Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Prostaglandin E1 Study Group. High-dose corticosteroids in patients with the adult respiratory distress syndrome. Functional and metabolic activity of polymorphonuclear leukocytes from patients with adult respiratory distress syndrome: results of a randomized double-blind placebo-controlled study on the activity of prostaglandin E1. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. Dazoxiben in human sepsis and adult respiratory distress syndrome. Indomethacin treatment of human adult respiratory distress syndrome. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. Effects of prostaglandin E1 in adult respiratory distress syndrome. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo-controlled, randomized, double-blind, multicenter clinical trial. Early steroid therapy for respiratory failure. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant.
Prostaglandin E1 (PGE1) was compared to placebo in a 100-patient (50 PGE1, 50 placebo) randomized, double-blind, clinical trial to determine whether PGE1 therapy enhances survival of patients with adult respiratory distress syndrome (ARDS) when infused through a central line at 30 ng/kg/min continuously for seven days. At 30 days postinfusion, 30 PGE1 and 24 placebo patients had died. Total deaths judged to be related to the syndrome were 32 and 28 in the PGE1 and placebo groups respectively at six months. We conclude that PGE1 did not enhance survival in patients with established ARDS. PGE1 augmented the hyperdynamic circulation of these patients by reducing systemic and pulmonary vascular resistance, which resulted in a reduction of blood pressures and increased stroke volume, cardiac output, and heart rate. An improvement in oxygen availability and oxygen consumption was observed with PGE1 therapy. PGE1 was associated with an increased incidence of diarrhea (six patients in the PGE1 group vs one in the placebo group, p less than 0.05). Other adverse effects included hypotension (ten patients in the PGE1 group vs seven in the placebo group), fever (six patients in the PGE1 group vs three in the placebo group), and non-fatal dysrhythmias (ten in the PGE1 group vs five in the placebo group). Corticosteroids are widely used as therapy for the adult respiratory distress syndrome (ARDS) without proof of efficacy. We conducted a prospective, randomized, double-blind, placebo-controlled trial of methylprednisolone therapy in 99 patients with refractory hypoxemia, diffuse bilateral infiltrates on chest radiography and absence of congestive heart failure documented by pulmonary-artery catheterization. The causes of ARDS included sepsis (27 percent), aspiration pneumonia (18 percent), pancreatitis (4 percent), shock (2 percent), fat emboli (1 percent), and miscellaneous causes or more than one cause (42 percent). Fifty patients received methylprednisolone (30 mg per kilogram of body weight every six hours for 24 hours), and 49 received placebo according to the same schedule. Serial measurements were made of pulmonary shunting, the ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen, the chest radiograph severity score, total thoracic compliance, and pulmonary-artery pressure. We observed no statistical differences between groups in these characteristics upon entry or during the five days after entry. Forty-five days after entry there were no differences between the methylprednisolone and placebo groups in mortality (respectively, 30 of 50 [60 percent; 95 percent confidence interval, 46 to 74] and 31 of 49 [63 percent; 95 percent confidence interval, 49 to 77]; P = 0.74) or in the reversal of ARDS (18 of 50 [36 percent] vs. 19 of 49 [39 percent]; P = 0.77). However, the relatively wide confidence intervals in the mortality data make it impossible to exclude a small effect of treatment. Infectious complications were similar in the methylprednisolone group (8 of 50 [16 percent]) and the placebo group (5 of 49 [10 percent]; P = 0.60). Our data suggest that in patients with established ARDS due to sepsis, aspiration, or a mixed cause, high-dose methylprednisolone does not affect outcome. Indirect and experimental evidence suggests that polymorphonuclear leukocytes, responding to an activating signal presumably related to the complement cascade activation, are involved in the pathogenesis of the adult respiratory distress syndrome (ARDS). The pathologic changes seem to be result of the polymorphonuclear leukocyte margination within the pulmonary capillary vessels and their activation with subsequent release of vasoactive peptides (thromboxane A2, prostaglandin E2) and toxic intracellular compounds. This study confirms that adherence, chemotaxis, and chemiluminescence are increased in polymorphonuclear leukocytes from patients with ARDS. Enhanced chemotactic and chemiluminescence capacities are likely specific to ARDS, whereas increased polymorphonuclear leukocyte adherence seems to be nonspecific. If increased polymorphonuclear leukocyte activation is important in the pathogenesis of ARDS, the inhibition of this phenomenon could play a therapeutic role. This double-blind prospective study was undertaken to assess if polymorphonuclear leukocyte activity is inhibited in vivo by the iv administration of prostaglandin E1 (PGE1) in patients with ARDS. A continuous infusion of PGE1 at a dose of 30 ng.kg-1.min-1 for 7 days did not modify the functional activity of polymorphonuclear leukocytes in patients with ARDS. Because hemodynamic instability was seen during infusion of this dose of PGE1, an increased dose was not tested. At the dose of PGE1 tested, no significant effect upon the function activity of polymorphonuclear leukocytes in patients with ARDS could be demonstrated. The inappropriate endogenous secretion of tumour necrosis factor (TNF) could play a role in the pathogenesis of acute respiratory distress syndrome (ARDS), one of the most frequent causes of death in cancer patients. Because of its capacity to inhibit TNF secretion in vitro, pentoxifylline (PTX) could be extremely useful in ARDS therapy. In this study 30 advanced cancer patients with ARDS were randomized to receive either the conventional care or conventional care plus PTX (100 mg i.v. twice a day for 7 days followed by an oral administration of 400 mg three times a day) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome. Serum levels of TNF were measured before and after 7 days of therapy. The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls (12/15 versus 3/15; P < 0.001). The mean survival time was significantly higher in the PTX-treated group than in the controls. A clinical and/or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group (P < 0.01). TNF mean levels significantly decrease in the PTX-treated group. These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS. Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects. Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival.
                We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days.
                The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups.
                The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function. To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome (ARDS).
                A prospective, double-blind, placebo-controlled, randomized, parallel, multicenter pilot clinical trial.
                A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome.
                Patients were randomized into four treatment groups in a 2:1:2:1 ratio, as follows: 12 hours of surfactant per day, 12 hours of 0.6% saline per day, 24 hours of surfactant per day, and 24 hours of 0.6% saline per day. Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration.
                Ventilatory data, arterial blood gases, and hemodynamic parameters were measured at baseline, every 4 or 8 hours during the 5 days of treatment, 24 hours after treatment, and 30 days after treatment, at which time mortality was also assessed. Safety was evaluated throughout the 30 days of the study.
                Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system. Although there were no differences in any physiological parameters between the treatment groups, there was a dose-dependent trend in reduction of mortality from 47% in the combined placebo group to 41% and 35% in the groups treated with 12 hours and 24 hours of surfactant per day, respectively.
                Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days; however, at the doses given, it did not result in significant improvements in patients with sepsis-induced ARDS. Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis. The purpose of this investigation was to evaluate the magnitude and duration of changes in lung function and oxygen transport in patients with adult respiratory distress syndrome (ARDS) receiving indomethacin. Ten patients with ARDS were randomized to receive intravenously either a single 50 mg dose of indomethacin or placebo. Comparing 1 hr postinfusion levels to baseline observations in the indomethacin group, PaO2 increased to 125 +/- 13 torr from 93 +/- 8 torr, PaO2/FIO2 ratio increased to 223 +/- 24 from 160 +/- 5, and Qs/Qt dropped to 0.20 +/- 0.03 from 0.27 +/- 0.03 (all P less than 0.05). These alterations in oxygenation gradually returned to baseline levels over the ensuing 8 hr. No such changes were noted in the placebo group. A 7-day infusion of prostaglandin E1 (PGE1), an immunomodulator, was evaluated in a prospective, randomized, placebo-controlled, double-blinded trial in surgical patients with the adult respiratory distress syndrome (ARDS). The drug seemed to improve pulmonary function--only two PGE1 patients died with severe pulmonary failure compared with nine placebo patients (p = 0.01). Survival at 30 days after the end of the infusion--the predetermined end point of the study--was significantly better in the patients given PGE1 (p = 0.03), with 15 of 21 PGE1 patients (71%) alive at this time compared with seven of 20 placebo patients (35%). Improvement in overall survival in the PGE1 patients did not reach statistical significance (p = 0.08). Overall survival in patients initially free of severe organ failure, however, was significantly better in the PGE1 patients (p = 0.03). Of the six PGE1 patients free of severe organ failure at time of entry, all survived to leave the hospital; of the 10 placebo patients initially free of severe organ failure, four survived. The drug had no serious side effects and did not potentiate susceptibility to infection. PGE1 is a promising agent for the treatment of ARDS. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis. We investigated whether GM-CSF therapy improved clinically diagnosed severe sepsis and respiratory dysfunction in critically ill patients. This randomized, double-blind, placebo-controlled phase II study added low-dose (3 mcg/kg) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients, with a further eight patients receiving placebo. GM-CSF-treated patients showed improvement in Pa(O(2))/FI(O(2)) over 5 days (p = 0.02) and increased peripheral blood neutrophils (p = 0.08), whereas alveolar neutrophils decreased (p = 0.02). GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction. GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function. We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration, despite functional activation of both circulating neutrophils and pulmonary phagocytes. In addition, GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome, suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction. To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine; Clintec Technologies Inc; Chicago [OTZ]) on these levels and on common physiologic abnormalities, and organ dysfunction associated with ARDS.
                Randomized, double-blind, placebo-controlled, prospective clinical trial.
                ICUs in five clinical centers in the United States and Canada.
                Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation.
                Standard care for ARDS and I.V. infusion, every 8 h for 10 days, of one of the following: NAC (70 mg/kg, n=14), OTZ (63 mg/kg, n=17), or placebo (n=15).
                Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period (47% and 49% increases from baseline values for NAC and OTZ, respectively). There was no difference in mortality among groups (placebo, 40%; NAC, 36%; OTZ, 35%). However, the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups (NAC/OTZ [+]14%; placebo [-]6%).
                Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this. Intravenous N-acetylcysteine (NAC) has been reported to improve systemic oxygenation and reduce the need for ventilatory support in patients with an acute lung injury. In the more serious form, namely established adult respiratory distress syndrome (ARDS) (PaO2/FIO2 < or = 200 mm Hg), we tested the hypothesis that treatment with intravenous NAC may be beneficial.
                Respiratory dysfunction was graded daily according to the need for mechanical ventilation and FIO2 and to the evolution of the lung injury score (LIS) and the PaO2/FIO2 ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course.
                NAC and placebo groups (22 and 20 patients, respectively) were comparable for demographic characteristics, ARDS categories, severity of illness (simplified acute physiology score [SAPS II]) LIS and PaO2/FIO2 ratio. Mortality rate was 32% for the NAC and 25% for the placebo group (difference not significant). At admission (day 1), 91% of patients in the NAC and 95% in the placebo group required ventilatory support; at days 2, 3, 5, and 7 after admission, the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1. Moreover, there were no differences between the two groups at the same observation days. In both groups, the FIO2 was significantly lower and the PaO2/FIO2 ratio was significantly higher than the initial values during the evolution (FiO2 at day 3, P < .01 for NAC and P < .05 for placebo; PaO2/FIO2 at day 3: P < .01 for NAC and P < .02 for placebo), but this improvement was similar for both groups and, moreover, the between-group comparison was never significantly different at the various collection days. The LIS decreased significantly in NAC group between days 1 and 3 (2.23 +/- 0.62 v 1.76 +/- 0.17; P < .05), whereas no changes were observed in the placebo group; at day 5, there was a significant difference between the two groups (1.53 +/- 0.21 for the NAC v 2.15 +/- 0.19 for the placebo group; P < .05). In the prevalent sepsis category (10 patients in the NAC and 9 in the placebo group), the mortality rate, the need of ventilatory support, the intensive care unit stay, and the PaO2/FIO2 evolution did not differ significantly in both subgroups.
                In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases, intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support. Three clinical studies have suggested that ketoconazole, a synthetic imidazole with anti-inflammatory activity, may prevent the development of acute respiratory distress syndrome (ARDS) in critically ill patients. However, the use of ketoconazole as treatment for acute lung injury (ALI) and ARDS has not been previously studied.
                To test the efficacy of ketoconazole in reducing mortality and morbidity in patients with ALI or ARDS.
                Randomized, double-blind, placebo-controlled trial conducted from March 1996 to January 1997.
                Twenty-four hospitals associated with 10 network centers in the United States, constituting the ARDS Network.
                A total of 234 patients with ALI or ARDS.
                Patients were randomly assigned to receive ketoconazole, 400 mg/d (n = 117), or placebo (n = 117), initiated within 36 hours of fulfilling study entry criteria and given enterally for up to 21 days.
                Primary outcome measures were the proportion of patients alive with unassisted breathing at hospital discharge and the number of days of unassisted breathing (ventilator-free days) during 28 days of follow-up. Secondary outcome measures included the proportion of patients achieving unassisted breathing for 48 hours or more, the number of organ failure-free days, and changes in plasma interleukin 6 (IL-6) and urinary thromboxane A2 metabolites (thromboxane B2 [TXB2] and 11-dehydro-TXB2).
                In-hospital mortality (SE) was 34.1% (4.3%) for the placebo group and 35.2% (4.3%) for the ketoconazole group (P=.85). The median number of ventilator-free days within 28 days of randomization was 9 in the placebo group and 10 in the ketoconazole group (P=.89). There were no statistically significant differences in the number of organ failure-free days, pulmonary physiology, or adverse events between treatment groups. The median serum ketoconazole level was 1.25 microg/mL and serum levels greater than 0.5 microg/mL were detected in 96% of patients assayed. Plasma IL-6, urinary TXB2, and 11-dehydro-TXB2 levels were unaffected by ketoconazole.
                In these patients with ALI or ARDS, ketoconazole was safe and bioavailable but did not reduce mortality or duration of mechanical ventilation or improve lung function. These data do not support the use of ketoconazole for the early treatment of ALI or ARDS. To determine the effects of intravenous N-acetylcysteine (NAC) on the development of severe adult respiratory distress syndrome (ARDS) and mortality rate in patients with mild-to-moderate acute lung injury and to analyze the duration of ventilatory support and FIO2 required as well as the evolution of the lung injury score.
                Three university hospital ICUs and one regional ICU in Switzerland.
                Sixty-one adult patients presenting with mild-to-moderate acute lung injury and various predisposing factors for ARDS received either NAC, 40 mg/kg/d, or placebo intravenously for 3 days.
                Respiratory dysfunction was assessed daily according to the need for mechanical ventilation and FIO2, the evolution of the lung injury score, and the PaO2/FIO2 ratio. The cardiovascular state, liver function, and kidney function were also monitored. Data were collected at admission (day 0), during the first 3 days, and on the day of discharge from the ICU.
                The NAC and placebo groups (32 and 29 patients, respectively) were comparable at ICU admission for severity of illness assessed by the simplified acute physiology score (SAPS) (10.8 +/- 4.6 vs 10.9 +/- 4.8) and lung injury score (LIS) (1.39 +/- 0.95 vs 1.11 +/- 1.08) (mean +/- SD). Three patients in each group developed ARDS. The 1-month mortality rate was 22 percent for the NAC group and 35 percent for the placebo group (difference not statistically significant). At admission, 22 of 32 patients (69 percent) in the NAC group were mechanically ventilated compared with 22 of 29 (76 percent) in the placebo group. At the end of the treatment period (day 3), 5 of 29 (17 percent) in the NAC group and 12 of 25 (48 percent) in the placebo group were still receiving ventilatory support (p = 0.01), The FIO2 was 0.37 less than admission value (day 0) in the NAC group, and 0.20 less in the placebo group (p < 0.04); the oxygenation index (PaO2/FIO2) improved significantly (p < 0.05) from day 0 to day 3 only in the NAC-treated group. The LIS showed a significant regression (p = 0.003) in the NAC-treated group during the first 10 days of treatment: no change was observed in the placebo group. No adverse effects were observed during the treatment with NAC.
                Intravenous NAC treatment during 72 h improved systemic oxygenation and reduced the need for ventilatory support in patients presenting with mild-to-moderate acute lung injury subsequent to a variety of underlying diseases. Development of ARDS and mortality were not reduced significantly by this therapy. To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome (ARDS) in man.
                Randomized, double-blind, placebo-controlled study.
                Medical and surgical ICU in a regional hospital.
                Sixty-six ICU patients with ARDS.
                Patients with ARDS (PaO2/FiO2 ratio less than 250 torr) were treated with either the antioxidant N-acetylcysteine 150 mg/kg as a loading dose and then 20 mg/kg/hr, or with placebo for 6 days.
                No improvement could be demonstrated in the PaO2/FiO2 ratio in the study group as compared with the control group on any day. Pulmonary compliance was higher in the N-acetylcysteine group than in the placebo group on all days, but this difference did not reach the chosen 5% level of significance. No difference between the two groups could be demonstrated on chest radiograph or on survival rate. We documented that N-acetylcysteine acts as an anticoagulant and perhaps decreases pulmonary fibrin uptake during ARDS.
                N-acetylcysteine might be of benefit in ARDS. Before further clinical studies are started, problems with N-acetylcysteine and coagulation have to be elucidated in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS. To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS).
                Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial.
                Forty-seven community and university-affiliated hospitals in the United States.
                A total of 350 patients with ARDS were enrolled in this clinical trial.
                Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period.
                The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 > 300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS.
                A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently.
                In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival. Herpes simplex virus (HSV) type I commonly occurs in the lower respiratory tract (LRT) of seriously ill patients, particularly those with the adult respiratory distress syndrome (ARDS), but it is not known whether HSV is a benign mucosal colonizer or a pathogen. The aims of this study were to determine whether the antiviral agent acyclovir could prevent this occurrence, and if so, whether prevention improved the outcome. Forty-five patients with ARDS underwent double-blind randomization into a treatment group (22 subjects) who received prophylactic acyclovir intravenously, 5 mg/kg every 8 h, and a control group (23 subjects). Upper and lower respiratory secretions were examined for the presence of HSV before randomization and twice weekly thereafter. Seven patients were excluded because of HSV detection prior to treatment. There were no significant differences between the remaining 17 acyclovir and 21 control patients in age, sex, distribution of primary diagnostic categories, and severity of primary illness. Only 1 patient (6%) in the acyclovir group developed HSV after treatment compared with 15 (71%) in the control group (p less than 0.001), but there was no improvement in the acyclovir group in the severity of respiratory failure, the duration of ventilator support (acyclovir, 20 +/- 19 days; control, 14 +/- 11 days), or mortality (acyclovir, 8 of 17, 47%; control, 9 of 21, 43%). We conclude that acyclovir is effective in preventing the high incidence of HSV in patients with ARDS, but that this prevention does not improve outcome. Routine prophylaxis of HSV is not recommended. Prostaglandin E1 (PGE1, Prostin VR) in doses of 30 ng/kg . min was studied in two series of severely ill surgical patients with adult respiratory distress syndrome (ARDS). First the drug was administered in an initial trial in six patients; then a prospective, randomized, blinded trial was conducted in 10 studies on nine patients. PGE1 markedly decreased pulmonary artery pressure, pulmonary and systemic vascular resistance indexed, and venous pressures, while increasing cardiac output, arterial PO2 (PaO2), oxygen delivery, and oxygen consumption when compared with the baseline preinfusion control values and with the response of the placebo-treated control series. The PGE1 responses were greater in patients whose ARDS was primarily attributed to the postoperative state with or without sepsis and least in patients with cirrhosis. The data are consistent with the concept that the drug reduces vasoconstriction primarily in the pulmonary circulation but also in the systemic circulation; improved PaO2 usually follows the hemodynamic effect. We conclude that PGE1 may be a useful adjunctive therapy for ARDS. This study investigates the effects of N-acetylcysteine (NAC) and rutin on the lung oxidative burden of patients with early adult respiratory distress syndrome (ARDS). The protection was evaluated by measuring expired ethane and malondialdehyde (MDA), and oxidized (GSSG) and reduced glutathione (GSH) in the epithelial lining fluid of 36 patients who developed ARDS less than 24 hours before enrollment in the study. The patients were randomly assigned to 3 groups, receiving 250 mL 5% dextrose in water (group 1), NAC 50 mg/kg body weight in 5% dextrose (group 2), and NAC 50 mg/kg + rutin 5 mg/kg in 5% dextrose (group 3). Ethane and MDA concentrations were significantly reduced in the treatment groups after day 6. GSH was 30% increased in the treatment groups. No significant variations were observed in the control group until day 9. The trial confirms that NAC and rutin are efficient in protecting the lungs of patients with ARDS. Lung surfactant is deficient in patients with acute respiratory distress syndrome (ARDS). We performed a randomized, prospective, controlled, open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy. Patients received either surfactant by endotracheal instillation in addition to standard therapy or standard therapy only. Three different groups of patients receiving surfactant were studied: patients receiving up to eight doses of 50 mg phospholipids/kg, those receiving up to eight doses of 100 mg phospholipids/kg, and those receiving up to four doses of 100 mg phospholipids/kg. Outcome measures included ventilatory support parameters, arterial blood gases, organ system failures, bronchoalveolar lavage (BAL) analyses, immunologic analyses, survival, and adverse events during the 28-d study period. Fifty-nine study patients were evaluable; 43 in the surfactant group and 16 in the control group. The FI(O2) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients (p = 0.011). Mortality in the same group of patients was 18.8%, as compared with 43.8% in the control group (p = 0.075). The surfactant instillation was generally well tolerated, and no safety concerns were identified. This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS, and provides rationale for further clinical study of this agent. To evaluate the safety and efficacy of liposomal prostaglandin E1 (TLC C-53) in the treatment of patients with the acute respiratory distress syndrome (ARDS).
                Randomized, prospective, multicenter, double-blind, placebo-controlled, phase II clinical trial.
                Eight community and university-affiliated hospitals in the United States.
                Twenty-five patients with ARDS.
                Patients were prospectively randomized in an unbalanced ratio within each site to receive either TLC C-53 (n = 17) or placebo (n = 8). Study drug was infused intravenously over 60 mins every 6 hrs for a 7-day period, starting at a dose of 0.15 micrograms/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 micrograms/kg/hr) was attained, intolerance to further increases developed, or invasive monitoring was discontinued. Patients received standard, aggressive, medical/surgical care throughout the trial.
                Outcome measurements were Pao2/FI0(2), dynamic pulmonary compliance, ventilator dependence on day 8, and 28-day all-cause mortality rate. At baseline, the distribution of variables describing Lung Injury Scores, Acute Physiology and Chronic Health Evaluation II scores, Pao2/FI0(2), pulmonary compliance, and time from onset of ARDS to first dose of study drug was similar between patients in the TLC C-53 and placebo treatment groups. On day 8, all eight patients given placebo required mechanical ventilation, while eight of 17 patients given TLC C-53 were healthy enough to be removed from the ventilator (p = .03). Improvement in PaO2/FIO2 during the initial 8-day study period was greater in patients receiving TLC C-53. This trend achieved statistical significance on day 3, when the increase in PaO2/FIO2 from baseline was 82.5 +/- 14.6 in the TLC C-53 group compared with 28.3 +/- 22.1 in the placebo group (p = .05). By day 8, lung compliance also increased from baseline significantly more in TLC C-53 patients than in placebo patients (5.7 +/- 1.7 vs -1.5 +/- 1.8 mL/cm H2O; p = .01). The 28-day mortality rate was 6% (1/17 patients) in the TLC C-53 group and 25% (2/8 patients) in the placebo group (p = .23). Drug-related adverse events were reported in 82% of the patients receiving TLC C-53 compared with 38% of the placebo group, with half of the adverse events in the TLC C-53 group being localized infusion site irritation. TLC C-53 was hemodynamically well tolerated, with transient hypotension occurring in three patients.
                In patients with ARDS, TLC C-53 was associated with improved oxygenation, increased lung compliance, and decreased ventilator dependency. We performed a randomized double-blind trial to determine the usefulness of early methylprednisolone therapy for patients with pulmonary failure. We selected 81 acutely ill, mechanically ventilated patients at high risk for adult respiratory distress syndrome (ARDS). Thirty-nine patients received methylprednisolone, 30 mg/kg, every six hours for 48 hours; 42 patients received mannitol placebo. All patients were given a positive end-expiratory pressure of 5 cm H2O, monitored with pulmonary artery catheters, and treated for their primary disease processes. Twenty-five steroid-treated patients (64%) and 14 placebo-treated patients (33%) developed ARDS. Early infectious complications occurred in 30 steroid-treated patients (77%) and 18 placebo-treated patients (43%). There were no significant differences in factors predisposing to ARDS, ventilatory requirements, or days of intensive care. These results do not support the use of methylprednisolone for ARDS. Steroids failed to improve pulmonary function and were associated with an increased infection rate. Intensive pulmonary and general supportive care remain the preferred therapy for ARDS. No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%.
                To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS.
                Randomized, double-blind, placebo-controlled trial.
                Medical intensive care units of 4 medical centers.
                Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure.
                Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment.
                Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections.
                Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO2 to fraction of inspired oxygen (FIO2), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO2 to FIO2 (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever.
                In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality. To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency.
                A multi-centre, randomized, double-blind, placebo-controlled clinical study.
                Thirty-one hospitals in six European countries.
                One hundred two patients with ARDS.
                Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h.
                Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23).
                TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation. We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant (Venticute) as treatment for the acute respiratory distress syndrome. Patients were prospectively randomized to receive either standard therapy or standard therapy plus one of two doses of exogenous surfactant given four times over 24 hours. Surfactant administration was well tolerated. No significant treatment benefit was associated with surfactant treatment. Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components, did not show evidence of improved surface tension lowering function, and had interleukin-6 concentrations that were significantly lower than control group values, consistent with an antiinflammatory treatment effect. The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours. Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule.
Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.