shown that increased platelet consumption (in the absence of sepsis or disseminated intravascular coagulation) occurs in patients with ARDS and is associated with increased platelet activity within the lung parenchyma. The rise in interstitial pressure from increased capillary permeability has also been postulated to create a relative decrease in pulmonary blood flow, promoting microthrombosis with platelet and leukocyte aggregation. 73 Activated platelets release adenine nucleotides and thromboxane A2 , one of the most powerful known vasoconstrictors in vivo. 4 The release of such vasoactive substances may explain the rise in pulmonary artery pressure that is sometimes seen with early respiratory failure, although this is not a constant clinical finding. 36 A further complicating factor is that several investigators have shown in animals that the infusion of fibrin degradation products, particularly fragment D, produce thrombocytopenia, neutropenia, and an associated respiratory failure. 54· 55 Since increased levels of fibrin degradation products are commonly seen in patients with sepsis and in those with trauma, even in the absence of disseminated intravascular coagulation, this has also been proposed as a possible initiating event in the sequence that results in ARDS. Products of arachidonic acid metabolism have been implicated as possible mediators of lung injury. When cellular injury occurs~ arachidonic acid, which is normally bound to phospholipids, may interact with phospholipase and, as a result, be released as free arachidonic acid. This acid can serve as a substrate for the genesis of many vasoactive substances, such as prostaglandin I2 (prostacyclin), a powerful vasodilator, and thromboxane ~, a vasoconstrictor. 6• 46 • 62 Arachidonate also serves as a signal or stimulus for the release of free fatty acids and leukotrienes, which have strong chemotactic activity. 30 This activity of some degradation products of arachidonate supports a hypothesis that links these substances to the presence of granulocytes and their destructive properties. Such a hypothesis has been proposed by Brigham, 7 although there are no animal or human studies to support such interactions at the present time. In summary, there is a vast amount of animal and in vitro research implicating various metabolites and platelets and leukocyte activity as possible initiators of the syndrome of ARDS. These data at present cannot be extrapolated to the clinical setting until further studies are performed. The initial event must obviously precede the development of hypoxemia. When cfinical manifestations finally become apparent, the initial cause-

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and-effect relationships may often be impossible to delineate. Present techniques used in the clinical setting are too insensitive to detect the earliest biochemical abnormalities. 7 Since a convincing hypothesis linking these experimental observations to clinical pathophysiology has not yet been made, we must rely upon mechanical maneuvers designed to improve gas exchange while we await therapy designed to block or correct the initiating causes.

TREATMENT

Research into the events leading to ARDS has thus far produced no significant changes in the clinical management of the syndrome. Positive end-expiratory pressure (PEEP) is still considered the most effective therapy for ARDS. 41, 88 Positive end-expiratory pressure has been shown to improve the diminished functional residual capacity and usually reverses the hypoxemia associated with ARDS to enable nontoxic levels of inspired oxygen to provide adequate arterial oxygenation. Despite more than 15 years of experience with PEEP, the "optimal level" or therapeutic end point is still controversial. As a general principle, however, PEEP should be carefully increased gradually and measurements made to ascertain that there have been no deleterious effects on cardiac output or oxygen transport. Hemodynamic monitoring and augmentation of cardiac output with increased preload and inotropic support have been used to prevent the occurrence of such effects. The optimal level of PEEP in terms of the patient's overall physiologic state and outcome is not known. Suter83 has defined his clinical end point as the point at which the maximal improvement in pulmonary compliance was encountered. This level was chosen because, in his series of patients, the maximal point of improvement in static compliance coincided with maximal oxygen transport; PEEP above this level caused diminished oxygen transport. Although arterial oxygen tension (Pao 2) continued to increase beyond this point, arterial oxygen content did not increase significantly, and cardiac output decreased at higher levels of PEEP. Since oxygen transport is defined as the product of arterial oxygen content and cardiac output the diminished cardiac output decreased oxygen transport. Suter did not investigate what might have happened to the compliance-transport relationship had oxygen content (by increasing hemoglobin) or cardiac output (by increasing preload or contractility) been manipulated so that higher levels of PEEP would not have had this effect upon oxygen transport. The PEEP was not raised above 15 em H 20 in any of his patients. 83 Other investigators have used the shape of expiratory pressure-volume curves to predict which patients should be treated with higher levels of PEEP. 43 Holzapfel demonstrated, in a small series, that patients in whom the expiratory compliance curve was concave responded to increasing levels of PEEP by a reduction in Q,/Q 1• If the expiratory static compliance curves were rectilinear, further elevations in PEEP did not improve Q,/Q 1• In these patients, cardiac output was kept constant by the

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ALVEOLAR DISTENDING PRESSURE Figure 1. Diagrammatic representation of lung compliance in normal, abnormal (depressed), and treated (after PEEP) states. In the normal lung, a small change in pressure is followed by a large increase in volume (not shown). The solid line at the bottom represents the change in pressure and its associated small change in volume with depressed compliance. If PEEP improves compliance, the same change in pressure (dotted line) is followed by an augmented change in volume. (From Civetta, J. M.: Ventilatory Assistance and Support. In William Glenn et al. (eds.): Thoracic and Cardiovascular Surgery. East Norwalk, Connecticut, Appleton-Century-Crofts, 1982; with permission.)

augmentation of preload and the use of inotropic agents, when necessary. The mean level of PEEP used in these patients was 14.6(±2.8) em H 20. 43 Results from recent studies in animals have been used to suggest that PEEP should be titrated to the level at which oxygen delivery to the tissues is optimized. 57. 84 Weisman88 reviewed controversial issues concerning PEEP in the treatment of ARDS and recommended that the best level was simply that which permitted the reduction of inspired oxygen fractions to minimal levels yet maintained adequate arterial oxygenation. This level was recommended because there were no prospective randomized trials proving that higher levels decreased mortality. However, because of experimental data suggesting that oxygen concentrations commonly used may act synergistically with the etiologic events of ARDS to worsen lung injury,67· 91 it may be beneficial to reduce the fraction of inspired oxygen to as low a level as possible. Others have defined optimal PEEP as the level at which the intrapulmonary shunt fraction is reduced to less than 20 per cent, H. 37 Studies done in the latter part of the last decade by Kirby, 52 Civetta, 12 and Gallagher34• 38 were interpreted by the authors to suggest that early intervention for acute respiratory failure in surgical patients may improve mortality by having as the goal the reversal of functional impairment of gas exchange in the lungs rather than simply improving arterial oxygenation to "satisfactory levels." The end point for optimizing PEEP in their studies was the return of the intrapulmonary shunt fraction to 15 to 20 per cent or an arterial oxygen tension-inspired oxygen fraction ratio (Pao/Flo2) of at least 300:1. This represented the level at which the onset of acute respi-

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ratory failure was usually defined. 52 This point could almost always be reached with a combination of intermittent mandatory ventilation (IMV), PEEP, and cardiovascular monitoring, with appropriate interventions to maintain cardiac output and oxygen uptake. Positive end-expiratory pressure therapy in these later studies34 was started early in the course of acute respiratory failure before all of the manifestations of ARDS, as described by Ashbaugh and Petty, 1 had developed. In particular, poor compliance and the bilateral infiltrates visible on chest roentgenogram were not always present; hypoxemia and increased physiologic shunt were present in all the reported cases. Complete details of this method of early intervention have been described. 37 At the present time, no prospective randomized studies testing different goals of therapy have been published. However, during the last few years, the impact of ARDS and especially early respiratory failure has apparently lessened, and the differences between parochial therapeutic protocols and end points have become much less pronounced. Of greater interest are preliminary findings in our prospective study, which suggest that different end points in oxygenation do not actually result from quantitatively different intentions. Thus, if the total thrust of intensive care is similar, the desire to achieve adequate oxygenation (Pao2 >70 torr at nontoxic concentrations of inspired oxygen (<0.5) or to achieve a 15 to 20 per cent shunt does not result in two distinct groups of patients after effective therapy has been utilized. In patients with significant dysfunction (Pao 2 <55 torr; Fl;i2>0.5), final levels of PEEP and the improvement in oxygenation are clinically similar. In patients with moderate impairment of gas exchange (Pao 2 between 70 and 110 torr; Flo2 = 0.45), treatment according to the shunt criterion is "busier"-more changes in the levels of PEEPbut severity of illness, use of the ICU, invasive monitoring, laboratory testing, and outcome appear similar. It would appear that consensus may be possible in the near future: The goals of ventilatory support should be adequate oxygenation, a safe Flo2 , maintained oxygen delivery, and judicious use of ancillary testing. Absorption atelectasis may occur, given sufficient time, unless FI0 2 is less than 0.5 (below the nontoxic level). Thus the goals might be an arterial Po 2 of 70 to 80 torr while the inspired oxygen concentration is less than 50 per cent. The most important goal is essentially, that values should be consistent with clinical results no matter what the initial stated desire is. Whatever end point is selected, it is apparent from many clinical studies that PEEP increases arterial oxygen tension to more normal levels. The exact mechanism by which this is accomplished is not known, but the effect of PEEP has been directly correlated with an increased functional residual capacity, which is attained by augmenting the volume of expanded alveoli and by recruiting collapsed alveoli. 70 .75 Early intervention could interrupt the pathophysiologic chain of events and thus abort the full syndrome of ARDS, but this hypothesis must be viewed with caution. Positive endexpiratory pressure does not decrease lung water, therefore, removal of fluid from the lungs is not a mechanism for improvement in gas exchange.17·86

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The use of glucocorticoids for the treatment of shock and ARDS remains controversial. An extensive review by Nicholson 60 concluded that there was no good evidence to support the use of steroids in ARDS. In vivo and in vitro studies show that steroids prevent the aggregation of granulocytes, probably by decreasing the rate of association between cell receptors and activation of granulocytes and production of free oxygen radicals, as suggested in the studies cited earlier. Steroids might be beneficial if they could be administered early in the course of the syndrome. To date, there are no results reported that support this hypothesis. 60 Other pharmacologic agents such as imidazole and indomethacin, which inhibit the production of metabolites of arachidonic acid, have been studied to determine whether they have a potentially therapeutic effect in ARDS models. 7 These agents must still be considered investigational at this time. High-frequency positive-pressure ventilation (HFPPV) has also been used for the treatment of ARDS. This type of mechanical ventilation is effective in treating bronchopleural fistulas complicating ARDS, 22 but it has not been shown to be any more successful than conventional forms of ventilation in terms of mortality.39, 74,78 The role of HFPPV should be examined in experimental protocols at the present time to establish its potential use in the treatment of ARDS. THE MANAGEMENT OF ACUTE RESPIRATORY FAILURE IN ARDS VENTILATORY SUPPORT

Empiric treatment of advanced pulmonary abnormalities without therapy to correct the specific pathophysiology of ARDS usually has resulted in an unsuccessful outcome. Because of this grim experience, another approach to patients who might develop ARDS is close monitoring and early therapy to restore pulmonary function to nearly normal levels as soon as signs of acute respiratory failure develop. Previous studiesl2,35,3B,52 propose that early intervention may improve outcome. Patients with one or more risk factors (Table 1) who develop signs of acute respiratory failure should be considered for early ventilatory support. An appropriate therapeutic regimen should incorporate measures to quantitate arterial oxygen tension (Pao 2) and alteration of expiratory lung volume and should provide sufficient mechanical movement of air to ensure adequate oxygenation and elimination of carbon dioxide. The quantitation of Pao2 is very important after each therapeutic intervention because the integrated function of the pulmonary and cardiovascular systems is necessary for adequate oxygen delivery to the tissues, and both mechanical ventilation and PEEP may compromise myocardial function, which would then reduce oxygen delivery. This effect on myocardial function will be discussed in greater detail later in the article. Adult respiratory distress syndrome is characterized by a decreased functional residual capacity (FRC). This FRC is composed of residual vol-

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Table I.

Risk Factors Associated with Development of ARDS

DEFINITE RISK FACTORS

Systemic sepsis Pulmonary contusion Aspiration

PROBABLE RISK FACTORS

Severe pancreatitis Diffuse pneumonia Multiple emergency blood transfusions

Inhalation of toxic substances Near drowning Fractures of long bones

ume and expiratory reserve volume. It is the latter that is diminished in acute respiratory failure associated with ARDS. With diminishing lung volumes, dependent small airways tend to collapse even in the absence of direct alveolar injury. 89 Measurement of closing volume is believed to represent the point in a forced vital capacity maneuver at which flow ceases through gravity-dependent small airways.rs When FRC is diminished below the level of closing volume, alveolar collapse occurs. This reduction of FRC may contribute to the explanation of the pathophysiologic changes associated with acute respiratory failure. The best-documented effect of PEEP on the lung is to increase expiratory reServe volume, thus improving FRC. 76 The effects of PEEP on small-airway closure are conflicting, but the improved FRC is probably accomplished by both increasing alveolar size and recruiting other collapsed alveoli. 76 Therapy with PEEP often improves compliance so that the tidal volume can be delivered at lower pressures (Fig. 1).25 Positive end-expiratory pressure is, therefore, the preferred treatment of acute respiratory failure associated with ARDS, since it directly counteracts the pathophysiologic changes causing hypoxemia. Mechanical ventilation, as the sole therapeutic modality, has only a limited role in the treatment of ARDS because it affects only inspiratory lung volumes. Since most patients with early acute respiratorj failure demonstrate hypocapnea, reflecting an increased minute volume, therapy designed solely to increase ventilation, especially controlled mechanical ventilation (CMV), is almost never needed. Furthermore, there are specific detrimental effects caused by CMV.25 Mechanical ventilation alters the intrapulmonary gas exchange especially by ventilating areas of poor perfusion and diminishing ventilation to areas of high perfusion, which creates increased physiologic dead space and areas of shuntlike effect. Controlled mechanical ventilation is usually associated with respiratory alkalosis, even if slow mechanical rates and dead space are added to the circuit of the ventilator. The resulting alkalemia shifts the oxyhemoglobin dissociation curve to the left, so that the release of oxygen to the tissues is impaired. Alkalemia also increases oxygen consumption, 49 thus compounding the problem of reduced oxygen delivery. In addition, respiratory alkalosis may induce apnea, which can result in wasting of the respiratory muscles, which will then lead to difficulty during weaning from the ventilator. The respiratory alkalemia also reduces the response of the central nervous sys-

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tern to elevated PaC0 2 .19 Mechanical ventilation may be related to barotrauma because it seems reasonable to assume that alveolar rupture occurs at peak inspiratory pressure, which occurs many more times per day during CMV. At a mechanical rate of eight breaths per minute, there are over 11,500 peaks of inspiratory pressure each day. The development of intermittent mandatory ventilation (IMV) provided a physiologic method of ventilatory support that could diminish these deleterious side effects. It permits and encourages spontaneous ventilation, with the addition of just enough mechanical ventilation to normalize PaC0 2 , and pH and maintain a clinically acceptable pattern of breathing. Respiratory alkalosis can be essentially eliminated, except in those patients in whom central stimulation is present. A reduction in the harmful side effects on cardiac function is an added benefit with decreased mechanical ventilation. 25 The likelihood of barotrauma should be reduced, since the number of breaths supplied by the ventilator is lowered. Ventilatory therapy should correct the specific derangement in gas exchange using a combination of PEEP and IMV. In most instances, the effects of each therapeutic intervention must be confirmed by analysis of blood gases and, in some cases, by profiles of oxygen delivery and cardiac function. Approach to Therapy Previously, we directed our therapeutic approach, with resp~ct t~ oxygenation, to the reduction of the intrapulmonary shunt fraction (Q,/Q1) to 15 to 20 per cent, which represented, in our opinion, a level of pulmonary function compatible with unassisted or unsupplemented ventilatory function and the level used to define acute respiratory failure. This approach was employed in a series of 315 consecutive patients. 34 Only 1 per cent of these patients died because of hypoxemic respiratory failure refractory to IMV and PEEP therapy, although the overall mortality for all other reasons was 28 per cent. The PEEP was raised by increments as soon as the intrapulmonary shunt increased to greater than 20 per cent (or the Pao/Flo2 ratio was less than 300:1), regardless of findings on chest roentgenogram or the presence of true hypoxemia. The level of PEEP required to reduce Q,/Q1 did not correlate with overall mortality. This method of therapy attempts to stabilize gas exchange at a nearly normal level until the underlying initiating factor can be identified and eliminated or until the cellular damage to the lung heals. The goal of maintaining adequate oxygenation (Pao 2 >70 torr) by using nontoxic levels of oxygen (Flo 2 <0.50) allows significant impairment of gas exchange to persist: With normal cardiac function, this impairment represents an intrapulmonary shunt fraction of 35 to 40 per cent, a level previously correlated with significant mortality. However, blood gas values do improve with time. This period does not appear to be different from the time required to wean patients from PEEP if the shunt criterion is used as a goal. Thus, the separation of patients into these two distinct groups after therapy has been difficult, and it may be possible to conclude that neither qualitative nor quantitative differences of clinical significance truly exist between these numerically different end points.

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CRITERIA FOR INSTITUTION OF VENTILATORY SUPPORT

If acute respiratory insufficiency is recognized during its early phase, then simpler modalities may be instituted with less risk to the patient. Early therapy should be easier and more effective than therapy instituted later in the course of the disease, if comparisons with cancer and other diseases can be used. Classic criteria for the initiation of ventilatory support incude a respiratory rate greater than 40 breaths per minute, a dead space-tidal volume ratio (VD/VT) greater than 0. 6: 1; elevated PaC02, cyanosis, and infiltrative changes on chest roentgenograms. 56· 79 We consider that these criteria represent late respiratory failure and that support should not be withheld until these signs and symptoms are present. In patients who are at risk for developing ARDS (Table 1), ventilatory assistance should be considered if a respiratory rate greater than 30 to 35 breaths per minute develops or if the Pao 2 is less than 55 torr (Fio2 = 0.21). At this stage of the disease, the PaC0 2 is usually below normal, but an elevated level would, of course, be an additional indication for starting ventilatory support. Infiltrates noted on chest roentgenograms should not be used as a basis for beginning support because the roentgenograms may, or perhaps should be, completely normal. However, evidence of pulmonary contusion or multiple rib fractures signifies major chest trauma and should be used to support initiation of therapy. The most sensitive and important indicator is progressive diminution of arterial oxygen tension. Arterial blood gas analysis is especially indicated if a patient at risk suddenly develops anxiety and a rapid, shallow pattern of ventilation; these clinical findings often represent incipient respiratory failure. Clinical Guidelines The first priority must always be reversal of life-threatening hypoxemia. If the disease process is not discovered until late in its course, then high inspired oxygen concentrations (greater than 0.5) may be necessary as a temporary measure to maintain a Pao 2 greater than 70 torr. As soon as possible, however, this level should be reduced to less than 50 per cent (perhaps less than 40 per cent) to prevent absorption atelectasis, which might further increase Q,/Q1 <. 18 It has been our experience that if the disease process is recognized early, then most patients can maintain a Pao 2 of at least 70 torr with an Fio2 equal to 0.45, although PEEP may be required to achieve this end. PEEP is increased in increments of 2 to 3 em H 2 0, and intrapulmonary shunt should be calculated 10 to 15 minutes after each increment until significant improvement Qudged clincally) has been attained. If a pulmonary artery catheter has not been inserted, PEEP is increased until a Pao/ Fio2 ratio of approximately 250 to 300:1 is reached. This ratio corresponds to an intrapulmonary shunt fraction of approximately 15 to 25 per cent if the arteriovenous oxygen content difference is normal. so We usually use a pulmonary artery catheter if compromise of cardiac function is suspected initially or if the Pao/FI0 2 ratio has not been corrected after the application of PEEP at 15 em H 2 0. Younger patients without known or suspected cardiac abnormalities can often be treated with higher levels safely because the pulmonary artery catheter does not add

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information of importance. However, whenever significant doubt remains, measurement of cardiovascular parameters and calculation of Q,/Q 1 < are prudent. The IMV is increased in increments of one to two breaths per minute to maintain a pH of 7.35 to 7.45 and a PaC0 2 of 45 torr or less (in a previously eucapneic patient). The ventilator is usually set to deliver a tidal volume of 12 to 15 ml per kg of body weight. Most patients receive adequate ventilatory assistance with two or four breaths per minute; they can generate 80 to 90 per cent of the work of breathing spontaneously. In general, the work of breathing is not significantly increased once optimal levels of PEEP are reached because compliance is usually improved (see Fig. 1). 25 Most patients maintain a spontaneous ventilatory rate of less than 30 breaths per minute when oxygenation is improved. Rates of IMV should be raised if the spontaneous ventilatory rate increases, labored breathing is noted, or the patient is anxious or subjectively uncomfortable. Many "IMV failures" result from inadequate equipment or malfunctioning circuitry. Increased resistance and inadequate inspiratory flow rates are common even in new ventilators. If any problems arise, these technical considerations must be carefully investigated before implicating the method of ventilatory support rather than its mode of implementation. Decision to Terminate Ventilatory Support

An assessment of the patient's total clinical condition in terms of the diagnoses and complications since the initiation of ventilatory support is the most important step in selecting an appropriate point to attempt elimination of support. If the underlying cause for ARDS, such as sepsis or pulmonary contusion, has not resolved, then weaning is almost certain to fail. This assessment includes knowledge of the disease process, review of the patient's clinical course, consideration of coexisting diagnoses, physical examination, determination of blood gas values, chest roentgenograms, and evaluation of relevant organ system function. We have found that if the pulmonary disease process is mild and of rapid onset and has been swiftly treated, it may be necessary only to maintain PEEP at the final level for 6 to 12 hours before attempting to wean. However, if the underlying disease process has been difficult to control or if support was begun late in the course of the disease, it seems desirable to maintain the selected level of treatment for at least 24 hours or more before weaning. Our experience has shown that a successful weaning process is more likely if the timing is modified according to the severity of the initial process and the time that has elapsed before therapy was started. The difficulty with which control was obtained and the level of therapy ultimately required should also influence the amount of time devoted to weaning. Priorities for weaning are based on consideration of the detrimental effects of ventilatory support. The first priority is to decrease the Fio2 to less than 0.4 to 0.5. It has been shown that higher levels of inspired oxygen cause lung units with low V/Q to collapse when oxygen is absorbed from the alveoli at a rate exceeding its replacement during alveolar ventilation.18 Others have hypothesized that higher levels of inspired oxygen inhibit pulmonary vasoconstriction and increase extra-alveolar intrapul-

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monary shunting of blood. 24 Of course, the most important consideration concerns the relationship between oxygen toxicity and high inspired oxygen tensions. No cases of oxygen toxicity have been reported in humans after prolonged administration of oxygen in less than 50 per cent concentration (Fio2 of 0.5). Some authors;25, oo have suggested Flo2 values of 0.4 or even lower; however, it is probably safe to assume that no significant difference in outcome will be related to these differing end points. The primary disease process, especially in surgical patients, is almost always the major determinant of outcome. Ventilatory support plays an effective role in preventing early deaths due to progressive hypoxemia and related complications, but long-term ventilatory support cannot change outcome resulting from sepsis, multiple organ system failure, head injury, and the other common causes of mortality in surgical patients. The second priority is reduction of the percentage of the minute ventilation provided by the ventilator by lowering the number of IMV breaths to the level that permits a normal pH (7.35 to 7.45) and a normal PaC02 (35 to 45 torr) at a satisfactory spontaneous respiratory rate (<30 per minute). This process should be continued until the rate has been reduced to two mechanical breaths per minute. We usually maintain patients at two breaths per minute until just before extubation because we found that arterial oxygenation was maintained at a higher level in this way. When the ventilatory rate was decreased to zero breaths per minute, arterial oxygen tension fell approximately 30 torr in some patients.35 The PEEP is lowered in increments of 2 to 3 em Hp as long as oxygenation remains satisfactory, that is, there is no major diminution in Pao2 • In patients who have been treated with high levels of PEEP to obtain this goal, PEEP should not be decreased at a rate greater than 10 em H 20 during a 24-hour period. This emP.iric plateau avoids the setbacks of sudden hypoxemia, which is then followed by a period of augmented therapy. To employ an analogy, the plateaus can be considered similar to the decompression stops used by a scuba diver. Weaning from PEEP therapy is continued until the pressure has been lowered to 5 em H 20. At this point, minimal ventilatory support would be defined as an IMV rate of two breaths per minute, a PEEP level of 5 em H 20, and an Flo2 value of less than 0.4 to 0.5. The necessity of confirming that blood gases are satisfactory at each stage must be considered from a new perspective of cost containment. Arterial oxygen tension serves as a marker for the severity of dysfunction in pulmonary gas exchange, and, by extension, of pulmonary pathophysiologic change. Rarely do we encounter levels that produce significant arterial desaturation. We monitor blood gases, then, to estimate severity and response to treatment rather than to detect marked diminution of oxygen delivery. Thus, confirmation of the response to therapy provides the highest level of security to the physician, and it should be possible to define specific situations in which the need for this degree of security is not appropriate. We should be able to limit sequential and repetitive blood gas analysis and thereby effect a significant cost saving. For example, we routinely provide three types of ventilatory support: (I) prophylactic (patients who have risk factors but no direct etiologic agent present); (2) early intervention (functional assessment based upon increased Q,/Q1 < without roentgenographic changes or diminished compli-

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CO= 2.5L A-V0 2 D = 10ml/dl

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Figure 2. A, Representation of normal capillary blood How and intrapulmonary shunt. With a normal cardiac output and arterial venous oxygen content difference, a moderate intrapulmonary shunt (20 per cent) diminishes the capillary P0 2 from 673 torr (ideally) to an arterial P0 2 of 250 torr. In this example, 100 per cent oxygen is inspired. B, In this example, cardiac output has been halved, whereas A-VO, difference doubled to maintain oxygen uptake. Note that the mixed venous oxygen tension fell from 40 torr to 18 torr. In addition, venous blood then "dilutes" the capillary P0 2 from 673 torr to an arterial PO, of 90 torr. The intrapulmonary shunt is the same as that in A; however, arterial P0 2, fell from 250 torr to 90 torr because of the decreased mixed venous oxygen tension (and content). (From Civetta, J. M.: Ventilatory assistance and support. In William Glenn et a!. (eds.): Thoracic and Cardiovascular Surgery. East Norwalk, Connecticut, Appleton-Century-Crofts, 1982; with permission.)

ance); and (3) therapy to reverse advanced disease (true ARDS). Quantitation and documentation of each step is appropriate for patients with ARDS. Conversely, when ventilatory support is used in patients with nearly normal function to prevent respiratory failure, weaning must be as simple as "weaning" from the effects of general anesthesia, and the confirmation, by blood gas determinations, of each change in ventilatory support is unnecessary, wasteful, time consuming, and costly. Criteria for Extubation Patients who tolerate minimal ventilatory support are considered for extubation if protection of the upper airway is not necessary. Intermittent mandatory ventilation is decreased to zero breaths per minute while maintaining a continuous positive airway pressure (CPAP) of 5 em H 2 0. If ventilatory criteria are met -a pH greater than 7.35, a PaC0 2 less than 45 torr, a spontaneous ventilatory rate less than 30 breaths per minute, a Pa0 2 >55 torr, and an Fio2 of 0.21-the patient can be extubated. Some have considered a CPAP of 5 em Hp as "physiologic." Although this point might be debated, our choice of this value is based upon our clinical experiences. Blood gas values taken when the patient inspires room air at a CPAP of 5 em H 20 are the closest approximation of those gases obtained after the patient has been extubated. Since the purpose of weaning is to determine whether the patient will be capable of maintaining adequate unassisted ventilation, we have found that the CPAP of 5 em H 20 is our best predictor. Measurement of negative inspiratory force and vital capacity is almost

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never needed if the criteria listed are met, and we do not routinely measure those parameters. They may be useful in the weaning of patients who have received ventilatory support for long periods or in patients with neuromuscular disorders. CARDIOVASCULAR SuPPORT

The pulmonary and cardiovascular systems must be closely monitored because the integrated function of both systems is necessary for adequate oxygen delivery to the tissues and because mechanical ventilation and PEEP may compromise myocardial function. 76 It is important to realize that arterial oxygenation is determined not only by pulmonary function but also by cardiac function and the level of oxygen consumption by the tissues.13· 40 The relationship between cardiac output, oxygen consumption, and mixed venous oxygen content is expressed by the Fick principle: oxygen consumption Cardiac output=-----"-=-:------'=-------;-:-;:;,---arteriovenous oxygen content difference We can probably assume that for a relatively short period-for instance, the time required to draw blood for blood gas assessment and measure cardiac output by the thermodilution method-oxygen consumption should remain relatively constant. Therefore, if cardiac output decreases, more oxygen will be extracted from the arterial blood, resulting in an increased arteriovenous oxygen content difference. Arterial blood, if the Pao 2 is more than 70 torr, is nearly completely saturated, and its content remains reasonably constant during physiologic changes in arterial oxygen tension. Thus, an increased arteriovenous oxygen content difference must reflect a decreased mixed venous content, venous oxygen tension (Pvo2), and venous saturation. This desaturated blood, when passing through areas of intrapulmonary shunting, causes a dramatic decrease in Pao 2 and arterial oxygen saturation, even though pulmonary function has not deteriorated (Fig. 2.) Because arterial oxygenation is affected by both systems (respiratory and cardiac), any system of ventilatory s~pport should include monitoring of cardiovascular function to quantifY QJQ~' Ca-Cv, and Pvo2 to determine their relative effects on arterial oxygenation. This type of monitoring is also important to detect an imbalance in oxygen delivery and supply. A high Ca-Cv (normal value, 3.5 to 5.0 ml per dl) a low Pvo 2 (normal value, 35 to 45 torr) and venous saturation (normal value, 70 to 75 per cent) may indicate inadequate cardiac function for the patient's present oxygen consumption despite a normal or even an increased cardiac index, according to textbooks or nomograms. Measures to augment cardiac function may be necessary if higher levels of ventilatory support (both PEEP and mechanical ventilation) are used. Appropriate intervention based upon estimations of preload, afterload, and contractility has usually improved cardiac function so that adequate oxygen delivery can be provided while sufficient ventilatory support is used to maintain pulmonary function at desired values. In these situa-

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tions, lower IMV rates are especially desirable to reduce the pressure-related detrimental effects on cardiac function. If they occur, these effects may then require additional interventions to achieve satisfactory cardiac function.

SUMMARY Adult respiratory distress syndrome remains one of the most lethal conditions treated in surgical and medical intensive care units. Mortality rates of 50 per cent are still reported in recent reviews. Many risk factors are linked with an increased incidence of ARDS, but sepsis and direct pulmonary injury from aspiration, pulmonary contusion, and other forms of trauma are the most commonly associated risk factors. Studies implicate various cellular and chemical mediators associated with acute lung injury. Many pharmacologic agents and various forms of high-frequency ventilation are being studied for their effectiveness in treating ARDS. We consider that the standard treatment continues to be PEEP and mechanical ventilation to reverse hypoxemia linked with the pathophysiologic changes of ARDS. There are no prospective randomized studies comparing the various end points of therapy used clinically at present. We believe, however, that early intervention, with institution of ventilatory support as soon as signs of acute respiratory failure develop, may eliminate some deaths due to progressive hypoxemia leading to the full adult respiratory distress syndrome. Therapy should be started at this time and maintained while the etiologic factors are identified and treated. Minimal ventilatory support should be continued until the primary diseases have resolved and the multisystem impact of the critical illness has lessened. Weaning from inspiratory (IMV) support, manipulation of expiratory pressures (PEEP), and airway control should then be more easily accomplished and more successful in practice.

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9. Brigham, K. L., Woolverton, W. C., Blake, L. H., et al: Increased sheep lung vascular permeability caused by Pseudomonas bacteremia. J. Clin. Invest., 54:792, 1974. 10. Carvalho, A. C. A., Bellman, S. M., Saullo, V. J., et al.: Altered factor VIII in acute respiratory failure. N. Engl. J. Med., 307:1113, 1982. 11. Civetta, J. M., Barnes, T. A., and Smith, L. 0.: "Optimal PEEP" and intermittent mandatory ventilation in the treatment of acute respiratory failure. Resp. Care, 20:551, 1975. 12. Civetta, J. M., Flor, R. J., and Smith, L. 0.: Agressive treatment of acute respiratory insufficiency. South. Med. J. 69:749, 1976. 13. Clemmer, T. P.: Oxygen transport. Present Concepts, 7:171, 1974. 14. Clowes, G. H. A.: Pulmonary abnormalities in sepsis. Surg. Clin. North Am., 54:993, 1974. 15. Cole, J. E.: Lung Function: Assessment and Application in Medicine. Edition 3. Philadelphia, J.B. Lippincott Co., 1975. 16. Craddock, P., Fehr, J., Dalmasso, A., et al.: Hemodialysis leukopenia: Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J. Clin. Invest., 59:879, 1977. 17. Crandall, E. D., Staub, N. C., Goldberg, H. S., et al.: Recent developments in pulmonary edema. Ann. Intern. Med., 99:808, 1983. 18. Dantzker, D. R., Wagner, P. D., and West, J. B.: Instability of lung units with low ViA! Q ratio during 0 2 breathing. J. Appl. Physiol. 35:886, 1975. 19. Delemos, R. A., and McLaughlin, G. W.: Technique of ventilation in the newborn: The use of intermittent mandatory ventilation. Reports of the Colloquiam, Port a Mousson, France, 1973, pp. 173-178. 20. Demling, R. H.: Fluid distribution during overload edema (abstract). Crit. Care Med., 6:123, 1973. 21. Demling, R. H., and Nerlich, M.: Acute respiratory failure. Surg. Clin. North Am., 63:337, 1983. 22. Derderian, S. S., Krishnan, R. R., Albrecht, P. H., et al.: High frequency positive pressure jet ventilation in bilateral bronchopleural fistulae. Crit. Care Med., 8:345, 1980. 23. Divertie, M. B.: The adult repiratory distress syndrome. Mayo Clin. Proc., 57:371, 1982. 24. Douglas, M. E., Downs, J. B., Dannemiller, F. J., et al.: Changes in pulmonary venous admixture with varying inspired oxygen. Anesth. Analg. (Cleve.), 55:688, 1975. 25. Downs, J. B., and Douglas, M. E.: Applied physiology and respiratory care. In Critical Care State of the Art. Volume 3, Society of Critical Care Medicine, Anaheim, California, 1982. 26. Fein, A. M., Goldberg, S. K., Lippman, M. L., et al.: Adult respiratory distress syndrome. Br. J. Anaesth., 54:723, 1982. 27. Fein, A. M., Lippman, M., Holtzman, H., et al.: The risk factors, incidence, and prognosis of ARDS following septicemia. Chest, 1:40, 1983. 28. Ferstefield, J. E., Schleuter, D. P., Rytel, M. W., et al.: Recognition and treatment of adult respiratory distress syndrome secondary to viral interstitial pneumonitis. Am. J. Med., 58:709, 1975. 29. Fischman, R. A., Marschall, K. E., Kislak, J. W., et al.: Adult respiratory distress syndrome caused by Mycoplasma pneumoniae. Chest, 74:471, 1978. 30. Ford-Hutchinson, A., Bray, M., Doig, M., et al.: Leukotriene B, a potent chemotactic and aggregating substance released from polymorphonuclear leukocytes. Nature, 286:264, 1980. 31. Fowler, A. A., Hamman, R. F., Good, J. T., et al.: Adult respiratory distress syndrome: Risk with common predispositions. Ann. Intern. Med., 98:593, 1983. 32. Fruchtman, S. M., Gombert, M. E., and Lyons, H. A.: Adult respiratory distress syndrome as a cause of death in pneumococcal pneumonia. Chest, 4:598, 1983. 33. Fulton, R. L., and Jones, C. E.: The cause of post-traumatic pulmonary insufficiency in man. Surg. Gynecol. Obstet., 140:179, 1975. 34. Gallagher, T. J., and Civetta, J. M.: Goal-directed therapy of acute respiratory failure. Anesth. Analg. (Cleve.), 59:831, 1980. 35. Gallagher, T. J., and Civetta, J. M.: Goal directed treatment of acute respiratory failure. In Abstracts of Scientific Papers of the European Society of Clinical Investigation, France, 1978, p. 34. 36. Gallagher, T. J., and Civettta, J. M.: Normal pulmonary vascular resistance during acute respiratory insufficiency. Crit. Care Med. 9:647, 1981.

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37. Gallagher, T. J., Civetta, J. M., and Kirby, R. R.: Terminology update: Optimal PEEP. Crit. Care Med., 6:323, 1978. 38. Gallagher, T. J., Civetta, J. M., Kirby, R. R., et al.: Post-traumatic pulmonary insufficiency: A treatable disease. South Med. J., 70:1308, 1977. 39. Gallagher, T. J., Klain, M. M., and Carlon, G. C.: Present status of high frequency ventilation. Crit. Care Med., 10:613, 1982. 40. Giovannini, I., Boldrini, G., Sganga, G., et al.: Quantification of arterial hypoxemia in critically ill patients. Crit. Care Med., 11:644, 1983. 41. Gong, H.: Positive pressure ventilation in the adult respiratory distress syndrome. Clin. Chest Med., 3:69, 1982. 42. Hammerschmidt, D. E., White, J. G., Craddock, P. R., et al.: Corticosteroids inhibit complement-induced granulocyte aggregation. J. Clin. Invest., 63:798, 1979. 43. Holzapfel, L., Dominique, R., Francois, P., et a!.: Static pressure-volume curves and effect of positive end-expiratory pressure on gas exchange in adult respiratory distress syndrome. Crit. Care Med., 11:591, 1983. 44. Horowitz, J. H., Carrico, C. I., and Shires, G. T.: Pulmonary response to major injury. Arch. Surg., 108:349, 1974. 45. Hudson, L. D.: Causes of the adult respiratory distress syndrome- clinical recognition. Clin. Chest Med., 3:195, 1983. 46. Hyman, A., Spannhake, E., and Kadowitz, P.: Prostaglandins and the lung. In Lung Disease: State of the Art. New York, American Lung Association, 1979, pp. 229-254. 47. Johnson, K., Chapman, W., and Ward, P.: Immunopathology of the lung: A review. Am. J. Pathol., 95:795, 1979. 48. Kaplan, R. L., Sahns, S. A., and Petty, T. L.: Incidence and outcome of the adult respiratory distress syndrome in gram-negative sepsis. Arch. Intern. Med., 139:867, 1979. 49. Karetsky, M., and Cain, S.: Effect of carbon dioxide on oxygen uptake during hyperventilation in normal man. J. Appl. Physiol. 28:8, 1970. 50. Keighley, G. R.: The arterial/alveolar oxygen tension ratio: An index of gas exchange applicable to varying inspired oxygen concentrations. Am. Rev. Respir. Dis., 109:142, 1974. 51. Kimura, T., Toung, J. K., Margolis, S., et al.: Respiratory failure in acute pancreatitis: The role of free fatty acids. Surgery, 87:509, 1980. 52. Kirby, R. R., Downs, J. B., Civetta, J. M., eta!.: High level positive end-expiratory pressure (PEEP) in acute respiratory insufficiency. Chest, 67:156, 1975. 53. Lava, J., and Gould, S. A.: Pulmonary dysfunction and sepsis: Is pulmonary edema the culprit? J. Trauma, 22:280, 1982. 54. Manwaring, D., and Curreri, P. W.: Cellular mediation of respiratory distress syndrome induced by fragment D. Ann. Chir. Gynaecol., 70:304, 1981. 55. Manwaring, D., and Curreri, P. W.: Platelet and neutrophil sequestration after fragment D-induced respiratory distress. Circ. Shock, 9:75, 1982. 56. McGuire, W. W., Spragg, R. G., Cohen, A. B., et al.: Studies on the pathogenesis of the adult respiratory distress syndrome. J. Clin. Invest. 69:543, 1982. 57. Mohsenifar, Z., Goldbach, P., Tashkin, D. P., et al.: Relationship between 0 2 delivery and 0 2 consumption in the adult respiratory distress syndrome. Chest, 84:267, 1983. 58. Myers, T. J., Cole, S. R., Klatsky, A. U., et al.: Respiratory failure due to pulmonary leukostasis following chemotherapy of acute nonlymphocytic leukemia. Cancer, 51:1808, 1983. 59. Nicholson, D. P.: Cortiocsteroids in the treatment of septic shock and the adult respiratory distress syndrome. Med. Clin. North Am., 67:717, 1983. 60. Nicholson, D. P.: Glucocorticoids in the treatment of shock and the adult respiratory distress syndrome. Clin. Chest Med., 3:121,1982. 61. O'Flaherty, J., Shamwell, H., and Ward, P.: Neutropenia induced by systemic infusion of chemotactic factors. J. Trauma, 118:1586, 1977. 62. Ogletree, M., and Brigham, K.: Arachidonate increases pulmonary vascular resistance without changing lung vascular permeability in unanesthetized sheep. J. Appl. Physiol., 48:581, 1980. 63. Palmovic, V., and McCarroll, J. R.: Fat embolism in trauma. Arch. Pathol., 80:630, 1975. 64. Pepe, P. E., Potkin, R. T., Reus, D. H., et al.: Clinical predictors of the adult respiratory distress syndrome. Am. J. Surg., 144:124, 1982.

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65. Petty. T. L.: Adult respiratory distress syndrome: Definition and historical perspective. Clin. Chest Med., 3:3, 1982. 66. Pontoppidan, H., Laver, M. B., and Geffin, B.: Acute respiratory failure in the surgical patient. Adv. Surg., 4:163, 1970. 67. Pratt, P. C., Vollmer, R. T., Shelburne, J. D., eta!.: Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. Am. J. Pathol., 95:191, 1979. 68. Rinaldo, J. E., and Rogers, R. M.: Adult respiratory distress syndrome: Changing concepts of lung injury and repair. N. Engl. J. Med., 306:900, 1982. 69. Robin, E. D., Cross, C. E., and Aelis, R.: Pulmonary edema. N. Engl. J. Med., 288:239, 1973. 70. Rose, D. M., Downs, J. B., and Heenan, T. J.: Temporal responses offunctional residual capacity and oxygen tension to changes in positive end-expiratory pressure. Crit. Care Med., 9:79, 1981. 71. Sacks, H. S., Lyons, R. W., and Lahire, B.: Adult respiratory distress syndrome in Rocky Mountain spotted fever. Am. Rev. Respir. Dis., 123:547, 1981. 72. Sacks, T., Moldow, C., Craddock, P., et a!.: Oxygen radicals mediate endothelial cell damage by complement stimulated granulocytes: An in vitro model of immune vascular damage. J. Clin. Invest., 61:1161, 1978. 73. Schneider, R. C., Zapol, W. M., and Carvalho, A. C.: Platelet consumption and sequestration in severe acute respiratory failure. Am. Rev. Respir. Dis., 122:445, 1980. 74. Schuster, D. P., Klain, M. M., and Snyder, J. V.: Comparison of high frequency jet ventilation to conventional ventilation during severe respiratory failure in humans. Crit. Care Med., 10:625, 1982. 75. Shapiro, B. A., Cane, R. D., and Harrison, R. A.: Positive end-expiratory pressure in acute lung injury. Chest, 3:558, 1983. 76. Shapiro, B. A., Cane, R. D., and Harrison, R. A.: Positive end-expiratory pressure therapy in adults with special reference to acute lung injury: A review of the literature and suggested clinical correlations. Crit. Care Med., 12:127, 1984. 77. Sib bald, W., Holliday, R., and Driedger, A.: Corticosteroids in the prevention and reversal of microvascular injury. In Conference on Mechanisms of Lung Microvascular Injury. New York, New York Academy of Sciences, 1983. 78. Sjostrand, U.: High frequency positive-pressure ventilation (HFPPV): A review. Crit. Care Med., 8:345, 1980. 79. Skillman, J. J., Malhotra, I. V., Pallot, J. A., eta!.: Determinants of weaning from controlled ventilation. Surg. Forum, 22:198, 1971. 80. Skubitz, K. M., Craddock, P. R., Hammerschmidt, D.E., eta!.: Cortiocosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro. J. Clin. Invest., 68:13, 1981. 81. Sprung, C. L., Pons, G., Elser, B., and Hauser, M. J.: The adult respiratory distress syndrome. Postgrad. Med., 74:253, 1983. 82. Staub, N. C.: Pulmonary edema. Physiol. Rev., 54:678, 1974. 83. Suter, P. M., Fairly, A. B., and lsenburg, M. D.: Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N. Engl. J. Med., 292:284, 1975. 84. Tabeling, B. B., and Modell, J. H.: Fluid administration increases oxygen delivery during continuous positive pre~sure ventilation after fresh water near-drowning. Crit. Care Med., 11:693, 1983. 85. Tate, R. M., and Repine, J. E.: Neutrophils and the adult respiratory distress syndrome. Am. Rev. Respir. Dis., 99:552, 1983. 86. Taylor, A. E.: Capillary fluid filtration: Starling forces and lymph How. Circ. Res., 49:557, 1981. 87. Taylor, A. E., Martin, D., and Parker, J. C.: The effects of oxygen radicals on pulmonary edema formation. Surgery, 94:433, 1983. 88. Weisman, I. M., Rinaldo, J. E., and Rogers, R. M.: Positive end-expiratory pressure in adult respiratory failure. N. Engl. J. Med., 307:1381, 1982. 89. West, J. B.: Respiratory Physiology-the Essentials. Baltimore, The Williams and Wilkins Co., 1974. 90. West, J.: Ventilation/Blood Flow and Gas Exchange. Edition 2. Oxford: Blackwell, 1970. 91. Witschi, H. R., Haschek, W. M., Klein-Szanto, A. J. P., et al.: Potentiation of diffuse lung damage by oxygen: Determining variables. Am. Rev. Respir. Dis., 123:98, 1981.

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92. Zimmerman, G. A.: Adult respiratory distress syndrome secondary to high altitude pulmonary edema. West. J. Med., 133:335, 1980. 93. Zimmerman, G. A., Renzetti, A. D., and Hill, H. R.: Circulating polymorphonuclear leukocyte activity in patients with the adult respiratory distress syndrome. Chest, 5:875, 1983. 94. Zimmerman, G. A., Renzetti, A. D., and Hill, H. R.: Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome. Am. Rev. Respir. Dis., 127:290, 1983. Department of Surgery United States Air Force Medical Center Keesler Air Force Base, Mississippi 39534