Pharmacology of Acute Lung Injury

S. Tasaka and A. Ishizaka

z Introduction

The acute respiratory distress syndrome (ARDS) is a process of acute inflammatory lung injury resulting from a variety of predisposing conditions including severe pneumonia, sepsis, massive transfusion and trauma [1]. Recent reports showed substantial improvement in the prognosis of acute lung injury (ALI)/ARDS over the last 2 decades [2]. In the 1980s, mortality rates in excess of 50% were commonly reported, whereas the current mortality of ARDS seems to be in the 30 to 40% range. This improvement in clinical outcomes of ARDS is likely to be due to the advances in supportive therapy and ventilatory management, because it has oc- curred in the absence of specific new pharmacological intervention for this disease. Although a number of clinical trials have been performed, it is a frequent and un- fortunate finding in this area that encouraging results from early studies are not re- plicated in larger, phase III studies [3]. This chapter, an update of the authors' 2002

Table 1. Possible pharmacological interventions for ARDS

Therapeutic agents for physiological abnormality in ARDS z Alveolar surfactant z b2-agonists z Diuretics and atrial natriuretic peptide z Prostaglandins and other vasodilators Therapeutic agents for acute inflammatory responses in ARDS z Ketoconazole z Neutrophil elastase inhibitor z Monoclonal antibodies (endotoxin, cytokines, adhesion molecules, etc) z TNF-a receptor fusion protein z IL-1 receptor antagonist z Pentoxifylline/Lisofylline z Prostaglandin E1 Therapeutic agents for abnormalities in coagulation system in ARDS z Activated protein C z Antithrombin z Tissue factor pathway inhibitor Therapeutic agents for fibroproliferative stage of ARDS z Glucocorticoids 74 S. Tasaka and A. Ishizaka

review [4], reviews the current status of pharmacological approaches to the treatment of ALI/ARDS (Table 1).

Anticytokine Therapy Since ALI/ARDS is often associated with systemic inflammation such as sepsis, it is reasonable to assume that therapy directed against the putative mediators might reduce the incidence of the syndrome. Because tumor necrosis factor (TNF)-a is thought to play a central role in the pathogenesis of sepsis, various TNF-a neutra- lizing compounds (monoclonal antibodies against human TNF-a and soluble TNF-a receptors) have been produced. Recent clinical trials using anti-TNF antibody fragment (afelimomab) for septic patients seem favorable [5, 6]. A dose-ranging study using afelimomab failed to show any beneficial effect on 28-day survival, but a post hoc analysis of this trial suggested that patients with baseline increased serum interleukin (IL)-6 concentrations (>1000 pg/ml) appeared to benefit from afelimomab [5]. In the patients with increased IL-6, a significant improvement in survival was observed in the afelimomab groupafter adjusting for the sepsis severity score [6]. Type I (55 kDa) and type II (75 kDa) TNF-a receptors (TNFR) have been identi- fied and used to bind TNF-a in patients with sepsis. Pittet and colleagues assessed the impact of therapy with TNFR fusion protein (p55-IgG) on the incidence of end- organ failures in patients with severe sepsis. Patients treated with p55-IgG had more organ failure-free days and shorter ICU stay than those who received placebo [7]. IL-1 is another important mediator in the pathogenesis of sepsis syndrome. IL-1 receptor antagonist (IL-1ra) is a naturally occurring human protein produced by macrophages and other cells and prevents cellular responses mediated by IL-1. Although IL-1ra decreased mortality in experimental endotoxemia, randomized, double-blind trials failed to demonstrate a clinical benefit of IL-1ra in patients with sepsis syndrome [8, 9].

z Anti-adhesion Molecule Therapy

One of the initial steps in ALI/ARDS is an interaction between neutrophils and pulmonary endothelial cells, which is mediated by various adhesion molecules. A small clinical study showed that administration of monoclonal antibody against CD18, an adhesion molecule on neutrophils, to trauma patients with hemorrhagic shock less than 6 hours after onset may be beneficial [10]. Because the onset of trauma is more definite compared with other events such as onset of sepsis, this measure provides a potent new approach to prevent the development of ALI/ARDS in at-risk groups.

z Alveolar Surfactant

Surfactant dysfunction or deficiency is thought to be important in the development of ALI/ARDS. Surfactant can be delivered either by an in-line nebulizer or by direct intrabronchial instillation by means of bronchoscopy. Because, in the alveolar spaces of established ARDS, the leakage of circulatory proteins and the inflamma- Pharmacology of Acute Lung Injury 75 tory exudates may adversely affect the administered surfactant, the lavage method of administering surfactant appears to offer advantages not experienced with the bolus method of administration. Two phase II trials of animal-based surfactant products containing apoprotein demonstrated survival advantages in ARDS patients, but the quantity of exogenous surfactant necessary to treat ARDS patients may preclude the use of natural surfactant because of cost and resource requirement [11, 12]. Since the protein compo- nent appears to enhance surfactant activity, KL4-surfactant, an artificial preparation containing a synthetic 21-amino-acid peptide (KL4-peptide) with properties similar to those of surfactant protein B, was developed. Wiswell and colleagues reported that sequential bronchopulmonary segmental lavage with KL4-surfactant (Surfax- in¾) improved oxygenation and outcome without any adverse effect in patients with ARDS [13]. Spragg and colleagues recently published the results of two phase III trials of a recombinant surfactant protein C-based surfactant (Venticute¾) as treatment for ARDS [14]. Patients were prospectively randomized to receive either standard therapy or standard therapy plus up to four intratracheal doses of Venticute¾ given within a period of 24 hours. Although the exogenous surfactant did not improve survival of ARDS patients, those who received surfactant had a greater improvement in gas exchange during the treatment period [14]. z Albuterol

Pulmonary edema is a common cause for severe hypoxemia in ARDS patients, and b2-agonists have been shown to accelerate edema clearance by regulating epithelial Na+ channels (ENaC) and other key proteins of alveolar epithelial active Na+ trans- port [15]. The ARDS Network plans to conduct the Albuterol versus Placebo in Acute Lung Injury (ALTA) study to test the safety and efficacy of aerosolized b2- agonist (albuterol sulfate) for reducing mortality in patients with ALI. z Pentoxifylline/Lisofylline

Pentoxifylline is a phosphodiesterase inhibitor that enhances intracellular levels of cyclic AMP. A derivative of pentoxifylline, lisofylline, is effective at down-regulating the inflammatory response in ALI [16]. In an NIH-sponsored ARDS Network study, 235 patients with ALI/ARDS were randomly assigned to receive either intravenous lisofylline (3 mg/kg every 6 hours) or placebo [17]. After the interim analysis, the trial was stopped, because the reported 28-day mortality for the lisofylline group was 31.9%, versus 24.7% in the placebo group. The trial also found no significant difference between lisofylline and placebo in ventilator-free days, resolution of organ failure, or infection-related mortality. z Ketoconazole

Ketoconazole is an antifungal agent and is also a potent inhibitor of thromboxane A2, which has been implicated as an important mediator in septic shock and the 76 S. Tasaka and A. Ishizaka

development of ARDS. A multicenter trial, under the auspices of the ARDS Net- work, was undertaken using ketoconazole as therapy for ALI/ARDS, and no difference in survival or ventilator-free days was noted in this trial [18].

z Atrial Natriuretic Polypeptide

Atrial natriuretic polypeptide (ANP) is a polypeptide hormone that is primarily synthesized in the right atrium in response to atrial stretch. Besides producing na- triuresis, ANP regulates vascular tone and may decrease vascular permeability in the lung. A prospective, randomized, study revealed that, in ALI patients, the measures of oxygenation and thoracic compliance were significantly improved at 24 h after initiating the ANP infusion, associated with decreases in lung injury score and shunt [19]. However, Bindels and co-workers compared ANP infusion and inhaled nitric oxide (NO) in ARDS and reported that, whereas inhaled NO reduced the mean pulmonary artery pressure and improved alveolar gas exchange, ANP infusion had no significant effects on these parameters [20].

z Prostaglandin E1

Prostaglandin E1 (PGE1) is an arachidonic acid derivative which blocks platelet ag- gregation, causes vasodilation, and modulates inflammatory response. In a randomized, double-blinded trial of liposomal encapsulated PGE1, it was noted that liposomal PGE1 was associated with a significantly shorter time to reach a PaO2/FIO2 ra- tio of >300 mmHg and to off mechanical ventilation, although the 28-day mortality did not differ [21].

z Glucocorticoids

The disappointing results of a series of clinical trials using a short course of glucocorticoids in the 1980s have prevented the use of steroids especially in the acute phase of ALI/ARDS. More recently, Meduri and colleagues described a small randomized trial of glucocorticoid as treatment for the later or fibroproliferative stage of ALI/ARDS [22]. Among 24 patients randomized, 16 were treated with a glucocorticoid at 2 mg/kg per day, started 7 days after the diagnosis of ARDS and con- tinued for 32 days, resulting in a significant reduction in lung injury and organ failure scores and improvement in oxygenation. Glucocorticoid treatment also decreased hospital-associated mortality from 62% in the placebo group to 12% in the treated group[22]. In 1997, the ARDS Network began the Late Steroid Rescue Study (LaSRS), a larger randomized, placebo-controlled, multicenter trial to com- pare the effect of corticosteroids with placebo in the management of late-phase ARDS. In the trial, ARDS patients between 7 and 28 days of onset and under con- tinuous mechanical ventilation were enrolled. Patients in the treatment groupre- ceived bolus injection of 2 mg/kg of methylprednisolone sodium succinate (mPSL), followed by 0.5 mg/kg every 6 hours for 14 days. LaSRS was designed to include 180 patients, and its primary endpoint is in-hospital mortality at 60 days. Second- ary endpoints include ventilator free days and organ failure free days. In the 2004 Pharmacology of Acute Lung Injury 77 international conference of the American Thoracic Society, the investigators pre- sented an interim report of the LaSRS. Although there was no difference in 60-day in-hospital mortality between the mPSL and the placebo groups, the ventilator free days and ICU free days to day 28 were significantly longer in the mPSL group. There were no differences in ICU free days or hospital free days in the placebo versus the mPSL groups. Further analyses are in process to evaluate mortality and morbidity endpoints at 180 days. z Coagulation System

Inflammatory cytokines, including TNF-a, IL-1b, and IL-6, are capable of activating coagulation and inhibiting fibrinolysis, whereas the procoagulant thrombin is capable of stimulating multiple inflammatory pathways [23]. Tissue factor is highly thrombogenic and occupies a central position in the extrinsic coagulation pathway. A recent phase II human study suggested that administration of tissue factor pathway inhibitor (TFPI), which regulates extrinsic pathway activity by suppressing tissue factor and factors VIIa and Xa, could reduce mortality associated with sepsis [24]. Antithrombin inhibits activated proteases, including factors IXa, Xa, and thrombin. Randomized, double-blind trials of antithrombin or antithrombin concentrates to septic patients revealed improvement in survival and sepsis-induced dissemi- nated intravascular coagulation (DIC) [25, 26]. A large clinical trial with nearly 2500 patients enrolled is presently investigating this hypothesis. Protein C is a vitamin K-dependent protein, which is activated by the thrombin- thrombomodulin complex on endothelial cells. Activated protein C (APC), with the cofactor protein S, cleaves and inactivates the procoagulant activity of activated factors V and VIII. Recently, the effect of recombinant human APC (drotrecogin alfa [activated]) was studied in a randomized, placebo-controlled trial of 1690 patients who had systemic inflammatory response syndrome (SIRS) and organ failure caused by suspected infection [27]. The two most common sites of infection reported were the lungs (53%) and abdomen (20%). Treatment with APC was associated with a significant reduction in the mortality at 28 days of approximately 6%. The relative risk of death was reduced by almost 20%. As the most important adverse effect reported was serious bleeding, the risks and benefits of APC therapy remain to be studied in patients at a higher risk of bleeding. The cost-effectiveness of the APC treatment has recently been evaluated, and it was noted that APC is rel- atively cost-effective when targeted specifically to patients who have severe sepsis, an APACHE II score higher than 25, and a long life expectancy if they survive the episode of sepsis [28]. z Neutrophil Elastase Inhibitor

Neutrophil elastase is a potent proteolytic enzyme, which decomposes various proteins including the extracellular matrix components, elastin, fibrinogen, proteogly- can and collagen. A randomized, double-blind trial with 230 SIRS patients in Japan revealed that high-dose sivelestat, a small molecular weight inhibitor of neutrophil elastase, significantly shortened ICU stay, although overall survival rate was not changed [29]. Since the methodological quality assessment score of the study is 78 S. Tasaka and A. Ishizaka

higher than the average, the sivelestat study in Japan is not considered methodolo- gically inferior [30]. Recently, Zeiher and colleagues reported results of the STRIVE study, in which 492 mechanically ventilated patients with ALI were enrolled [31]. They found no effect of sivelestat on the primary end points of ventilator-free days or 28-day all-cause mortality. The STRIVE study group, however, concluded that their findings do not preclude benefit of sivelestat in ALI patients, because the patients in their study had more non-pulmonary organ failures and worse baseline measures of lung function [31].

z Future Direction

In the past few decades, there has been substantial progress in the understanding of ALI/ARDS. Although the progress in specific treatment has lagged behind basic research to date, a number of ongoing clinical trials of new ventilatory and pharmacological strategies should further reduce mortality from this common clinical syndrome.

References

1. Ware LB, Matthay MA (2002) The acute respiratory distress syndrome. N Engl J Med 342:1334±1349 2. Hudson LD, Steinberg KP (1999) Epidemiology of acute lung injury and ARDS. Chest 116:74S±82S 3. McIntyre RC Jr, Pulido EJ, Bensard DD, Shames BD, Abraham E (2000) Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med 28:3314±3331 4. Tasaka S, Hasegawa N, Ishizaka A (2002) Pharmacology of acute lung injury. Pulm Pharma- col Ther 15:83±95 5. Reinhart K, Menges T, Gardlund B, et al (2001) Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study. Crit Care Med 29:765±769 6. Panacek E, Marshall J, Fischkoff S, Barchuk W, Teoh L, MONARCS Study Group(2000) Neu- tralization of TNF by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis: Results of the MONARCS trial. Chest 118:88S (abst) 7. Pittet D, Harbarth S, Suter PM, et al (1999) Impact of immunomodulating therapy on morbidity in patients with severe sepsis. Am J Respir Crit Care Med 160:852±857 8. Opal SM, Fisher CJ Jr, Dhainaut JF, et al (1997) Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 25:1115±1124 9. Fisher CJ Jr, Dhainaut JF, Opal SM, et al (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271:1836±1843 10. Vedder N, Harlan J, Winn R (1997) Pilot phase 2 clinical trial of a humanized CD11/CD18 monoclonal antibody in hemorrhagic shock. In: Faist E (ed) 4th International Congress on the Immune Consequences of Trauma, Shock and Sepsis: Mechanisms and Therapeutic Ap- proaches. Mondezzi editore, Bologna, pp 941 11. Gregory TJ, Steinberg KP, Spragg R, et al (1997) Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 155:1309±1315 12. Kesecioglu JM, Schultz MJ, Lundberg D, Lauven PM, Lachmann B (2001) Treatment of acute lung injury (ALI/ARDS) with surfactant. Am J Respir Crit Care Med 163:A813 (abst) 13. Wiswell TE, Smith RM, Katz LB, et al (1999) Bronchopulmonary segmental lavage with Sur- faxin (KL4-surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care Med 160:1188±1195 Pharmacology of Acute Lung Injury 79

14. Spragg RG, Lewis JF, Walmrath HD, et al (2004) Effect of recombinant surfactant protein C- based surfactant on the acute respiratory distress syndrome. N Engl J Med 351:884±892 15. Mutlu GM, Sznajder JI (2004) b2-agonists for treatment of pulmonary edema: Ready for clinical studies? Crit Care Med 32:1607±1608 16. Hasegawa N, Oka Y, Nakayama M, et al (1997) The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs. Am J Respir Crit Care Med 155:928±936 17. The ARDS Clinical Trial Network (2002) Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 30:1±6 18. The ARDS network (2000) Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome. JAMA 283:1995±2002 19. Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Amaha K (1998) Beneficial effect of atrial natriuretic peptide on pulmonary gas exchange in patients with acute lung injury. Chest 114:223±228 20. Bindels AJ, van der Hoeven JG, Groeneveld PH, Frolich M, Meinders AE (2001) Atrial natriuretic peptide infusion and nitric oxide inhalation in patients with acute respiratory distress syndrome. Crit Care 5:151±157 21. Abraham E, Baughman R, Fletcher E, et al (1999) Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. Crit Care Med 27:1478±1485 22. Meduri GU, Headley AS, Golden E, et al (1998) Effects of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 280:159±165 23. Hasegawa N, Husari AW, Hart WT, Kandra TG, Raffin TA (1994) Role of the coagulation system in ARDS. Chest 105:268±277 24. Laterre PF, Wittebole X, Dhainaut JF (2003) Anticoagulant therapy in acute lung injury. Crit Care Med 31:S329±S336 25. Balk R, Emerson T, Fourrier F, et al (1998) Therapeutic use of antithrombin concentrate in sepsis. Semin Thromb Hemost 24:183±194 26. Eisele B, Lamy M, Thijs LG, et al (1998) Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 24:663±672 27. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699±709 28. Angus DC, Linde-Zwirble WT, Clermont G, et al (2003) Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 31:1±11 29. Tamakuma S, Shiba T, Hirasawa H, Ogawa M, Nakajima M (1998) A phase III clinical study of a neutrophil elastase inhibitor; ONO-5046´Na in SIRS patients. J Clin Ther Med (Japan) 14:289±318 30. Bellomo R, Uchino S, Naka T, Wan L (2004) Hidden evidence to the West: multicentre, ran- domised, controlled trials in sepsis and systemic inflammatory response syndrome in Japa- nese journals. Intensive Care Med 30:911±917 31. Zeiher BG, Artigas A, Vincent JL, et al. (2004) Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 32:1695±1702