ACUTE RESPIRATORY DISTRESS SYNDROME

ACUTE RESPIRATORY DISTRESS SYNDROME

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ACUTE RESPIRATORY DISTRESS SYNDROME Potential Pharmacologic Interventions Barrett D. Conner, MD, and Gordon R. Bernard, MD

The acute respiratory distress syndrome (ARDS) is probably one of the two or three most studied pathophysiologic processes occurring in the medical intensive care unit. Most of the current understanding about this severe clinical illness and the mediators associated with it has come from the study of relevant animal models. In the mid-l970s, the development of the sheep model of ARDS and, later, the porcine model led to the discovery of a wide variety of lipid mediators, amines, cytokines, proteases, etc. Documentation of the presence of highly toxic mediators associated with the development of ARDS has led to a flurry of activity in drug development in this area. A substantial number of new therapies have been suggested and examined in recent years, many of which remain controversial. The following is a critical appraisal of the potential therapeutic options under investigaThis work was supported in part by the National Institutes of Health and National Heart, Lung, and Blood Institute grant HL 19153 (SCOR in Acute Lung Injury) and by the National Heart, Lung, and Blood Institute grant HL RO1 43167 Cardiopulmonary effects of ibuprofen in sepsis.

tion in recent years for the management of ARDS. TISSUE MALFUNCTION AND INJURY

The mediators thought to be responsible for the development of ARDS, for the broader concept of acute lung injury (ALI), or for aggravating its clinicopathophysiologic effects have been discussed elsewhere in detail and are not reviewed here in detail. In brief, the current concept is that inciting eventse.g., release of endotoxin into the circulation-trigger a cascade of events involving cytokines, proteases, bioactive lipids, bioactive amines, and free radicals. These mediators, sometimes referred to as second messengers, cause physiologic abnormalities such as altered lung mechanics, hypoxemia, granulocytopenia, leukocyte sequestration in the lung, increased pulmonary microvascular permeability, pulmonary hypertension, systemic hypotension, and altered surfactant. Sepsis, the commonest cause of ARDS, is responsible for 30% to 40% of all cases of ARDS, frequently complicates ARDS from other

From the Center for Lung Research, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University (BDC, GRB); and the Medical Intensive Care Unit, Vanderbilt University Medical Center (GRB), Nashville, Tennessee

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causes, and is highly lethal.20, lZ6 For the purposes of this discussion, agents aimed at ameliorating the septic or systemic inflammatory response are considered potentially useful in the treatment or management of ARDS. As a result, a variety of inhibitors of the inciting agents have been developed and many are either in clinical trials or are in the final stages of preclinical testing. These agents can be grouped into general categories, as indicated in Table 1, and are discussed subsequently. Antagonism of Endotoxin Antagonism of endotoxin is a particularly attractive concept because such an approach Table 1. PHARMACOLOGIC APPROACHES TO TREATMENT AND PREVENTION OF ARDS 1. Antagonism of endotoxin Monoclonal/ polyclonal

antibodies to endotoxin, bacterial permeabilityincreasing protein, lipid x, polymixin B 2. Anti-inflammatory agents Corticosteroids, cyclooxygenase inhibitors, prostaglandin-El 1E, liposome-encapsulated prostaglandin 1, interleukin-10 Vitamin E, N3. Antioxidants/radical scavengers acetylcysteine, oxothiazolidine carboxylate (OTC or Procysteine OTC) superoxide dismutase, vitamin C, lazeroids 4. Vasodilators Prostacyclin, liposomal prostaglandin-El, inhaled prostaglandinEl, nitric oxide 5. Antiproteases a,-Antiprotease, secretory leukoprotease inhibitor, anti-elastases, anticollagenases 6 . Cytokineslcytokine Granulocyte macrophage inhibitors colony-stimulating factor, IL-6, IL-1 receptor antagonists, antagonists to tumor necrosis factor 7. Surfactant Bovine surfactant, synthetic surfactant, recombinant human surfactant 8. Other Almitrine bismesylate, pentoxifylline, lisofylline, modes of mechanical ventilation, permissive hypercapnia

could conceivably impact the cascade of events at a very early stage. Further, there is no evidence to date that active removal of endotoxin from the circulation could have deleterious effects and this is not necessarily true of some the agents to be discussed subsequently. Hellman and Warren,76as well as Wheeler and Bernard,lB2have provided thorough reviews on anti-endotoxin strategies, several of which are discussed in this article. Methods of antagonism of endotoxin that have been studied include passive immunization (with both polyclonal and monoclonal antisera), lipopolysaccharide (LPS)-binding agents, extracorporeal removal of endotoxin, and competitive analogues of lipid A. Early studies with human-derived polyclonal antibodies to endotoxin suggested that this type of therapy could be highly effective. Because of supply considerations and the problems with transmission of disease from human to human from pooled human sera, however, a recombinant DNA approach to produce monoclonal antibodies was undertaken. The two human recombinant monoclonal antibodies studied in large-scale clinical trials of sepsis syndrome are XOMEN E5, a monoclonal IgM antibody derived from mutant Escherichia coli J5-immunized mice, and HAlA, a chimeric human-mouse monoclonal antibody. Initial studies using E5 therapy in animal models of gram-negative sepsis produced variable results, which also indicated some species specificity.1B4a, Greenman et a166 conducted the first human trial of E5 in patients with gram-negative sepsis and found an improvement in 30-day survival ( P = 0.01) in a subset of patients who did not have refractory shock at the time of treatment initiation. Therefore, a second trial was performed which was limited to those patients without refractory shock. The results of the second trial were equally disappointing, because E5 did not improve mortality but lead to higher mortality in the E5 recipients (30%) as compared with control patients (26%).165 Wedel et subsequently reanalyzed the data, combining the two studies and performing a meta-analysis. They concluded that the E5 recipients experienced a more rapid resolution of organ failure, and improved survival.67 A clinical trial of HAlA in patients with sepsis syndrome failed to demonstrate a sig-

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nificant difference in mortality at 28 days between the HAlA recipients and placebo recipients. This study received much criticism for its failure to use an unrelated antibody preparation as a control, and for differences in severity of illness (as measured by the Acute Physiology and Chronic Health Evaluation [APACHE]-I1 scores) between the two groups? Likewise, subsequent studies with both agents have failed to confirm the earlier results, and it is doubtful that these first-generation anti-endotoxins will become licensed for clinical use. A major limitation of these two agents, possibly explaining the lack of success in clinical studies, is that neither neutralizes the physiologic effects of endotoxin. Agents that can bind to and, perhaps, neutralize LPS toxicity therefore are more attractive options. Several agents are known to bind LPS and are under active study. When released into the circulation, LPS forms complexes with circulating proteins and lipoproteins that are involved in activation of the inflammatory response, and in LPS detoxification and its c l e a r a n ~ e .Lipopoly~~ saccharide also binds to the acute-phase reactant, lipopolysaccharide-binding protein (LBP), which facilitates the transfer of LPS to CD14 and to 1ipoproteins.i'Z125, 151, 169, 170. 187, 188 Lipopolysaccharide-binding protein is a lipid transfer protein that facilitates the transfer of the LPS molecule to the LPS receptor, CD14, on the phagocyte surface, or to CD14 in the soluble form. Studies have shown that cell signaling in response to LPS is markedly increased in the presence of LBP.76Initial studies using soluble CD14, and anti-CD14, have produced conflicting results, with one primate study reporting that passive administration of anti-CD14 protected against endotoxininduced shockg8and another showing that high levels of soluble CD14 in sepsis were associated with increased mortality.95One recent study with mice has shown that large amounts of exogenously administered LBP can block the activation of cells and secondary cytokine production, protecting against LPS and bacterial challenge.94More study is needed with regard to these agents to determine clinical usefulness in the future. As reported in the studies of Hailman et alR and Schumann et al,151 endotoxin (LPS) binds to lipoproteins and lipid-containing

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particles such as high-density lipoprotein (HDL), low-density lipoprotein, and very low-density lipoprotein. Several investigators have demonstrated that these lipoprotein particles facilitate the detoxification and eventual clearance of endotoxin by the hepatobiliary system, as reported by Hellman et al.76 In hypolipidemic animals, there is an increased sensitivity to endotoxin, which is reversed by recovery of normal lipid levels via exogenous administration of Several animal studies have demonstrated that artificially elevated levels of lipoproteins from exogenous sources reduces cytokine expression and decreases mortality upon LPS challenge. These early studies, however, were contradicted by subsequent animal studies. Human studies have also produced conflicting results. Human studies have employed reconstituted HDL and, in one controlled human study, reduced symptoms (except fever) and decreased cytokine levels. In addition, lowerthan-predicted white blood cell counts were seen in response to endotoxin in the HDLtreated ~ 0 1 u n t e e r ~Increasing .'~~ serum triglycerides to supranormal levels had no effect, however.'" Bactericidal / permeability-increasing protein (BPI) is an endotoxin-binding protein found in neutrophil granules. It binds to the lipid A region of LPS, attenuates LPS activity, and increases bacterial membrane permeability. In addition, BPI has bactericidal properties. In primates with E . coZi bacteremia, infusion of BPI decreases inflammatory cytokine levels and reduces levels of circulating endo141 A toxin, but does not improve surviva1.l4O* phase I1 human trial demonstrated no apparent toxicity caused by recombinant BPI (rBPI,) infusion and decreased cytokine proIn an duction in response to LPS ~hal1enge.l~~ uncontrolled preliminary trial of recombinant BPI for fulminant meningococcemia in children, a significant reduction in mortality compared with historic controls was noted.62As a result of these early, encouraging results, prospective, controlled trials of recombinant BPI are underway. The cathelicidins are a group of unique antibacterial peptides, of which hCAP18 is the only one found in humans. hCAPl8 is found in neutrophil-specific granules and, after degranulation and modification, is found in a

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physically shorter and more active form.70 The antibacterial properties of hCAP18 are believed to be attributable to its ability to bind LPS and to disrupt bacterial membranes. Animal studies have shown a decreased response to LPS challenge with infusion of a peptide that mimics the C-terminus of hCAP18. To the authors' knowledge, however, no human trials are taking place at this time with hCAP18 or its peptide analogues. Other LPS-binding agents of great interest are limulus anti-LPS factor (LALF) and polymixin B (PMB). Limulus anti-LPS factor is an anticoagulant protein found in the amebocytes, or granular hemocytes of horseshoe crabs. Amebocytes are the only cells found in the hemolymph of this species. In the horseshoe crab, LALF inhibits the LPSinduced activation of the coagulation system. It binds to LPS with high affinity and neutralizes most of the activity of lipid A.11h,177 A recombinant form of LALF has been developed and is named endotoxin-neutralizing protein (ENP). Studies indicate that the recombinant form retains the properties of the native molecule; animal studies demonstrate that it protects against gram-negative bacteria and LPS ~hallenge.~, 6o Perhaps the most encouraging aspect of this agent is that ENP was found to confer protection against endotoxemia in a recent animal study with mice, even when administered 24 hours after LPS challenge.145 Presently, no human trials are underway with this agent, but preliminary studies do seem encouraging. Polymixin B (PMB) is a cationic cyclic polypeptide antibiotic agent, used clinically as a topical antibiotic. It also has the unique property of binding to lipid A and neutralizing most of its biologic Renal and central nervous system toxicity has prevented extensive clinical studies, and attention now is focused on development of conjugates and derivatives with decreased 49 Conjugation of PMB to larger molecules extends its half-life and lessens the nephrotoxicity associated with its administration. Animal studies have demonstrated improved hemodynamic parameters in sheep pretreated with a PMBdextran c ~ n j u g a t eThere . ~ ~ is a human clinical trial employing PMB or PMB conjugates in progress. Another method that employs PMB is that of extracorporeal removal of endotoxin

by venovenous hemoperfusion through PMBimmobilized polystyrene-derivative fiber. Controlled studies in animal models of endotoxemia and bacteremia have shown decreases in mortality using this method.41 In an uncontrolled clinical trial of extracorporeal removal of endotoxin using a PMB-immobilized fiber, Aoki et a19 reported clinical improvement. Even if future clinical studies demonstrate efficacy and improved survival, however, the high expense and limited access to dialysis equipment in most hospitals will certainly limit access to this mode of therapy. Lipid A is the toxic moiety found in the LPS molecule. Analogues to lipid A exist that are structurally similar but have significantly less or no toxicity. Being similar in structure, these analogues are competitive inhibitors of LPS for binding to the LBP molecule, thereby inhibiting activation of macrophages and neutrophil~.~ Lipid X is a lipid A precursor that has been shown to have weak antagonistic activity versus lipid A. Administration of lipid X provides some protection against LPS challenge in animal models.64A more recent development is that of a synthetic lipid A analogue that has potent LPS antagonist activity without agonist activity. This lipid A analogue has been shown to antagonize in vitro activation of immune cells by LPS, thereby attenuating cytokine elaboration and decreasing mortality after LPS challenge in mice.42,R9 Monophosphoryl lipid A, on the other hand, is a lipid A analogue without potent lipid A antagonism. In early animal studies, pretreatment with monophosphoryl lipid A improved short-term mortality following endotoxin admini~tration.'~, 39 A subsequent study in healthy human volunteers showed no significant toxicity to monophosphoryl A, and that pretreatment with monophosphoryl lipid A induced tolerance to endotoxin challenge, as demonstrated by decreased flu-like symptoms and an attenuated cytokine response.'2 Anti-Inflammatory Agents: Corticosteroids and Cyclooxygenase Inhibitors

The role of tissue injury and the inflammatory cascade in the pathogenesis of ARDS and ALI have been reviewed elsewhere and are

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Several studies in animal models of sepsis and lung injury show that corticosteroids decrease morbidity and mortality if given simultaneously or before the experimental insult. This was demonstrated in studies using bac168, lS5and acid teremia,"', 130, 168 endot~xemia,~~, a s p i r a t i ~ n . In ' ~ ~a 1976 study by S c h ~ m e r , ' ~ ~ high-dose corticosteroids significantly reduced mortality in septic patients. The study received much criticism, however, because part of the data collection was randomized and prospective and another part was retrospective. In addition, different antibiotic agents were used, and the total dose of corticosteroids differed among patients. Several subsequent, large, randomized, controlled, prospective trials have re-examined the use of high-dose corticosteroids. Sprung et found no change in mortality of septic patients, although a trend toward reversal of shock was noted. In both the Veterans Administration Cooperative Study5and the study of Bone et no change in mortality or decrease in the risk of ARDS was shown, although Bone et alZ6noted an increased mortality in a subset of septic patients with renal insufficiency who received corticosteroids. These findings were confirmed in subsequent trials.'00In 1987, Bernard et alZ0 reported the results of a large, multicenter, prospective, randomized, double-blind, placebo-controlled trial of methylprednisolone in patients with ARDS. They observed no statis-

not repeated here.137Regardless of the insult, activation of the inflammatory cascade leads to generation of the products of arachadonic acid metabolism, through both the cyclooxygenase and lipooxygenase pathways, and contributes to the development of ARDS. Products of cyclooxygenase contribute to pulmonary vasoconstriction, whereas lipooxygenase products are associated with increased vascular ~ermeability.~~ Modulation of the inflammatory cascade therefore has been a major focus of research into the prevention and treatment of ALI and ARDS. Corticosteroids The use of corticosteroids in the treatment of ARDS has been the subject of great controversy and debate over the years. Although their exact mechanism of action is unknown, corticosteroids inhibit a host of potent inflammatory mediators and have been shown to improve morbidity and mortality in animal models of sepsis and lung injury if given prior to, or simultaneously with, the experimental insult.21It has been shown, however, that most ARDS patients who die commonly do so not as a result of worsening respiratory dysfunction, but rather recurrent sepsis and multiple organ failure.'14,180 Given their potent anti-inflammatory effects, corticosteroids may actually predispose patients to sepsis, making their use not without risk. 100

Placebo (N= 49)

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Figure 1. Comparison of the survival of patients with acute respiratory distress syndrome (ARDS) over the first 45 days after entry into the study, according to treatment with methylprednisolone or placebo. There were no significant differences in survival at any time during the 45-day follow-up period (P=0.77). (From Bernard GR, Luce JM, Sprung CL, et al: High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 317:1565-1570, 1987, with permission. Copyright @ 1987 Massachusetts Medical Society. All rights reserved.)

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Figure 2. Comparison of the percentage of patients in whom ARDS was reversed through reversal of the arterial blood gas criteria alone after treatment with either methylprednisolone (n=50) or placebo (n=49). There were no significant differences in the reversal rates between the two groups at any point during the 45-day follow-up period ( P= .74). (From Bernard GR, Luce JM, Sprung CL, et al: High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 317:1565-1570, 1987; with permission. Copyright 0 1987 Massachosetts Medical Society. All rights reserved.)

tically significant difference between the methylprednisolone group and the placebo group at 45 days with respect to mortality or reversal of ARDS (Figs. 1-3). Among patients with ARDS and prolonged respiratory failure, many have a significant fibroproliferative response, which can progress to varying degrees of obliterative scarring of the lung parenchyma and cyst formation. Several investigators have suggested that using corticosteroids in lower doses and later in the course of ARDS (fibroproliferative phase, 1 to 2 weeks into ARDS) may be of benefit, based on uncontrolled studies.”, lo4 One must bear in mind, however, the possible increased incidence of sepsis, impaired wound healing, altered glucose metabolism, and other effects associated with corticosteroid treatment. In 1994, Meduri et allo5reported the results of an uncontrolled trial using corticosteroid “rescue,” for persistent respiratory failure and pulmonary fibrosis in the late, fibroproliferative phase of ARDS. They reported a significant improvement in lung function in the corticosteroid group. Most critics point to the fact that this was an uncontrolled study, however, and that the initiation of treatment was at about 2 weeks into ARDS, a time at which the survival curve in the course of ARDS is relatively flat, suggesting that most of these patients were destined to reverse their respiratory failure with or without corticosteroids. In a 1997 study by

Meduri et a1,1°6 using prolonged corticosteroid treatment in ARDS, the researchers found a significant change in mortality between the two groups at day 10 of treatment-0% (0 of 16 patients) in the methylprednisolone group compared with 62% (five of eight patients) in the placebo group. They also reported an improved arterial partial pressure of oxygen-to-inspired oxygen fraction (Pao,/FIo,) ratio and a decreased multiple-organ dysfunction syndrome score (0.7 versus 1.8) in the methylprednisolone group. They speculated that the early removal of high-dose corticosteroid treatment in the previous randomized trials, which used short-term corticosteroid treatment, may have reversed any early beneficial effect of treatment or overturned the ability to detect a beneficial effect. This study was criticized for its small sample size and design. The small sample size produced wide confidence intervals, indicating the results must be interpreted carefully. Also, the study design required that patients who did not respond to the initially prescribed treatment be crossed over. This reflects the researchers’ bias that every patient should be given corticosteroids, which further confounds interpretation of the study.34 Several additional studies using high-dose corticosteroids in the treatment of late ARDS have shown improved survival and outcomes 30, lo4,lost lo7 compared with historic

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L ENTRY 2 3 4 5 DAY OF STUDY Figure 3. Comparison of patients treated with methylprednisolone (solid line) (n=50) or placebo (doffed line) (n=49), according to chest radiograph score (0 = normality; 1 = mild; 2 = moderate; 3 = severe pulmonary edema). Effective total thoracic static lung compliance (static compliance), and ratio of arterial to alveolar partial oxygen pressures (PaoJ PAoJ are shown. There were no significant differences between the methylprednisolone and placebo groups at the time of entry or during the 5 days immediately following entry ( b . 0 5 ) . (From Bernard GR, Luce JM, Sprung CL, et al: High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 317:1565-1570, 1987; with permission. Copyright 0 1987 Massachusetts Medical Society All rights reserved.)

Contrary to nonsurvivors, survivors demonstrated a clinical response to corticosteroids within the first 7 days. Open lung biopsy revealed intact alveolar architecture, myxoid fibrosis associated with intraluminal bronchiolar fibrosis, and no evidence of subintiA sigruficant reducma1 fibropr01iferation.l~~ tion in the level of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid was also

noted in late-phase ARDS patients treated with corticosteroids.lo8,lO9 Clearly the debate regarding the role of corticosteroids in A R D S continues. Presently the National Institutes of Health/National Heart, Lung, and Blood Institutes (NWNHLBI) ARDS Network is conducting a large, multicenter trial examining the role of corticosteroids in late ARDS. Despite the obvious controversy sur-

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rounding their use in ARDS, corticosteroids have been shown to be beneficial in two specific groups of ALI and ARDS patients. The first is patients at risk for fat embolism syndrome (e.g., long bone fractures), in whom corticosteroids given prophylactically have been shown to decrease the risk of respiratory failure.88,99, I5O It must be stressed, however, that the treatment must be prophylactic because corticosteroids would not be expected to have any benefit in established ARDS, as noted previously.20 The second group in which corticosteroids have shown benefit is patients with Pneumocystis carinii pneumonia. Five studies conducted in 1989 to 1990 established a role for corticosteroids in patients with l? carinii pneumonia and h y p o ~ i a .43,~ ~ , 59, 113 In the largest of these studies, which included 251 patients, the incidence of oxygenation failure, use of mechanical ventilation, and death, were all reduced by approximately 50% in those who received corticosteroids concomitantly with antimicrobial therapy.,' The recommendations for corticosteroids in l? carinii pneumonia are outlined in a consensus statement published in 1990.6

Cyclooxygenase Inhibitors In inflammatory states, arachidonic acid is metabolized to thromboxane (Tx) A, and prostaglandins via the cyclooxygenase pathway. These compounds may have adverse effects in the lung during ARDS because they promote neutrophil chemotaxis and adhesion, bronchoconstriction, increased vascular permeability, and platelet aggregation. Animal studies have shown that endotoxin administration causes a rapid increase in the production of cyclooxygenase-derived lipid mediators of inflammation. In the sheep model of acute lung injury, TxA, a potent vasoconstrictor and platelet pro-aggregate, appears to play a major Animal studies have demonstrated that cyclooxygenase inhibitors attenuate lung injury. In a porcine model of septic lung injury, sulindac improved pulmonary hypertension and hypoxemia when given prior to the infusion of Pseudomonus.162In a porcine model of LPS-induced ARDS, indomethacin administered prior to E. coli infusion improved re-

sponses compared with those who received delayed treatment.2s Ibuprofen, a cyclooxygenase inhibitor in general clinical use, has been studied as pretreatment for septic lung injury. In this doseresponse study, ibuprofen produced a biphasic response, which suggests that lower doses of ibuprofen may enhance neutrophilic alveolitis, whereas larger doses attenuate the inflammatory response.'3HIbuprofen has also been shown to reduce pulmonary hypertension and lung lymph flow when administered after the onset of sepsis in animal m0dels.6~ This experiment more closely duplicates the treatment of clinical sepsis, in which pharmacologic intervention is only possible after the development of the sepsis syndrome. Ibuprofen has also been shown to reduce the ARDSlike effect of exogenous tumor necrosis factor (TNF) administered to In 1997, Bernard et alZ4published the results of a large, 5-year, randomized, doubleblind, placebo-controlled trial of intravenous ibuprofen in 455 patients with sepsis. Septic patients who received ibuprofen had significant decreases in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis. Treatment with ibuprofen did not lead to a reduction in the duration of shock or ARDS, however. Most notably, ibuprofen did not significantly improve survival (30-day mortality, 37% with ibuprofen versus 40%" with placebo). In a subsequent analysis of the same data from the Ibuprofen Sepsis Study Group, Arons et all" found that hypothermic septic patients had significantly elevated urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-a and IL-6 compared with febrile septic patients. The incidence of this hypothermic subset of septic patients was approximately 10% and their mortality rate was twice that of febrile septic patients (70% versus 35%). In the hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate, from 94% (18 of 20 placebo recipients), to 54% (13 of 24 ibuprofen recipients).'O Ibuprofen administration in this

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subset of septic patients therefore may improve survival. A potentially confounding issue regarding the use of cyclooxygenase inhibitors is that cyclooxygenase inhibition could prevent the production of beneficial eicosanoids during sepsis and ARDS. In the sheep model of sepsis, the vasodilator prostaglandin E, (PGE,) and prostacyclin (PGI,) canattenuate the pulmonary response to endotoxin. Also, PGE, has been shown to have anti-inflammatory n section on vasodilaproperties32,32a, 49a, l Z T(see tors). The relevance of these effects is not well understood and they cannot be assumed to be physiologically beneficial in true sepsis and ARDS. As discussed subsequently, vasodilators can be deleterious in ARDS, and the endogenous vasodilators (e.g., prostacyclin) may actually mediate a maladaptive loss of hypoxic vasoconstriction, thereby potentially increasing shunt fraction and worsening oxygenation. Another theoretical concern with the use of cyclooxygenase inhibitors is that the cyclooxygenase products do not appear to mediate the entire response to endotoxin, as seen in sheep. After administration of endotoxin in sheep, there is an increased flow of protein-rich lung lymph, indicating increased permeability of the pulmonary microvasculature, which is unaffected by cyclooxygenase inhibition. In other animal models, however, cyclooxygenase inhibitors do appear to blunt permeability increases caused by sepsis.37,149 As already noted, the inflammatory cascade is a complex interaction of various mediators with pro-inflammatory and antiinflammatory roles. Endogenous anti-inflammatory substances, such as PGEI, PGE, and cytokines such as IL-10, have also been investigated for their anti-inflammatory properties. The anti-inflammatory properties of the prostaglandins, however, are overshadowed by their potent vasoactive properties, limiting their use as anti-inflammatory agents (see section on vasodilators). Interleukin (1L)10, on the other hand, is a potent anti-inflammatory cytokine that has shown promise in recent studies. In patients with ALI, recombinant IL-10 (rIL-10) administration causes decreased levels of IL-6, IL-8, and TNF in the bronchoalveolar lavage (BAL) These results warrant further studies.

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Vasodilators: Prostaglandins and Nitric Oxide Prostag/andins

Theoretically, the ideal pharmacologic agent for treatment of ALI and ARDS would have the following properties: 1. It would selectively dilate ventilated regions in the lung. 2. It would increase oxygenation and decrease ventilation and perfusion mismatching. 3. It would have minimal side effects. 4. It would produce improved outcomes and increased patient survival. The prostaglandins and nitric oxide have both been studied as potential therapies in ARDS. Prostaglandins have been the focus of a great deal of research in possibly altering the course of ARDS. In a 1986 study of surgical patients with ARDS, Holcroft et a179reported improvement in oxygenation and survival in patients treated with intravenous liposomal PGE, (TLC C-53). In a larger, multicenter trial, Bone et alZ7found no improvement in patients treated with liposomal PGE,. These data were contrary to encouraging animal studies using a neutrophil-mediated model of inflammation, which showed a decrease in the severity of capillary leak, neutrophil infiltration, and IL-1 production in lung-injured rats.85Liposoma1 PGE, was also found to improve survival in rats given endotoxin, even when TLC C-53 was administered 16 hours after endotoxin challenge.R4A randomized, placebo-controlled, double-blind, phase I1 clinical trial was conducted in patients with the onset of ARDS less than 24 hours prior to enrollment, and Pao,-to-F~o,ratios less than 225 mm Hg. The study was composed of 25 patients, 17 of whom were randomized to receive TLC C-53 and eight to receive placebo. Results of the study demonstrated improved oxygenation and lung compliance and a shorter duration of mechanical ventilation in the treatment group. The authors noted that the survival in the treatment group proved greater than expected for the severity of lung injury and overall degree of illness (Pao,/ FIO, ratio,

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APACHE-I1 score). Improvement in 28-day mortality rate failed to reach statistical significance, however.2 In 1999, Abraham et all reported the results of a randomized, prospective, multicenter, double-blind, placebo-controlled, phase I11 clinical trial. The study comprised 350 patients with ARDS, randomized in a 1:l ratio to receive either liposomal PGE, or placebo. They found no statistically significant differences between the groups with regard to the number of days to discontinuation of mechanical ventilation or 28-day mortality. The liposomal PGE,-recipient group had a shorter time to achieve a Pao,/FIo, ratio equal to or greater than 300 mm Hg, however. In addition, the time to discontinuation of mechanical ventilation was statistically shorter in a subgroup of patients who received a higher total dose of liposomal PGE, (>45.9 kg/kg). Drug-related adverse events of all kinds were reported in 69% of the treatment group, compared with 33% of the placebo group, the most common reaction in the treatment group being hypotension (52%) and hypoxia (24%). The authors concluded that, in the intentto-treat population of patients with ARDS, treatment with liposomal PGE, (TLC C-53) accelerated improvement in oxygenation, but did not decrease the duration of mechanical ventilation, nor did it improve 28-day mortality.’ Prostaglandin administration by way of inhalation has ,also been studied. The rationale behind the use of inhalation is similar to that for the use of inhaled nitric oxide (NO). That is, intravenous vasodilators cause a decrease in the pulmonary artery pressure (PAP), but at the expense of increasing venous admixture (increasing shunt fraction), whereas inhaled vasodilators selectively dilate the pulmonary vasculature associated with ventilated alveoli, thereby improving the ventilation/ perfusion ratio and arterial oxygenation.1M, An attractive feature of inhaled prostaglandins is that they have not been shown to have any cytotoxicity. This is in contrast to NO, which, in the presence of oxygen free radicals, may promote production of peroxynitrite, an oxygen species that has been shown to cause DNA breakdown, lipid peroxidation, and cell death.56, In early

studies of the prostaglandins in ALI, aerosolized PGI, was found to improve oxygenaPGI, is not metabolized t i ~ n175;~ ~however, , in the lung, giving rise to the possibility of significant levels reaching the systemic circulation, resulting in decreased systemic vascular pressure.l12,176 Prostaglandin El, on the other hand, has a pulmonary clearance of approximately 70% to 80%, which may translate into improved hemodynamic tolerance.’12 In a 1997 study conducted by Meyer et alllo 15 consecutive postsurgical patients with ALI, who had failed maximal therapy and had a Pao2/F~o2 ratio of less than 160 mm Hg, were given inhaled PGE,. The PGE, recipients demonstrated improvement in parameters of pulmonary function, with increased Pao2, increased Paoz/ F102 ratio, and decreased venous admixture. The most significant changes occurred in the first 4 hours of treatment and did reach statistical significance. Improvement in hemodynamics was also noted, but these changes did not reach statistical significance.”O The study was criticized for its lack of a control group and failure to demonstrate that the changes were actually attributable to the experimental treatment and not time or other interventions (e.g., mechanical ventilation). The study also failed to demonstrate an improved outcome. Given the significant improvement in parameters of pulmonary function in patients with ALI treated with PGE,, larger, controlled, prospective trials are warranted. Nitric Oxide

Nitric oxide is an endogenous endothelium-derived relaxing factor that acts as a potent vasodilator. When inhaled, NO produces local vasodilatation in ventilated lung units and reverses hypoxemia-induced pulmonary vasoconstriction.25The advantages of NO are obvious. Unlike intravenous prostacyclin (PGI,), NO is delivered as a gas directly to ventilated areas, producing selective pulmonary vasculature vasodilatation. It therefore selectively decreases mean PAP and shunt fraction, and increases the PaoJ F102 ratio and right ventricular ejection fraction, without causing systemic vasodilatation and 143 This is in contrast to intrahypoten~ion.5~.

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venous prostacyclin (PGI,), which has a nonselective vasodilatory effect on pulmonary vasculature, leading to increased ventilation/ perfusion mismatching and worsening oxygenation. It has also been associated with systemic vasodilatation and hypotension. Multiple studies, including a phase I1 and phase I11 noncomparative trial of NO in patients with ARDS have been completed, as well as trials combining NO with intravenous (IV) prostacyclin and inhaled prostacyclin. In addition, a study comparing IV PGEl, inhaled PGE,, NO, and conventional treatment has been completed. Disappointingly, none of the studies demonstrated improvement in patient outcomes or survival. In a 1993 study, Rossaint et all" compared the use of NO with IV prostacyclin in ARDS. Compared with prostacyclin, NO produced an equivalent decrease in PAP, but only prostacyclin produced a decrease in the mean arterial pressure. NO produced an increase in the PaoJFIo, ratio and a decrease in the shunt fraction (changes were statistically sigruficant, P = 0.000 and 0.028, respectively). Intravenous prostacyclin produced the opposite effect, however, leading to worsening oxygenation. Nitric oxide was also compared with aerosolized prostacyclin (PGI,) and aerosolized PGI, (epoprostenol), the rationale being to deliver the drug to ventilated units, as in NO delivery. In a 1996 study by Walmrath et NO and inhaled prostacyclin were compared directly in a small trial consisting of 16 patients with ARDS. The researchers found that both NO and prostacyclin improved oxygenation, increasing the Pao2/F102ratio and the Pao2by 29 and 21 mm Hg, respectively. More detailed analysis demonstrated that a decrease in the shunt fraction was the major contributor to improvement in oxygenation. The authors further concluded that both NO and inhaled prostacyclin redistributed blood flow to well-ventilated areas, improved oxygenation, and had "nearly identical efficacy profiles."176A similar but smaller trial comparing NO and inhaled prostacyclin produced similar results,192as did a study comparing NO and inhaled PGE,.133 Phase I1 and I11 clinical trials have been completed, and the results were disappointing. In a phase 11, prospective, multicenter,

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randomized, double-blind, placebo-controlled study, 177 patients with ARDS received inhaled NO at various fixed concentrations or placebo. In the treatment group, an increase in the Pao2 of equal to or greater than 20% was seen in 60% of the recipients of NO; no significant difference was noted between the dose groups. Likewise, no statistically significant differences were seen between the NO group and placebo group with respect to mortality rate, number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation requirements for extubation. There was, however, a statistically significant difference in these parameters in the NO-dose group receiving the 5ppm dose. In a post hoc analysis, in the 5-ppm-dose group, the percentage of patients alive and off mechanical ventilation at day 28 was 62%, versus 44% in the placebo group (P 50.05). Additionally, there was no significant difference in the number or type of adverse events between the NO recipients, compared with placebo recipients. Trends were also observed with regard to decreases in the intensity of mechanical ventilation and improved patient benefits in the 5-ppm inhaled dose; however, because of the small sample group, statistical significance was not achieved.47In a letter to the editor, Preiser and Sza1b0'~l criticized the study for its failure to show improved mortality, and suggested that the random assignment of NO recipients to a fixed NO dose was a significant study design flaw. They point out that the randomly prescribed, fixed dose of NO may have been too high or too low for a given clinical situation, in some cases leading to a high concentration of inhaled NO with a high FIO, which has been associated with increased production of This peroxynitrite, a toxic oxygen toxic molecule has been shown to amplify the hyperoxia-induced lung injury in animal m0de1s.l~~ An additional limitation of the study by Dellinger et a147was its failure to control for various modes of mechanical ventilation. Likewise as discouraging are the preliminary results of a large phase 111, prospective, randomized, unblinded, multicenter European trial of inhaled NO and conventional treatments versus conventional therapy alone in the treatment of ALI. This study

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demonstrated no difference in 30-day mortality between the groups.1o1In the same study, they actually noted an increased incidence of mortality and renal failure in ARDS patients treated with NO, as noted in an editorial by Zapol.lol,Iy1 Despite promising results in many smaller trials, no large study to date has demonstrated an improvement in patient survival with use of inhaled NO in ARDS. Currently, the use of inhaled NO in the treatment of ARDS must be considered on an individual basis, and reserved for use in patients with severe hypoxemia refractory to other interventions.

Antioxidants

Oxygen radicals are highly reactive species that are thought to play a major role in tissue injury associated with the systemic inflammatory response. These species are produced in significant quantities by activated neutrophils and macrophages, and are vital to the ability of these cells to destroy microorganisms. Following stimulation by inflammatory mediators (e.g., TNF-a, interleukins), neutrophils respond with a "respiratory burst," producing the superoxide radical (-0,), which, through subsequent reactions, can result in the generation of a toxic hydroxyl radical (.OH). Superoxide radical (-0, - ), through reaction with superoxide dismutase (SOD), can also be converted to hydrogen peroxide (H202),which can either oxidize chloride ions to form hypochlorous acid, an antimicrobial substance, or form -OH. Free radicals are also produced during biosynthesis of prostaglandins and leukotrienes by the enzyme xanthine oxidase, which can be activated by neutrophils or inflammatory mediators. Although they are needed for host defense, free radicals can also cause cellular damage. This cellular damage is normally prevented by elaborate antioxidant mechanisms that involve enzymes (SOD, catalase), sulfhydryl-bearing peptides and proteins (most notably, glutathione), and low-molecular-weight scavengers (vitamin C, vitamin E, P - c a r ~ t e n e )During .~~ states of extensive inflammatory activity, however, the oxidant load generated by the -

numerous inflammatory pathways may overwhelm these antioxidant defenses and become injurious. In isolated perfused lungs, oxidant injury is associated with high-permeability pulmonary edema similar to ARDS. Increased amounts of H,O, are found in the exhaled breath of ARDS patients and may be indicative of a high degree of intrapulmonary oxidant activity.'6, Several studies, using cells, isolated lungs, and whole animals, have supported the concept that free radicals are important in the production of ALI and are the subject of reviews el~ewhere.~" 17y In an attempt to ameliorate tissue injury produced by toxic oxygen species, methods of augmenting antioxidant defenses have been studied for the treatment of sepsis and ARDS. Supplementation of antioxidant enzymes, although attractive, has produced mixed results in animal studies. As is common in the initial studies of complex systems in vivo, comparison is made difficult by the various models and dosages used. Administration of SOD, alone or with other antioxidants, has had effects that range from beneficial to ineffective to harmful. As described previously, high levels of SOD may, at times, indirectly produce deleterious amounts of .OH or H,O,. It is likely that native SOD penetrates cell membranes poorly, and the administration of polyethylene glycol-stabilized SOD, or SOD encapsulated in liposomes, has been shown to reduce some types of experimental oxidant or septic lung injury. In animal studies, catalase given in various forms has been shown to have some protective effects. As with SOD," its usefulness in clinical sepsis and ARDS has not been established." The replenishment of glutathione (GSH) is one of the best-studied approaches to antioxidant therapy. Glutathione is a tripeptide that contains a cysteine residue, the sulfhydryl group of which provides reducing potential. Glutathione is important in the synthesis of DNA and proteins, amino acid transport, metabolism, enzyme activity, and cell protection. In the presence of glutathione peroxidase, glutathione acts to reduce hydroperoxides, neutralizing their injurious effects on cells.122 In the lung, alveolar lining fluid contains some of the highest extracellular concentrations of reduced glutathione as well as disul-

ACUTF RESPIRATORY DISTRESS SYNDROME

fide glutathione (GSSG) in the body. This is important because the highest concentrations of oxygen to which the body is exposed are found in the alveolus. In patients with ARDS and in animal models of endotoxin-induced lung injury, decreases in glutathione levels in alveolar lining fluid, as well as in plasma and red blood cells, have been shown.65,122, la In preliminary reports from Guidot et al,71lung lavage fluid from ethanol-fed rats had a greater than 75% reduction in glutathione levels, and the lungs had more edematous injury after exposure to endotoxin compared with controls, supporting a direct role for glutathione depletion in ethanol-mediated susceptibility to lung injury. Augmentation of glutathione levels therefore appears to be an attractive therapy. It could potentially be achieved by administration of glutathione itself, a glutathione derivative, cysteine, or a cysteine analog. Exogenous glutathione does not enter cells readily in its intact form and might, itself, be a source of free radicals under certain conditions. Glutathione ethyl ester is more lipophilic and penetrates cells more easily. Its use as a form of glutathione replacement is being investigated. The administration of free cysteine is potentially toxic in large amounts, is quickly metabolized to cystine, and, like glutathione, does not enter cells readily. This makes use of cysteine less likely. The cysteine analogue oxothiazolidine, however, which is metabolized intracellularly into cysteine, may be exploited as a means of delivering cysteine into cells. N-acetylcysteine (NAC), a commercially available cysteine analogue, is a thiol donor that has been used for its mucolytic properties and its ability to improve depleted glutathione stores in the treatment of acetaminophen toxicity. In animal models of lung injury, NAC has been shown to reduce endotoxinand hyperoxia-induced lung injury. In a randomized, double-blind, pilot study using IV NAC in the treatment of sepsis-induced ARDS, plasma and red blood cell glutathione levels were significantly increased.18 Subsequently, Bernard et aIz2 conducted a large, multicenter, randomized, double-blind, placebo-controlled, prospective trial comparing the effects of NAC and oxothiazolidine (Procysteine [OTZ], Clintec Technologies, Chi-

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cago) in patients with ARDS. Both of the antioxidant agents repleted red blood cell glutathione. There also was a decrease in the number of days of ALI and a significant increase in the cardiac index in both the NAC and OTZ treatment groups. There was, however, no difference in mortality among the three groups-NAC, OTZ, and placebo. This study suggests that repletion of glutathione may be achieved with NAC or OTZ in patients with ALI and ARDS, and treatment may shorten the duration of ALI.22Larger studies are needed to confirm these benefits of antioxidant treatment in ARDS. Another method of administration of antioxidants in the critically ill patient is by enteral nutrition. In a recent prospective, multicenter, double-blind, randomized controlled trial in ARDS patients, enteral feeding with eicosapentaenoic acid (EPA; fish oil), ylinolenic acid (GLA; borage oil), and antioxidants was compared to controls who received standard enteral feeding. The EPA plus GLA recipients had significant decreases in neutrophils in their bronchoalveolar lavage (BAL) fluid, significant increases in oxygenation, and lower ventilatory requirements; required significantly fewer days of mechanical ventilation compared with controls (11 versus 16.3 days); and had a significant decrease in the number of days in the intensive care unit (12.8 versus 17.5). Also, there was a significant decrease in cases of new organ failure during the study in the EPA plus GLA recipients compared with controls (4 of 51, 8% for EPA GLA versus 13 of 47, 28% for cont r o l ~ )These . ~ ~ results suggest that this enteral formula may be a useful adjunct to the clinical management of ARDS patients, or those at risk for development of ALI and ARDS.

+

Antiproteases Activated inflammatory cells release proteolytic enzymes that are particularly injurious to the lung. The levels and activities of proteases in the BAL fluid of patients with ARDS have been examined, and increased amounts of immunologically detectable proteases, particularly the serine protease neutrophi1 elastase, are commonly 96, lo3, 17*, The proteolytic activity, however, has

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not been consistently elevated; this is probably indicative of variable levels of inactivation by local antiproteases. Given the elevation of elastase in the BAL fluid of ARDS patients, it may well be that elastase activity is associated 164 Interestwith ARDS in patients at ingly, urinary excretion of desmosine, an indirect indicator of ongoing elastolyis, seems to correlate with the degree of lung injury in ARDS patients.167Also, in animal experiments, the administration of neutrophil elastase causes increased vascular permeability, leukocyte accumulation, pulmonary hemorrhage, and parenchymal injury, all of which are characteristic features of ARDS.77,147 The ability of excessive proteolysis to damage the lung (as in hereditary a,-antiprotease [aU,-AP] deficiency) is well known, and therapies designed to enhance antiprotease activity in ARDS seem reasonable. The use of al-AP replacement is well tolerated and currently is used for treatment of hereditary al-AP deficiency. Raising the levels of endogenous alAP levels by the use of gene therapy is under active investigation. Animal studies have demonstrated that exogenous antiproteases can blunt lung injury. In a rat model of endotoxin-induced lung injury, gabexate mesilate, a synthetic protease inhibitor, given prior to endotoxin insult, was shown to significantly attenuate endotoxin-induced pulmonary vascular injury. Gabexate mesilate also significantly inhibited the endotoxin-induced increase in serum TNF-a, which may have a major role in the development of sepsisrelated lung injury, suggesting that this was its major mechanism of action.l18 In a study of endotoxin-induced lung injury in rabbits, pretreatment with ONO-5046 (On0 Pharmaceutical Co, Osaka, Japan), a specific elastase inhibitor, attenuated lung injury. In the BAL fluid of the treatment group, there were decreases in activated complement C5a, IL-6, IL8, and thromboxane-B, suggesting that the benefits of ONO-5046 may be attributable both to its inhibitory effects on elastase and the reduction in inflammatory mediators.lZ0 The association between cardiopulmonary bypass (CPB) and the development of lung injury is well documented and has been shown to be neutrophil-mediated.36.87, 171 Using a pig model, Carney et a13* used CPB

and endotoxin (LPS) infusion to induce lung injury. They then examined the effects of CMT-3 (CollaGenex Pharmaceuticals, Newtown, PA), a chemically modified tetracycline that is a potent matrix metalloproteinase (MMP) inhibitor and elastase inhibitor, on the development of lung injury. They found that treatment with CMT-3 reduced both elastase and MMP activity, decreased neutrophil infiltration into the pulmonary interstitium, and decreased protein leak. There was also improvement in oxygenation in the CPB + LPS + CMT-3 recipients, compared with recipiLPS. This study provides iments of CPB petus to further investigate antiprotease strategies for the prevention and treatment of ARDS.

+

Anticytokine Agents

Cytokines are small proteins produced by immune effector cells, primarily macrophages and monocytes. They are major components of the inflammatory-immuneresponse, stimulating production of a host of mediators, in addition to stimulating their own production. They are normally found in low concentrations, but can be released in large amounts in sepsis. The role of cytokines in the systemic inflammatory response has been well de63 Tumor necrosis factorscribed el~ewhere.~’ a and IL-1, -6, and -8 have been the subject of research for possible means of altering cytokine production and their subsequent inflammatory effects. In an experimental animal model of sepsis, the initial septic insult is followed by a predictable sequence of increases in cytokine levels. An initial rise in TNF-a in 1 to 2 hours is followed by increasing levels of IL-1 and -6 approximately 1 hour later. Tumor necrosis factor-a appears to be the stimulus for the resulting cascade because it has been shown that blocking TNF-a levels reduces the subsequent levels of IL-1 and -6. When TNF-a is infused in animals, the result is a syndrome much like sepsis and ARDS. Interleukin-1 appears to be less potent but acts synergistically with TNF-a. In human patients with sepsis, large and prolonged levels of circulating 45, 46, TNF-a and IL-6 imply a poor outcome.40*

ACUTE RESPIRATORY DISTRESS SYNDROME lo*,lZ9 Increased levels of TNF-a have also been found in the BAL fluid of ARDS 157 High levels seem to predict the development of ARDS in patients at risk.lU Cytokine localization in the lungs may be more important pathogenetically than its presence in the systemic circulation because high BAL levels are not associated with high serum levels.la In addition, high plasma cytokine levels do not consistently correlate with the development of ARDS in patients at risk.lM,144 High levels of IL-8, a potent chemoattractant, have been found in the lungs of patients with ARDS but, again, plasma levels are generally undetectable. Given the high lung-to-plasma gradient of this cytokine, IL-8 may be the major contributor to the neutrophilic influx into the lungs of ARDS patient~.~~ Given the significant effects that cytokines have in mediating the pathophysiologic responses in sepsis and ARDS, pharmacologic modulation of their concentrations may offer options for treatment. Another possibility is that of blocking cytokines; however, this may impair host defenses or may deprive the organism of low-level exposure to cytokines, which induces tolerance to subsequent septic or cytokine-induced insult. Because cytokine levels do not rise immediately in response to the injurious agent, this provides a potential window of opportunity in which patients may receive anticytokine treatments. In clinical practice, this time window is long past by the time treatment can be initiated. Anticytokine therapies therefore must be hypothesized to work on subsequent releases of cytokines, not on their initial e1ab0ration.l~ In animal models of sepsis, pretreatment with anti-TNF-a antibodies decreases mortality. Therapy given shortly after the septic insult has also been found to be protective. Increased survival is seen in animal models of sepsis with administration of IL-1 receptor antagonist (IL-lra), a naturally occurring acute-phase reactant. Similarly, soluble receptors that bind TNF-a are also released into the circulation. Administration of soluble exogenous receptors has also been associated with improved survival in animal models of endotoxemia. Whether these manipulations

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could prevent sepsis-related ARDS is not known.19 Anti-TNF-a antibodies, soluble TNF-a receptors, and exogenous IL-lra have all been tested in human trials. In a study of 80 septic patients, administration of murine monoclonal anti-TNF-a was well tolerated, but no improvement in survival was noted.% In a larger trial of a murine monoclonal anti-TNFa antibody in sepsis, no benefit was demonstrated, and treatment-group patients in a phase I1 trial of soluble TNF-a receptors demonstrated dose-related increases in mortality.l19 In an open-label phase I1 trial of recombinant IL-lra, patients appeared to have an overall survival benefit? that was enhanced in patients who had particularly high levels of circulating IL-6. These beneficial effects were not confirmed in a subsequent large, blinded, multicenter phase I11 trial, h0wever.5~ In a retrospectively defined subset of severely ill patients, however, the later study of Fisher did reveal improved survival. Unfortunately, a follow-up trial designed to verify this improved survival benefit was terminated when interim analysis revealed that a survival benefit was very unlikely to be shown. In a recent phase 11, multicenter, doubleblind, controlled trial, patients with severe sepsis were randomized to receive polyclonal anti-TNF-a (anti-TNF) Fab fragments, or placebo. The study showed that anti-TNF rapidly cleared TNF from the plasma and decreased levels of IL-6, a potent inflammatory cytokine. Anti-TNF also reduced the duration of mechanical ventilation and number of intensive care unit days; a trend toward lower mortality was also seen in the anti-TNF recipi e n t ~These . ~ ~ results ~ are indicative of the potential for this class of agents in modifying the inflammatory response seen in sepsis and ARDS. In summary, anticytokine strategies in sepsis have not proved to be beneficial in large trials to date. Given that sepsis is a very common and deadly complication of ARDS, interference with the cytokine system has the real potential of causing deleterious effects on the host's ability to fight infection. This may limit the utility of these agents in treating septic patients.

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Surfactant

Surfactant is a complex of phospholipids, neutral lipids, and several specific proteins, which is secreted by type I1 pneumocytes. Its physiologic roles are to reduce the high surface tension of the alveolar air-liquid interface and prevent alveolar collapse at low transpulmonary pressures. Reduced surfactant function, or "lack of" surfactant, is classically associated with infant respiratory distress syndrome, and can have numerous deleterious effects. Because of the resulting increased surface tension at the alveolar airliquid interface, atelectasis occurs. This produces ventilation-perfusion mismatch and intrapulmonary shunt, with resulting hypoxemia. To worsen matters, lung compliance is reduced, thereby increasing work of breathing. In the mechanically ventilated patient, the high inspiratory pressures provided to overcome low compliance predispose to impaired cardiac function and barotrauma. Furthermore, artificial disruption of surfactant function in animal studies can result in pulmonary edema, possibly because of increased hydrostatic gradient between the high surface tension alveoli and the adjacent microvasculature. These findings are quite similar to those in ARDS. In early studies of ARDS, it was found that the abnormal pressure-volume behavior of diseased lungs was associated with surfactant dysf~nction.'~~, 128 Surfactant recovered from BAL fluid of ARDS patients is structurally abnormal and has poor function and abnormally high surface tension.", 73 The normal function of surfactant may be impaired by the inflammatory mediators released by activated granulocytes.'46In animal models of ARDS, surfactant is inactivated by pulmonary edema fluid.9',154 This may be a result of the accumulation of soluble proteins such as fibrin monomers or albumin in the alveoli, caused by loss of the normal sieving function of the injured pulmonary endothelium in lung injury. Although inflammatory mediators have been shown, in vitro, to inhibit surfactant synthesis, reduced surfactant synthesis has not been observed consistently in ALI and sepsis. Although surfactant replacement therapy has been evaluated extensively in the new-

born,14, 86 experience in ARDS is limited. In animal studies of lung injury, surfactant appears to improve lung mechanics and gas exchange. Small, uncontrolled trials of surfactant in human patients with ARDS transiently improved lung function. Therapy with surfactant was also well tolerated.75,159 In 1996, Anzueto et alRreported the results of a large, randomized, placebo-controlled trial in which 725 ARDS patients received aerosolized synthetic surfactant or placebo. There was no significant improvement in gas exchange or in mortality at 30 days,s although this study may have been compromised by inadequate dose delivery. Despite encouraging results in animal studies, no beneficial effect on patient outcome has been demonstrated, and the routine use of surfactant in the treatment of ARDS cannot be recommended.

Other Agents

Almitrine bismesylate is a piperazine derivative that stimulates chemoreceptors in the carotid and aortic bodies, thereby stimulating respiration. This is especially true during hypoxemia. Is has also been shown to potentiate hypoxia-induced pulmonary vasoconstriction, resulting in an increase in oxygenation.61 Several small trials using almitrine have been performed, but no large, multicenter, randomized trials have been reported to date. In a small, uncontrolled trial of almitrine in patients with chronic obstructive pulmonary disease (COPD) and hypoxemia, almitrine increased Pao, and decreased Paco2 compared with baseline levels.'86Similar improvements in arterial blood gases were seen in a 2-year study comparing the use of almitrine versus placebo in hypoxemic COPD patients; despite improvement in blood gases, however, no improvement in survival was seen.I7Two small trials using almitrine in patients with ARDS are reported in the literature, comparing almitrine with positive end-expiratory pressure (PEEP), and almitrine with controls. The first trial compared the use of PEEP (10 cm H,O) versus almitrine, and demonstrated that both PEEP and almitrine improved Pao, and decreased venous admixture. The use of PEEP was also associated with a significant de-

ACUTE RESPIRATORY DISTRESS SYNDROME

crease in mean arterial blood pressure, however, whereas almitrine had no effect on hem o d y n a m i c ~ . The ' ~ ~ second trial compared the use of almitrine in ARDS patients with controls, and showed a significant increase in Pao2 and a reduction in both the Paoz-PAOz gradient and venous admixture. Similar results have been reproduced in other small The use of almitrine bismesylate with NO has also been investigated. In theory, a selective pulmonary vasoconstrictor should augment hypoxia-induced vasoconstriction in the pulmonary vasculature. When used in combination with inhaled NO, vasoconstrictors should augment the decrease in shunting by enhancing the vasoconstriction in nonventilated regions, shifting more pulmonary blood flow to the NO ventilated and vasodilated units, thereby improving oxygenation. Papazian et aP'' conducted a prospective, randomized trial comparing responses to a nonselective vasoconstrictor, norepinephrine (NE); the selective pulmonary vasoconstrictor, almitrine; and inhaled NO, each alone and in combination, in 16 patients with ARDS. The results demonstrated that inhaled NO and almitrine alone both improved oxygenation; NE had no effect. A synergistic effect on oxygenation with combined inhaled NO and almitrine (P
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for several years for its ability to enhance perfusion in chronic peripheral vascular disease. It is a phosphodiesterase inhibitor and adenosine receptor antagonist, and it possesses anti-inflammatory properties. Pentoxifylline blunts granulocyte oxidant production and attenuates the response of granulocytes to stimulation by endotoxin and cytokines. In animal models of sepsis and lung injury, it has been shown to inhibit the endotoxin-stimulated release of tumor necrosis factor-a (TNF-a), as well as decrease neutrophilic lung injury and pulmonary hypertension associated with e n d o t ~ x i n .93,~ ~155, In the murine model of septic shock, increased survival was seen when the drug was given up to 4 hours after the experimental insult,148although delayed treatment has not been as impressive in other animal m0de1s.I~~ In a small study of patients with ARDS, pentoxifylline was associated with a small increase in heart rate, and a trend toward increased arterial oxygen content was noted. *I5 In 1997, Bacher et all5 reported the results of a small clinical trial in which 19 ventilated patients, both septic and nonseptic, were treated with intravenous pentoxifylline over 3 hours. In the septic patients, pentoxifylline was associated with an increase in cardiac index, with resulting improvement in oxygen transport and oxygen uptake, but without improvement in oxygen e ~ t r a c t i 0 n . lThese ~ changes occurred without significant change in the pulmonary artery wedge pressure. A pilot study in ARDS patients was performed, in which substantial doses of pentoxifylline over a short period appeared to be safe.115A multicenter, prospective, randomized, placebo-controlled trial of lisofylline, another methylxanthine derivative, to determine whether it has a role in the management of ARDS, was recently halted because of lack of clinically important effect. Ketoconazole, an antifungal agent in general clinical use, is a potent inhibitor of thromboxane-A, an inflammatory mediator that plays a significant role in the development of ARDS.55Two small studies have examined the use of ketoconazole as prophylaxis against the development of ARDS. In the first trial, critically ill patients who were randomized to receive ketoconazole had a

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significant reduction in the incidence of ARDS vary substantially, a major problem beARDS compared with controls (6% in the ketcause the endpoint of studies in ARDS is oconazole group versus 31% in controls; P typically mortality. Another problem in conr0.01).158The second trial was a randomized, ducting studies in ARDS is the relative scarprospective, controlled trial using septic surcity of patients in any given medical center at gical patients as subjects. It also noted a sigany one time. Although the incidence of nificant reduction in the incidence of ARDS ARDS is widely reported at 150,000 cases per in ketoconzole recipients compared with conyear or more, the number that can actually be trols (15% versus 64%; P 50.00Z).190In a large recruited into clinical trials is quite small. multicenter study conducted by the ARDS Other issues complicating the study of ARDS network investigating the role of ketoconais the short time available between developzole in ARDS, however, Steinberg reported ment of the syndrome and study enrollment. preliminary results that showed a lack of efOnly recently has there been substantial fectiveness.161 agreement on the definition of ARDS among The use of permissive hypercapnia as a investigators and it is not yet clear that physimeans of decreasing the risk of barotraumas cians at the bedside are like-minded on defiis common in the treatment of patients with nitions, especially across disciplines (e.g., ARDS. Its effects on ALI remain relatively medical critical care, surgical critical care, trauma, burn units). It is generally accepted unknown. In a recent study, hypercapneic acidosis was found to decrease LPS-induced leuthat truly useful clinically applicable results kocyte adhesion to human pulmonary artery will be obtained only from prospective, ranendothelial cells by 31%. There were also dedomized trials with placebo controls, alcreased levels of NF-KB activation and dethough, in some studies, the latter will not be creased intercellular adhesion molecule-1 possible. Studies that rely on historical con(ICAM-1) expression. This indicates that pertrols are generally useful only for hypothesis missive hypercapnia may have beneficial efgeneration, pharmacokinetics, design of future randomized protocols, and safety inforfects in ARDS beyond mechanical protection, mation in the case of new agents. It is difficult and may protect against pulmonary inflamenough to obtain well-matched groups (i.e., mation secondary to endotoxin.166In a recent balanced in important prognostic variables) trial of low tidal volumes versus high tidal in prospective randomized trials. All too frevolumes in mechanically ventilated ARDS quently, trials using historical controls dempatients, it was found that patients who onstrate improved outcome with the new received higher tidal volumes ("hightherapy. This may be because of the time stretch")-12 mL/ kg-had increased indicalapse between the collection of data on the tors of lung inflammation and increased incidence of multiple system organ fai1u1-e.~~ controls and the experimental patients, allowing for intercurrent effects of many unThese results are very encouraging, and the controlled variables. During this lapse, a large data are awaiting publication. variety of intervening factors (e.g., new antibiotics, better ventilators, changes in attitudes CLINICAL TRIAL CONSIDERATIONS toward life support, etc.) could influence the outcome of sepsis patients. Even in prospective, randomized trials, variations in clinical Although substantial attention has been management introduce uncontrolled varigiven to the preclinical development of many ables that must be dealt with during the data of the mediator antagonists, agents have been slow to be introduced into clinical trials. Alanalysis process. Clinical studies in ARDS could be facilithough there are many reasons for this latated if standardization of routine care were tency, a principal cause is the difficulty in possible to minimize variability between conducting clinical trials in ARDS. For one thing, clinically, ARDS is a heterogeneous distreatment groups. Because clinical care is not order, resulting from insults as diverse as sepcurrently standardized, the process would have to be protocol driven and would require sis and aspiration of gastric contents. The substantial cooperation from patients atmortality of the disease processes underlying

ACUTE RESPIRATORY DISTRESS SYNDROME

tending physicians, and other caregivers-not a trivial task.

Endpoints in Phase 111 Clinical Trials in Acute Respiratory Distress Syndrome

The endpoint usually sought in phase I11 clinical trials in ARDS is short-term (28-day or 30-day) mortality. Contrary to common belief, although death itself is unequivocal, death is not unequivocal as an endpoint in clinical studies. The definition of death is a difficult issue, however. Many studies use "all-cause mortality" because assigning cause of death in ICU patients is often very difficult. Duration of follow-up can be quite variable, as well, with 1Cday or 28-day mortality being the most common. Still others use risk-adjusted mortality, which is to say that the mortality risk associated with the patient's condition at the time of study entry would be taken into consideration in the statistical analysis of the results. Mortality therefore is variably defined from study to study. Further complicating this issue is the fact that life-support decisions (e.g., resuscitation status, living wills, etc.) can have a major impact on mortality measured in these ways. Aside from these problems, mortality endpoints in ARDS trials have been problematic for several other reasons: (1) ARDS patients very often die from their underlying illness rather than respiratory failure. One would not expect most investigational agents to affect the mortality of the underlying illness (e.g., multiple trauma). (2) Because of our poor ability to determine this underlying mortality rate, the reported mortality of ARDS has varied widely, from 10% to more than 90%, even when similar definitions of ARDS are used. (3) Mortality is a dichotomous endpoint (it either happens or it doesn't), making it relatively insensitive. If a drug were able to completely reverse ARDS, for example, it would be expected that this would translate into improved survival. Because mechanical ventilation is so readily available and reasonably safe, however, acute respiratory failure patients may survive the first 30 days of ARDS

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at nearly the same rate as those who were "cured by the investigational agent. SUMMARY

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