Adult respiratory distress syndrome in cases of severe trauma--the prophylactic value of methylprednisolone sodium succinate. Octreotide Treatment in Patients with Severe Acute Pancreatitis N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. A double‐blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome Prevention of the adult respiratory distress syndrome with dipyridamole Effect of Aprotinin in Adult Respiratory Distress Syndrome Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. HA-1A in septic patients with ARDS: Results from the pivotal trial Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis* The influence of liposome-encapsulated prostaglandin E1 on hydrogen peroxide concentrations in the exhaled breath of patients with the acute respiratory distress syndrome. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. Filgrastim in patients with pneumonia and severe sepsis or septic shock. 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 Preliminary report of a prospective randomized study of octreotide in the treatment of severe acute pancreatitis. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Granulocyte colony-stimulating factor (G-CSF) stiffens leukocytes but attenuates inflammatory response without lung injury in septic patients. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Prostaglandin E1 and Survival in Patients with the Adult Respiratory Distress Syndrome: A Prospective Trial Ketoconazole prevents acute respiratory failure in critically ill surgical patients. The effects of prostaglandin E1 on non-pulmonary organ function during clinical acute respiratory failure. The Prostaglandin E1 Study Group. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Effect of surfactant on respiratory failure associated with thoracic aneurysm surgery. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome. Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Potential of N-acetylcysteine as treatment for the adult respiratory distress syndrome. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome Indomethacin treatment of human adult respiratory distress syndrome. 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. Physiologic effects and side effects of prostaglandin E1 in the adult respiratory distress syndrome. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Antioxidant treatment with N‐acetylcysteine during adult respiratory distress syndrome: A prospective, randomized, placebo‐controlled study Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo-controlled, randomized, double-blind, multicenter clinical trial. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. High-dose corticosteroids in patients with the adult respiratory distress syndrome. Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand. Pulmonary Response of Massive Steroids in Seriously Injured Patients Systematic Reviews: Synthesis of Best Evidence for Clinical Decisions Dazoxiben in human sepsis and adult respiratory distress syndrome An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome. A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial.
The more important known pathogenetic mechanisms apparently responsible for the development of adult respiratory distress syndrome ( ARDS ) are briefly discussed . Reactions in the development of ARDS for which corticosteroids are possibly beneficial are pointed out . A prospect i ve study involving 92 patients was design ed to determine the prophylactic value of methylprednisolone sodium succinate ( MPSS ) ( Solu-Medrol ; Upjohn ) in preventing ARDS .  MPSS was administered to 47 seriously injured patients and omitted from the management regimen of 45 patients comparable as regards age and severity of injury . The percentage of patients who developed ARDS was significantly lower in the group that received MPSS than in the control group We investigated the effect of octreotide in the treatment of  severe acute pancreatitis  in a case – control study . Experimental and clinical studies on the effect of octreotide in the treatment of acute pancreatitis have shown controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the effect of octreotide in severe acute pancreatitis , in three hospitals in Israel . The entering criteria included three or more of the Ranson prognostic signs and CT findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg subcutaneously three times a day ) . The end points of the study included : complication rate ( ARDS , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality .  From January 1992 to December 1996 , 60 patients entered the study . After evaluating the files , 10 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 50 patients , 25 were assigned to octreotide ( treatment group ) and 25 to conservative treatment only ( control group ) . The two groups matched with regard to age , sex , etiology , and severity of the disease . The complication rate was lower in the treatment group with regard to sepsis ( 24 % vs 76 % , P = 0.0002 ) and ARDS ( 28 % vs 56 % , P = 0.04 ) . The hospital stay was shorter in the treatment group ( 20.6 vs 33.1 days , P = 0.04 ) . Two patients died in the treatment group and eight in the control group ( P < 0.019 ) . These results suggest that octreotide may have a beneficial effect in the treatment of severe acute pancreatitis OBJECTIVE 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 . SETTING Three university hospital ICUs and one regional ICU in Switzerl and . PATIENTS 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 . MEASUREMENTS 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 . RESULTS 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 . CONCLUSIONS 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 BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because  mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use Objective : To determine if ketoconazole , a thromboxane A2 synthetase inhibitor , given within the first 24 hrs after diagnosis and arrival in the intensive care unit ( ICU ) would decrease the frequency of adult respiratory distress syndrome in the septic patient population . Design : Prospect i ve , r and omized , double-blind , placeocontrolled study . Setting : Twelve-bed , surgical ICU in a university-affiliated hospital . Patients : Fifty-four consecutive patients admitted to the surgical ICU with the diagnosis of sepsis composed the study sample . Sepsis was defined as including two or more of the following signs in a patient with a systolic blood pressure of < 80 mm Hg or a systemic vascular resistance of < 800 dyne-sec/cm5 : a ) temperature ≥39 ° C or ≤35 ° C ; b ) white blood cell count of > 12,000 leukocytes , or ≤4000 leukocytes/μL , or ≥20 % immature cells ; c ) positive blood culture ; d ) known or strongly suspected source of infection from which a known pathogen was cultured . Interventions : Patients were r and omized to receive either ketoconazole ( 400 mg ) or placebo in a double-blind fashion as early as possible and in < 24 hrs after surgical ICU admission or after the diagnosis of sepsis was established . Measurements and Main Results : Adult respiratory distress syndrome ( ARDS ) was diagnosed if the following criteria were met : a ) intrapulmonary shunt of > 20 % , or a PaO2/Fio2 ratio of < 150 requiring ventilatory support for > 48 hrs ; b ) pulmonary artery occlusion pressure of < 18 nun Hg and no clinical signs of heart failure ; and c ) diffuse infiltrates on chest radiograph . Treatment result ed in significant ( p = .002 ) reduction in the frequency of ARDS compared with the placebo group , 64 % vs. 15 % in the ketoconazole treated group . The mortality rate was also reduced from 39 % in the placebo group to 15 % in the ketoconazole group ( p = .05 ) . A statistically significant reduction in ventilator and ICU days was not achieved . Conclusions : Ketoconazole ( 400 mg through the gastrointestinal tract ) given early in the septic course may prevent ARDS and decrease the mortality rate in high-risk , septic patients . ( Crit Care Med 1993 ; 21:1635–1642 Because the formation of platelet thrombi has been incriminated in the development of the adult respiratory distress syndrome ( ARDS ) , we tested trie hypothesis that early administration of antiplatelet agents might protect the lungs in patients at risk to develop ARDS after circulatory shock . This double-blinded study included 40 patients treated with either 3 mg/kg ± 24 h of dipyridamole or a corresponding dose of placebo after an episode of hemorrhagic , traumatic , or septic shock . Each patient also received 100 mg of aspirin daily . Arterial blood gases and chest x-rays were not significantly different between dipyridamole and placebo groups . Moreover , two patients receiving dipyridamole but none receiving placebo developed ARDS . This pilot study does not support a beneficial effect of dipyridamole in the prevention of ARDS after circulatory shock The possible beneficial effect of aprotinin , a broad protease inhibitor , on the incidence and outcome of ARDS was examined in two complementary studies . In the first study , the effect of aprotinin was assessed in 147 patients admitted with multiple trauma or shock . In the 57 patients who developed ARDS , mortality was significantly less in those who had previously received aprotinin ( 8/20 , 40 % ) than in those who had not ( 26/37 , 70 % ) . Although both treatment groups were well matched , this was a retrospective study and a second prospect i ve , r and omised , controlled study was therefore carried out . In 78 patients at risk of ARDS , there was no significant difference between treated and control patients in the incidence , duration or severity of ARDS , or in mortality or other major complications . It is concluded that aprotinin is not effective in improving any aspect of ARDS or its outcome in seriously ill patients 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 prospect ively r and omized to receive either st and ard therapy or st and ard 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 Objective To evaluate the effects of HA-1A , a human monoclonal antiendotoxin antibody , in septic patients with ARDS . Design Sub study of a multicenter , double-blinded , placebo-controlled trial of HA-1A in septic patients . Patients 63 septic patients with ARDS at the time of study entry . InterventionA single intravenous injection of HA-1A ( 100 mg ) or placebo . Results A quantitative radiographic score , the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3 , 5 and 7 days after treatment . The duration of endotracheal intubation did not differ between the two groups . 15 of 30 HA-1A treated patients ( 50 % ) and 23 of 33 placebo-treated patients ( 69.7 % ) died within 28 days . The daily mortality was always lower in the HA-1A group , but this difference was not statistically significant at 28 days . The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different ( p=0.07 ) . Using logistic regression , a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days ( p=0.03 ) but not at 14 and 28 days . Conclusion A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival Objective To determine the safety and efficacy of filgrastim ( r-metHuG-CSF ) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis . Design This study was multicenter , double-blind , and r and omized . Setting Intensive care units Patients Adult patients with bacterial pneumonia , either acquired or nosocomial , as confirmed by chest radiograph and positive culture or Gram-negative stain , and severe sepsis , defined as sepsis-induced hypotension or organ dysfunction . Interventions St and ard antibiotic therapy with or without filgrastim ( 300 & mgr;g/day ) or placebo administered as a 30-min intravenous infusion . The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached > 75.0 × 109 cells/L. Measurements and Main Results The primary end point was the occurrence of mortality through day 29 ; secondary end points included occurrence of subsequent organ dysfunction , time to discharge from intensive care unit , number of days on mechanical ventilatory support , and time to death . Study -related observations were recorded through day 10 and included vital signs , onset of organ dysfunction , clinical laboratory variables , and adverse events . Filgrastim increased the white blood cell count to a median peak of 31.7 × 109 cells/L from a baseline of 12.3 × 109 cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events , time to death , occurrence of end-organ dysfunction , days of intensive care unit hospitalization , or days on mechanical ventilatory support . Mortality was low in both treatment groups ; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups . Conclusions The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe , but not efficacious in reducing mortality rates or complications from this infection UNLABELLED Hydrogen peroxide ( H2O2 ) levels are increased in the exhaled breath of patients with the acute respiratory distress syndrome ( ARDS ) . Because liposome-encapsulated prostagl and in E1 ( PGE1 ) downregulates the CD11/CD18 receptor of the neutrophil , thereby limiting endothelial adhesion , the use of this drug should decrease the excretion of H2O2 in the expiratory condensate of patients with ARDS . Patients > 11 yr of age with ARDS ( diffuse , patchy infiltrates by chest radiograph ; Pao2/fraction of inspired oxygen [ P/F ] ratio < or = 200 mm Hg ; pulmonary capillary wedge pressure < or = 18 mm Hg ; and the requirement for mechanical ventilation ) were r and omized to receive placebo ( n = 14 ) or escalating doses ( 0.15 - 3.6 micrograms/kg ) of liposomal PGE1 ( n = 14 ) every 6 h for up to 7 days . Condensate was collected every morning from the expiratory tubing that was submerged in an ice saltwater bath ( -5 degrees C ) . H2O2 levels were measured by using a horseradish peroxidase assay . Other data collected included white blood cell count and P/F ratios . There was no significant difference in the concentration of H2O2 in the expiratory condensate between the liposomal PGE1 group and the control group either before ( 0.99 + /- 0.52 vs 0.93 + /- 0.48 mumol/L ) or during treatment ( 1.04 + /- 0.45 vs 0.76 + /- 0.25 mumol/L ) . Liposomal PGE1 treatment improved the P/F ratio and decreased the white blood cell count over time . Despite its ability to downregulate the CD11/CD18 neutrophil receptor , liposomal PGE1 did not reduce exhaled H2O2 excretion . IMPLICATION S White blood cells ( WBC ) are thought to be part of the cause of the acute respiratory distress syndrome , a lung disease . WBC in the lung produce hydrogen peroxide , which is exhaled . Liposomal PGE1 inhibits WBC function but was found to have no effect in decreasing exhaled hydrogen peroxide in patients with the acute respiratory distress syndrome 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 r and omized 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 PURPOSE 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 . MATERIAL S AND METHODS Respiratory dysfunction was grade d 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 . RESULTS 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 . CONCLUSIONS 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 Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome . Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation . Because endotoxin is a potent and clinical ly important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure , we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin . We studied the effects of protective ( tidal volume [ VT ] 5 ml . kg(-)(1 ) , positive end-expiratory pressure [ PEEP ] 10 to 12.5 cm H(2)O ) versus nonprotective ( VT 12 ml . kg(-)(1 ) , PEEP zero ) ventilatory strategy on translocation of endotracheally instilled endotoxin . Anesthetized New Zeal and White rabbits were subjected to saline lung lavage , and 32 were r and omized to one of four groups : PS ( protective ventilation + instilled saline ) ; PE ( protective ventilation + instilled endotoxin ) ; NS ( nonprotective ventilation + instilled saline ) ; NE ( nonprotective ventilation + instilled endotoxin ) , and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group , and remained low and unchanged in the other groups . Peak levels of plasma tumor necrosis factor-alpha ( TNF-alpha ) were higher in NE versus other groups . Pa(O(2 ) ) and mean arterial pressure ( Pa ) were lowest , and requirement for pressor and bicarbonate support greatest , in the NE group . Finally , plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors . These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin . This translocation depends on ventilatory strategy , and suggests a pathophysiologic link between ventilatory strategy and outcome STUDY OBJECTIVES Evaluate the safety of filgrastim ( recombinant methionyl human granulocyte colony-stimulating factor ) administration , combined with st and ard therapy , in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation . DESIGN Multicenter , double-blind , r and omized , placebo-controlled study . SETTING ICU , multicenter . PATIENTS Eighteen patients with pneumonia and hypotension , or in the absence of shock , two or more end-organ dysfunctions , were enrolled and treated . Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim ( n = 12 ) and placebo ( n = 6 ) groups were 25.0 and 49.5 years and 31.5 and 56.5 years , respectively . INTERVENTION Filgrastim ( 300 microg ) or placebo was administered IV daily for up to 5 days . MEASUREMENTS AND RESULTS Study end points included safety ; biological response , including endogenous cytokine levels , endotoxin levels , and neutrophil counts ; and mortality . Cytokine and endotoxin levels were highly variable in both groups . By day 29 , 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died . There were no differences in types and occurrences of adverse events , including ARDS , or in outcome between the two groups . Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients . CONCLUSION Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock . Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted CONTEXT 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 % . OBJECTIVE To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Medical intensive care units of 4 medical centers . PARTICIPANTS Twenty-four patients with severe ARDS who had failed to improve lung injury score ( LIS ) by the seventh day of respiratory failure . INTERVENTIONS 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 . MAIN OUTCOME MEASURES 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 . RESULTS 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 . CONCLUSIONS 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 Abstract . Objective : 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 . Design : A multi-centre , r and omized , double-blind , placebo-controlled clinical study . Setting : Thirty-one hospitals in six European countries . Patients : One hundred two patients with ARDS . Interventions : Patients were r and omized 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 µg/kg per h , rising over 24 h to a maximum dose of 1.8 µg/kg per h. Measurements and main results : 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 ) . Conclusions : TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation BACKGROUND Experimental and clinical studies on the effect of octreotide in the treatment of patients with acute pancreatitis have presented controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the clinical effect of octreotide in severe acute pancreatitis , at three hospitals in Israel . STUDY DESIGN The entering criteria included three or more of the Ranson 's prognostic signs and computed tomographic findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg injected subcutaneously three times a day ) . The end points of the study included : complication rate ( adult respiratory distress syndrome [ ARDS ] , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality . RESULTS During the first two years ( from January 1992 to December 1993 ) , 51 patients entered the study . After evaluation , 13 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 38 patients , 19 were assigned to octreotide ( treatment group ) and 19 to conservative treatment alone ( control group ) . The two groups were matched with regard to age , sex , etiology , and severity of disease . The complication rate was lower in the treatment group compared with the control group with regard to sepsis ( 26 compared with 74 percent , p = 0.004 ) and ARDS ( 37 compared with 63 percent , p = 0.1 ) . The hospital stay was shorter in the treatment group compared with the control group ( 17.9 compared with 34.1 days , p = 0.02 ) . Death occurred in two patients in the treatment group and six patients in the control group . CONCLUSIONS Although some of the parameters did not reach statistical significance , these preliminary results suggest that octreotide may have a beneficial effect in the treatment of patients with severe acute pancreatitis . This study is scheduled to continue for two more years Objective To determine whether the administration of lisofylline ( 1-[5R-hydroxyhexyl]-3,7-dimethylxanthine ) would decrease mortality in patients with acute lung injury ( ALI ) or acute respiratory distress syndrome ( ARDS ) . Design A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter study . Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network . Patients A total of 235 patients who met eligibility criteria were enrolled in the study ( 116 into the lisofylline group , 119 into the placebo group ) . Interventions Patients were r and omized to receive either lisofylline or placebo . The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs . The intravenous solution of study drug was administered over 10 mins every 6 hrs . Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing . Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis . The patient groups had similar characteristics at enrollment . No significant safety concerns were associated with lisofylline therapy . There was no significant difference between groups in the number of patients who had died at 28 days ( 31.9 % lisofylline vs. 24.7 % placebo , p = .215 ) . There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures , ventilator-free days , infection-related deaths , or development of serious infection during the 28-day study period . The median number of organ failure – free days for the five nonpulmonary organ failures examined ( cardiovascular , central nervous system , coagulation , hepatic , and renal ) was not different between the lisofylline and placebo groups . Although lisofylline has been reported to decrease circulating free fatty acid levels , we did not find any such treatment effect compared with placebo . Conclusions In this study , there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS Because animal studies have demonstrated that mechanical ventilation at high volume and pressure can be deleterious to the lungs , limitation of airway pressure , allowing hypercapnia if necessary , is already used for ventilation of acute respiratory distress syndrome ( ARDS ) . Whether a systematic and more drastic reduction is necessary is debatable . A multicenter r and omized study was undertaken to compare a strategy aim ed at limiting the end-inspiratory plateau pressure to 25 cm H2O , using tidal volume ( VT ) below 10 ml/kg of body weight , versus a more conventional ventilatory approach ( with regard to current practice ) using VT at 10 ml/kg or above and close to normal PaCO2 . Both arms used a similar level of positive end-expiratory pressure . A total of 116 patients with ARDS and no organ failure other than the lung were enrolled over 32 mo in 25 centers . The two groups were similar at inclusion . Patients in the two arms were ventilated with different VT ( 7.1 + /- 1.3 versus 10.3 + /- 1.7 ml/kg at Day 1 , p < 0.001 ) and plateau pressures ( 25.7 + /- 5 . 0 versus 31.7 + /- 6.6 cm H2O at Day 1 , p < 0.001 ) , result ing in different PaCO2 ( 59.5 + /- 15.0 versus 41.3 + /- 7.6 mm Hg , p < 0.001 ) and pH ( 7.28 + /- 0.09 versus 7.4 + /- 0.09 , p < 0.001 ) , but a similar level of oxygenation . The new approach did not reduce mortality at Day 60 ( 46.6 % versus 37.9 % in control subjects , p = 0.38 ) , the duration of mechanical ventilation ( 23.1 + /- 20.2 versus 21.4 + /- 16 . 3 d , p = 0.85 ) , the incidence of pneumothorax ( 14 % versus 12 % , p = 0 . 78 ) , or the secondary occurrence of multiple organ failure ( 41 % versus 41 % , p = 1 ) . We conclude that no benefit could be observed with reduced VT titrated to reach plateau pressures around 25 cm H2O compared with a more conventional approach in which normocapnia was achieved with plateau pressures already below 35 cm H2O OBJECTIVE To determine whether granulocyte colony-stimulating factor ( G-CSF ) administration changes leukocyte deformability result ing in lung injury in patients with sepsis . METHODS Twenty-five consecutive septic patients were divided r and omly into two groups . Twelve patients were given recombinant human G-CSF subcutaneously at 2 microg/kg once a day for 5 days ( group G ) . The remaining 13 patients were given sterilized saline as placebo ( group N ) . Leukocyte count ; concentrations of C-reactive protein ( CRP ) and thrombomodulin ( TM ) ; respiratory index ( RI ) and lung injury score ( LIS ) ; and APACHE II score and Goris MOF index were determined before and after G-CSF or placebo administration . Leukocyte deformability was observed in a microchannel array etched on a single-crystal silicon tip , which simulates the microvasculature . The number of microchannels obstructed ( NOM ) by stiffened leukocytes was counted . Transit time ( TT ) , that is , the time taken for 100 microL of whole blood to pass through the microchannel , was determined . RESULTS G-CSF administration significantly increased leukocyte count and decreased CRP concentration . In group G , both NOM and TT increased significantly 5 days after G-CSF administration ; they did not change in group N. However , RI , LIS , and TM did not change , suggesting that no patient developed lung injury . CONCLUSION G-CSF causes leukocyte stiffness but attenuates inflammatory response without inducing lung injury in septic patients Lung surfactant is deficient in patients with acute respiratory distress syndrome ( ARDS ) . We performed a r and omized , prospect i ve , 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 st and ard therapy or st and ard 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 A 7-day infusion of prostagl and in E1 ( PGE1 ) , an immunomodulator , was evaluated in a prospect i ve , r and omized , 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 PGE , 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 PGE , 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 Effective prophylaxis against acute respiratory failure ( ARDS ) has not been established . This study investigated whether or not ketoconazole could prevent ARDS in critically ill surgical patients . Seventy-one Surgical Intensive Care Unit ( SICU ) patients without liver dysfunction received either ketoconazole ( n = 35 ) , 200 mg daily via the gastrointestinal tract , or placebo ( n = 36 ) , for 21 days or until discharge from the SICU , in a prospect i ve , r and omized , double-blind study . Patients were monitored clinical ly for signs of ARDS , defined as all the following : intrapulmonary shunt greater than 15 % , a PaO2/FIO2 ratio less than 150 , normal central venous , pulmonary capillary wedge , or left atrial pressure , no other cause of hypoxemia , and a consistent chest X-ray .  Thirteen patients ( 18 % ) developed ARDS with significantly increased mortality versus non-ARDS patients ( 69 % vs. 29 % ) . The incidence of ARDS was decreased among ketoconazole patients compared to placebo ( 6 % vs. 31 % ; p less than 0.01 ) , as was median SICU stay ( 7.0 days vs. 15.5 days ; p less than 0.05 ) , and median SICU cost ( + 5,600 . vs. + 12,400 . ; p less than 0.05 ) . Mortality is increased with ARDS after trauma and surgery . We conclude that ketoconazole prevents ARDS , shortens SICU stay , and lowers hospital costs The effects of prostagl and in E1 ( PGE1 ) on non-pulmonary vital organs in critically ill patients are not well defined . This study evaluated the role of exogenous PGE1 in systemic homeostasis during the adult respiratory distress syndrome ( ARDS ) . Indicators of end-organ function were analyzed retrospectively in 146 septic or post-trauma patients with ARDS who received PGE1 ( 30/ng/kg/min ) or placebo IV for up to 7 days in a r and omized , double-blind clinical trial . Hemodynamic variables and serum levels of creatinine , bilirubin , and SGOT , platelet count , and changes in the white blood cell count were measured daily . Our results indicate that mean arterial pressure , pulmonary artery pressure , and systemic and pulmonary vascular resistance indices were significantly lower in the PGE1 group versus the placebo-treated group . Cardiac index , stroke index , and oxygen delivery index were significantly increased in the PGE1 group . Serum bilirubin and SGOT were decreased significantly among PGE1-treated patients compared with placebo-treated patients , while the white blood cell count increased more significantly from baseline values with PGE1 treatment . Intergroup differences in platelet count and serum creatinine levels were not statistically significant . The results indicate that PGE1 improves cardiovascular performance , hepatic function , and leukocyte availability during clinical ARDS . Prostagl and in E1 did not affect platelet counts and renal function in this study CONTEXT When clinicians assess the validity of r and omized controlled trials ( RCTs ) , they commonly evaluate the blinding status of individuals in the RCT . The terminology authors often use to convey blinding status ( single , double , and triple blinding ) may be open to various interpretations . OBJECTIVE To determine physician interpretations and textbook definitions of RCT blinding terms . DESIGN AND SETTING Observational study undertaken at 3 Canadian university tertiary care centers between February and May 1999 . PARTICIPANTS Ninety-one internal medicine physicians who responded to a survey . MAIN OUTCOME MEASURES Respondents identified which of the following groups they thought were blinded in single- , double- , and triple-blinded RCTs : participants , health care providers , data collectors , judicial assessors of outcomes , data analysts , and personnel who write the article . Definitions from 25 systematic ally identified textbooks published since 1990 providing definitions for single , double , or triple blinding . RESULTS Physician respondents identified 10 , 17 , and 15 unique interpretations of single , double , and triple blinding , respectively , and textbooks provided 5 , 9 , and 7 different definitions of each . The frequencies of the most common physician interpretation and textbook definition were 75 % ( 95 % confidence interval [ CI ] , 65%-83 % ) and 74 % ( 95 % CI , 52%-90 % ) for single blinding , 38 % ( 95 % CI , 28%-49 % ) and 43 % ( 95 % CI , 24%-63 % ) for double blinding , and 18 % ( 95 % CI , 10%-28 % ) and 14 % ( 95 % CI , 0%-58 % ) for triple blinding , respectively . CONCLUSIONS Our study suggests that both physicians and textbooks vary greatly in their interpretations and definitions of single , double , and triple blinding . Explicit statements about the blinding status of specific groups involved in RCTs should replace the current ambiguous terminology 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 r and omly 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 OBJECTIVE To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome ( ARDS ) . DESIGN A prospect i ve , double-blind , placebo-controlled , r and omized , parallel , multicenter pilot clinical trial . PATIENTS A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome . INTERVENTION Patients were r and omized 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 . MAIN OUTCOME MEASURES 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 . RESULTS 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 . CONCLUSIONS 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 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 clinical ly diagnosed severe sepsis and respiratory dysfunction in critically ill patients . This r and omized , 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 OBJECTIVE To study the effects of surfactant administration on the left lung after surgical repair of descending aortic aneurysms on postoperative respiratory failure . DESIGN R and omized , prospect i ve , controlled study . SETTING Clinical investigation . PATIENTS Eleven patients with respiratory failure associated with thoracic aneurysm surgery . INTERVENTION Eleven adult patients with acute respiratory failure ( PaO2/FIO2 < 300 torr [ < 40 kPa ] ) after surgical repair of descending aortic aneurysms . The artificial surfactant ( 30 mg/kg ) was given to the operated side of the lung by intrabronchial instillation in six patients ( surfactant group ) , whereas nothing was instilled in the other five patients ( control group ) . MEASUREMENTS AND MAIN RESULTS Hemodynamic parameters , blood gas , and peak inspiratory pressure were measured at the end of surgery , before surfactant instillation , and at 2 , 6 , 12 , 24 , and 48 hrs after surfactant instillation . At the end of surgery , the mean + /- SEM values of the PaO2/FIO2 ratio were 204 + /- 25 torr ( 27.2 + /- 3.3 kPa ) in the surfactant group and 240 + /- 26 torr ( 32.0 + /- 3.5 kPa ) in the control group . After 2 , 6 , 12 , and 48 hrs , improvements in the PaO2/FIO2 ratios were observed in the surfactant group , whereas the control group showed no improvement . Two hours after surfactant instillation , the mean value in the PaO2/FIO2 ratio was significantly higher in the surfactant group ( 318 + /- 24 torr [ 42.4 + /- 3.2 kPa ] ) ( p < .05 ) compared with the control group values ( 240 + /- 34 torr [ 32 + /- 4.5 kPa ] ) . CONCLUSION Surfactant administration immediately after surgery restored gas exchange in postoperative respiratory failure associated with thoracic aneurysm surgery From November 1 , 1982 through December 31 , 1985 , there were 19 centers and 382 patients that evaluated the effect of methylprednisolone sodium succinate ( MPSS ) on the septic syndrome . Seventeen of these centers enrolled 304 patients in a prospect i ve , r and omized , double-blind , placebo-controlled study to determine if early treatment with MPSS would decrease the incidence of severity of the adult respiratory distress syndrome ( ARDS ) in patients at risk of ARDS from sepsis . To ensure early institution of the MPSS or placebo therapy ( PLA ) , patients with the presumptive diagnosis of sepsis were identified . That diagnosis was based on the presence of fever or hypothermia ( temperature greater than 38.3 degrees C or less than 35.5 degrees C , rectal ) , tachypnea ( greater than 20 bpm ) , tachycardia ( greater than 90 bpm ) and the presence of one of the following indices of organ dysfunction : a change in mental status , hypoxemia , elevated lactate levels or oliguria . The treatment , either MPSS 30 mg/kg or PLA , was given in four 20-minute infusions six hours apart and was initiated within two hours of the presumptive diagnosis of sepsis . The development and reversal of the adult respiratory distress syndrome ( ARDS ) was followed and result ed in data on 304 of the 382 r and omized patients . A trend toward increased incidence of ARDS was seen in the MPSS group 50/152 ( 32 percent ) compared to the placebo group 38/152(25 percent ) p = 0.10 . Significantly fewer MPSS patients reversed their ARDS 15/50 ( 31 percent ) compared to placebo 23/38 ( 61 percent ) p = 0.005 . The 14-day mortality in patients with ARDS treated with MPSS was 26/50 ( 52 percent ) compared to placebo 8/22 ( 22 percent ) p = 0.004 . We conclude that early treatment of septic syndrome with MPSS does not prevent the development of ARDS . Additionally , MPSS treatment impedes the reversal of ARDS and increases the mortality rate in patients with ARDS Background : Despite intensive research , there are no universally accepted clinical definitions for acute lung injury ( ALI ) or the acute respiratory distress syndrome ( ARDS ) . A recent joint American-European Consensus Conference on ARDS formally defined the difference between ALI and ARDS based on the degree of oxygenation impairment . However , this definition may not reflect the true prevalence , severity and prognosis of these syndromes . Methods : During a 22-month period , 56 consecutive mechanically ventilated patients who met the American-European Consensus definition for ARDS [ arterial oxygen tension/fractional inspired oxygen ( PaO2/FIO2≤ 200 mmHg regardless of the level of positive end-expiratory pressure ( PEEP ) , bilateral pulmonary infiltrates , and no evidence of left heart failure ] were admitted into the intensive care units ( ICU ) of the Hospital del Pino , Las Palmas , Spain , and prospect ively studied . The diagnosis of ALI and ARDS was made by a PEEP-FIO2 trial , 24 h after patients met the Consensus inclusion criteria . Patients were classified as having ALI–24 h if the PaO2/FIO2 was > 150 mmHg with PEEP = 5 cmH2O , and ARDS–24 h if the PaO2 /FIO2 was ≤ 150 mmHg with PEEP ≥ 5 cmH2O . Results : Overall mortality was 43 % ( 24 of 56 ) . However , 24 h after inclusion , PaO2 response to PEEP 5 cmH2O allowed the separation of our patients into two different groups : 31 patients met our ALI–24 h criteria ( PaO2/FIO2 > 150 mmHg ) and their mortality was 22.6 % ; 25 patients met our ARDS–24 h criteria ( PaO2/FIO2≤ 150 mmHg ) and their mortality was 68 % ( p = 0.0016 ) . The differences in the respiratory severity index during the first 24 h of inclusion , PaO2/FIO2 ratio at baseline and at 24 h , maximum plateau airway pressure , maximum level of PEEP , and number of organ system failures during the ICU stay were statistically significant . Conclusions : Since the use of PEEP in the American-European Consensus criteria for ARDS is not m and atory , that definition does not reflect the true severity of lung damage and outcome . Our data support the need for guidelines based on a specific method of evaluating oxygenation status before the American-European Consensus definition is adopted We conducted a prospect i ve , r and omized , double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury , including the adult respiratory distress syndrome ( ARDS ) , or improve mortality when administered early in septic shock . All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1 , 1983 and August 29 , 1986 were eligible for admission to the study if they had either ( 1 ) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values ( in already hospitalized patients ) , or ( 2 ) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg ( in newly admitted patients ) . Patients meeting these criteria were excluded if they ( 1 ) had severe immunodeficiency , ( 2 ) were less than 18 or greater than 76 yr of age , ( 3 ) had multilobar roentgenographic infiltrates , or ( 4 ) were already receiving corticosteroids . Eighty-seven patients enrolled in the study received either methylprednisolone , 30 mg/kg per dose , or mannitol placebo for a total of 4 doses every 6 h , following the presumptive diagnosis of septic shock . Of these patients , 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry . Thirteen of the patients who received methylprednisolone developed ARDS , compared to 14 patients who received placebo . Lesser degrees of parenchymal lung injury did not differ between the 2 groups . ( ABSTRACT TRUNCATED AT 250 WORDS The adult respiratory distress syndrome ( ARDS ) , often referred to as non-cardiac pulmonary oedema , is now regarded as a very complicated inflammatory process with oedema being only one facet . In recognition of this , pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of r and omized clinical trials . Unfortunately , corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process . We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine ( NAC ) . We have found that the response to endotoxin is markedly blunted in sheep treated with NAC . In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations , that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery , improved lung compliance and resolution of pulmonary oedema BACKGROUND In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases , but the pathophysiologic role of these prostagl and ins is unclear . In animal models , inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival . In pilot studies of patients with sepsis , treatment with ibuprofen led to improvements in gas exchange and airway mechanics . METHODS From October 1989 to March 1995 , we conducted a r and omized , double-blind , placebo-controlled trial of intravenous ibuprofen ( 10 mg per kilogram of body weight [ maximal dose , 800 mg ] , given every six hours for eight doses ) in 455 patients who had sepsis , defined as fever , tachycardia , tachypnea , and acute failure of at least one organ system . RESULTS In the ibuprofen group , but not the placebo group , there were significant declines in urinary levels of prostacyclin and thromboxane , temperature , heart rate , oxygen consumption , and lactic acidosis . With ibuprofen therapy there was no increased incidence of renal dysfunction , gastrointestinal bleeding , or other adverse events . However , treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days ( mortality , 37 percent with ibuprofen vs 40 percent with placebo ) . CONCLUSIONS In patients with sepsis , treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever , tachycardia , oxygen consumption , and lactic acidosis , but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival OBJECTIVE To assess the safety and potential efficacy of a mechanical ventilation strategy design ed to reduce stretch-induced lung injury in acute respiratory distress syndrome . DESIGN Prospect i ve , r and omized , controlled clinical trial . SETTING Eight intensive care units in four teaching hospitals . PATIENTS Fifty-two patients with acute respiratory distress syndrome . INTERVENTIONS Traditional tidal volume patients : tidal volume 10 - 12 mL/kg ideal body weight , reduced if inspiratory plateau pressure was > 55 cm H2O ( 7.3 kPa ) . Small tidal volume patients : tidal volume 5 - 8 mL/kg ideal body weight , to keep plateau pressure < 30 cm H2O ( 4.0 kPa ) . MEASUREMENTS AND MAIN RESULTS Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg , respectively ( p < .001 ) , with mean plateau pressure = 30.6 and 24.9 cm H2O ( 3.3 kPa ) , respectively ( p < .001 ) . There were no significant differences in requirements for positive end-expiratory pressure or FIO2 , fluid intakes/outputs , requirements for vasopressors , sedatives , or neuromuscular blocking agents , percentage of patients that achieved unassisted breathing , ventilator days , or mortality . CONCLUSIONS The reduced tidal volume strategy used in this study was safe . Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a ) the sample size was too small to discern small treatment effects ; b ) the differences in tidal volumes and plateau pressures were modest ; or c ) reduced tidal volume ventilation is not beneficial BACKGROUND 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 . METHODS We conducted a prospect i ve , multicenter , double-blind , r and omized , 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 r and omly 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 . RESULTS 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 r and omization 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 . CONCLUSIONS 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 Arachidonic acid metabolites , especially thromboxane-A2 and prostacyclin , have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome ( ARDS ) and play a major pathophysiologic role . This study was design ed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae . We conducted a double-blind , placebo-controlled trial of ibuprofen ( 800 mg given rectally every 4 h for three doses ) in 30 patients with sepsis syndrome defined by abnormal vital signs , the appearance of serious infection , and at least one major organ failure .  Urinary concentrations of the metabolite of thromboxane-A2 , 2,3-dinor-TxB2 , and prostacyclin , 2,3-dinor-6-keto-prostagl and in F2 alpha , were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients . The urinary concentration of TxB2 and 6-keto-prostagl and in F1 alpha , which reflect renal production of TxA2 and prostacyclin , respectively , were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen . Coincident with the reduction in metabolite levels , the ibuprofen-treated group , but not the placebo-treated group , experienced a significant decline in temperature , heart rate , and peak airway pressure , and a trend towards more rapid reversal of shock ( p = 0.12 ) . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND In patients with the acute respiratory distress syndrome , massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury . We determined whether a ventilatory strategy design ed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome . METHODS We r and omly assigned 53 patients with early acute respiratory distress syndrome ( including 28 described previously ) , all of whom were receiving identical hemodynamic and general support , to conventional or protective mechanical ventilation . Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure ( PEEP ) for acceptable oxygenation , with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels ( 35 to 38 mm Hg ) . Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve , a tidal volume of less than 6 ml per kilogram , driving pressures of less than 20 cm of water above the PEEP value , permissive hypercapnia , and preferential use of pressure-limited ventilatory modes . RESULTS After 28 days , 11 of 29 patients ( 38 percent ) in the protective-ventilation group had died , as compared with 17 of 24 ( 71 percent ) in the conventional-ventilation group ( P<0.001 ) . The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group ( P=0.005 ) : the rates of clinical barotrauma were 7 percent and 42 percent , respectively ( P=0.02 ) , despite the use of higher PEEP and mean airway pressures in the protective-ventilation group . The difference in survival to hospital discharge was not significant ; 13 of 29 patients ( 45 percent ) in the protective-ventilation group died in the hospital , as compared with 17 of 24 in the conventional-ventilation group ( 71 percent , P=0.37 ) . CONCLUSIONS As compared with conventional ventilation , the protective strategy was associated with improved survival at 28 days , a higher rate of weaning from mechanical ventilation , and a lower rate of barotrauma in patients with the acute respiratory distress syndrome .  Protective ventilation was not associated with a higher rate of survival to hospital discharge OBJECTIVE To evaluate the safety and efficacy of E5 , a murine , monoclonal antibody directed against endotoxin , in the treatment of patients with Gram-negative sepsis . DESIGN A multicenter , r and omized , double-blind , placebo-controlled trial . SETTING Fifty-three hospitals across the United States , including university medical centers , Veterans Affairs Medical Centers , and community hospitals . PATIENTS 847 patients were r and omized into this study . Enrolled patients met criteria for three conditions : a ) known or suspected Gram-negative infection ; b ) clinical evidence of sepsis ; and c ) signs of end-organ dysfunction . Patients with refractory shock were excluded from the study . INTERVENTIONS Two doses of E5 ( 2 mg/kg/day by intravenous infusion 24 hrs apart ) , or placebo that was identical in appearance were administered . In addition , all patients received st and ard supportive therapy and broad-spectrum antibiotics . MEASUREMENTS AND MAIN RESULTS The primary end point was mortality over 30 days . Secondary outcome measures included the resolution and prevention of organ failure in the same two population s. Additionally , the safety of E5 was evaluated . There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo ( n = 530 ; p = .21 ) . In addition , E5 did not improve survival for patients with Gram-negative sepsis and organ failure ( n = 139 ; p = .3 ) . However , a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5 , compared with those patients who received placebo ( n = 139 ; 48 % E5 vs. 25 % placebo ; p = .005 ) . This result extended to all patients who entered the study with one or more major organ failures , regardless of the etiology of the infection ( n = 225 ; 41 % E5 vs. 27 % placebo ; p = .024 ) . E5 also provided protection against the development of some organ failures , but significant prevention was only observed for adult respiratory distress syndrome ( p = .007 ) and central nervous system dysfunction ( p = .050 ) . Hypersensitivity reactions attributable to E5 occurred in 2.6 % of patients . An asymptomatic antibody response occurred in 44 % of the E5-treated patients and in 12 % of the patients who received placebo . CONCLUSIONS In this study , E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure . However , E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis . This benefit extended to those patients with suspected Gram-negative etiology . This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results . In addition , E5 result ed in the prevention of adult respiratory distress syndrome and central nervous system organ failure . However , more studies are needed to determine if this result can be extended to organ failure in general . E5 is safe as a treatment for patients with Gram-negative sepsis Objective Trials of potential new therapies in acute lung injury are difficult and expensive to conduct . This article is design ed to determine the utility , behavior , and statistical properties of a new primary end point for such trials , ventilator-free days , defined as days alive and free from mechanical ventilation . Describing the nuances of this outcome measure is particularly important because using it , while ignoring mortality , could result in misleading conclusions . Design To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial . To determine the appropriate test statistic for the new measure and derive a formula for power . To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement . To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses . Setting Intensive care units . Patients Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference . Main Results The proposed model fit the clinical data . Ventilator-free days were improved by lower tidal volume ventilation , but the improvement was mostly caused by the improved mortality rate , so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality . Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score . On the other h and , if patients are divided into two groups on the basis of the lung injury score , both the duration of ventilation and mortality are lower in the low lung injury score group . A trial of a treatment that had a similar clinical effect would have a large increase in power , allowing for a reduction in the required sample size . Conclusions Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality . It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days . This would be especially true if the treatment were also required to produce a nominal improvement in mortality 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 r and omized 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 OBJECTIVE To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostagl and in E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase III clinical trial . SETTING Forty-seven community and university-affiliated hospitals in the United States . PATIENTS A total of 350 patients with ARDS were enrolled in this clinical trial . INTERVENTION Patients were prospect ively r and omized in a 1:1 ratio to receive either liposomal prostagl and in 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 st and ard aggressive medical/surgical care during the infusion period . OUTCOME MEASURES 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 . RESULTS 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 prostagl and in 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 prostagl and in E1 group compared with the placebo group ( median number of days to off mechanical ventilation , 16.9 in patients receiving liposomal prostagl and in 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 prostagl and in E1 group and 50 of 170 ( 29 % ) in patients receiving placebo ; p = .55 ) . In contrast , treatment with liposomal prostagl and in 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 prostagl and in 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 prostagl and in E1 ( median number of days to discontinuation of ventilation , 10.3 in the liposomal prostagl and in 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 prostagl and in E1 ( 40 % ) or placebo-treated ( 37 % ) groups . Drug-related adverse events of all kinds were reported in 69 % of the patients receiving liposomal prostagl and in E1 compared with 33 % of the placebo group , with hypotension and hypoxia ( occurring in 52 % and 24 % of the liposomal prostagl and in E1-treated patients , respectively , and 17 % and 5 % of the placebo-treated patients , respectively ) being noted most frequently . CONCLUSIONS In the intent-to-treat population of patients with ARDS , treatment with liposomal prostagl and in E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival Because PGE1 previously has been reported to increase survival of patients with ARDS , we evaluated physiologic effects and side effects of PGE1 in a prospect i ve open-label study of patients with ARDS . Seventeen patients with ARDS who did not have significant renal or hepatic dysfunction received PGE1 by continuous central venous infusion ( 30 ng/kg/min ) . Seventeen control patients with ARDS without renal or hepatic dysfunction who had similar APACHE II and ARDS scores and causes of ARDS did not receive PGE1 . Prostagl and in E1 significantly decreased the SVRI and oxygen extraction ratio . Concentrations of total and polymorphonuclear leukocytes , but not platelets , increased significantly during PGE1 infusion , but did not change in control patients . There was no change in the Do2I and Vo2I during the course of the PGE1 infusion . There were no differences in Do2I and Vo2I during PGE1 infusion between survivors and nonsurvivors . Prostagl and in E1 was infused for a mean of 5.9 + /- 1.8 days ( + /- SD ) and was discontinued on ten occasions in seven patients because of supraventricular dysrhythmias ( n = 4 ) , hypotension ( n = 3 ) , thrombocytopenia ( n = 3 ) , and cardiac arrest ( n = 2 ) . Nonsurvivors had PGE1 discontinued prematurely more frequently than survivors ( 56 percent [ 5/9 ] vs 25 percent [ 2/8 ] , respectively ) . The prevalence of multiple-system organ failure and the in-hospital mortality of both PGE1-treated and control patients were not different . Although PGE1 causes significant systemic vasodilation and possibly decreased intrapulmonary polymorphonuclear leukocyte sequestration , PGE1 does not influence multiple-system organ failure or mortality of patients with ARDS without renal or hepatic dysfunction BACKGROUND A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome . The goal is to reduce lung injury due to overdistention . However , the efficacy of this approach has not been established . METHODS Within 24 hours of intubation , patients at high risk for the acute respiratory distress syndrome were r and omly assigned to either pressure- and volume-limited ventilation ( limited-ventilation group ) , with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less , or to conventional ventilation ( control group ) , with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram . All other ventilatory variables were similar in the two groups . RESULTS A total of 120 patients with similar clinical features underwent r and omization ( 60 in each group ) . The patients in the limited-ventilation and control groups were exposed to different mean ( + /-SD ) tidal volumes ( 7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram , respectively ; P<0.001 ) and peak inspiratory pressures ( 23.6+/-5.8 vs. 34.0+/-11.0 cm of water , P<0.001 ) . Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group ( relative risk , 1.07 ; 95 percent confidence interval , 0.72 to 1.57 ; P=0.72 ) . In the limited-ventilation group , permissive hypercapnia ( arterial carbon dioxide tension , > 50 mm Hg ) was more common ( 52 percent vs. 28 percent , P=0.009 ) , more marked ( 54.4+/-18.8 vs. 45.7+/-9.8 mm Hg , P=0.002 ) , and more prolonged ( 146+/-265 vs. 25+/-22 hours , P=0.017 ) than in the control group . The incidence of barotrauma , the highest multiple-organ-dysfunction score , and the number of episodes of organ failure were similar in the two groups ; however , the numbers of patients who required paralytic agents ( 23 vs. 13 , P=0.05 ) and dialysis for renal failure ( 13 vs. 5 , P= 0.04 ) were greater in the limited-ventilation group than in the control group . CONCLUSIONS In patients at high risk for the acute respiratory distress syndrome , a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity BACKGROUND Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation ( DIC ) . Numerous uncontrolled clinical studies have reported that antithrombin III ( ATIII ) substitution might prevent DIC and death in septic shock . METHODS We conducted a r and omized double-blind placebo-controlled trial in patients with a documented septic shock and DIC . The patients received either a placebo or ATIII ( 90 to 120 IU/kg in loading dose , then 90 to 120 IU/kg/d during 4 days ) . Administration of fresh frozen plasma , platelets , and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time , platelet count , and fibrinogen levels . RESULTS Thirty-five patients entered the study ( 18 placebo , 17 ATIII )  . Both groups were well balanced for all demographic , hemodynamic , and biologic data . Three patients were excluded before the treatment allocation code was broken . In the ATIII group ,  ATIII levels were rapidly corrected and remained over normal levels until day 10 ; sequential protein C and protein S levels were not modified . The duration of DIC was significantly reduced : in the ATIII group , 64 percent of patients were cured of DIC at day 2 , and 71 percent were cured at the end of treatment vs in the placebo group , 11 percent ( p < 0.01 ) and 33 percent ( p < 0.05 ) , respectively . In the 32 included patients , the mortality in ICU was reduced by 44 percent in the ATIII group ( p = 0.22 , NS ) . Care loads and transfusion requirements were not different . No side effect was observed . CONCLUSIONS Mortality was reduced by 44 percent in this trial , but the difference did not reach the statistical significance . Circulating protein C and protein S levels were not modified by ATIII supplementation . High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock . The trend toward improved survival suggests further r and omized studies Objective To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome ( ARDS ) in man . Design R and omized , double-blind , placebo-controlled study . Setting Medical and surgical ICU in a regional hospital . Patients Sixty-six ICU patients with ARDS . Interventions Patients with ARDS ( Pao2/FIO2 ratio < 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 . Measurements and Main Results 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 . Conclusions N-acetylcysteine might be of benefit in ARDS . Before further clinical studies are started , problems with N-acetylcysteine and coagulation have to be eluci date d in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS OBJECTIVE To evaluate the safety and efficacy of liposomal prostagl and in E1 ( TLC C-53 ) in the treatment of patients with the acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase II clinical trial . SETTING Eight community and university-affiliated hospitals in the United States . PATIENTS Twenty-five patients with ARDS . INTERVENTIONS Patients were prospect ively r and omized 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 st and ard , aggressive , medical/surgical care throughout the trial . MEASUREMENTS AND MAIN RESULTS 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 . CONCLUSIONS In patients with ARDS , TLC C-53 was associated with improved oxygenation , increased lung compliance , and decreased ventilator dependency OBJECTIVE 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 . DESIGN R and omized , double-blind , placebo-controlled , prospect i ve clinical trial . SETTING ICUs in five clinical centers in the United States and Canada . PATIENTS Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation . INTERVENTION St and ard 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 ) . MAIN RESULTS 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 % ) . CONCLUSIONS 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 Corticosteroids are widely used as therapy for the adult respiratory distress syndrome ( ARDS ) without proof of efficacy . We conducted a prospect i ve , r and omized , 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 Pentoxifylline , an inhibitor of tumor necrosis factor , has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria . Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok , Thail and , and r and omly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1 ) placebo , 2 ) low-dose pentoxifylline ( 0.83 mg/kg/hr ) , or 3 ) high-dose pentoxifylline ( 1.67 mg/kg/hr ) . All 45 patients had one or more manifestations of severe malaria such as cerebral malaria ( n = 18 ) , renal failure requiring hemodialysis ( n = 9 ) , azotemia ( n = 8) , jaundice ( n = 25 ) , or hyperparasitemia ( n = 30 ) . The overall severity was comparable in the three groups . Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients . In addition , a number of subsidiary outcome variables were examined in specific subgroups , including the recovery time from coma for patients with cerebral malaria , the duration of intubation in patients with respiratory distress , the number of hemodialysis treatments needed for patients with acute renal failure , and the number of units of blood administered to patients requiring transfusion . Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment . No significant differences among the three treatment groups were found for any of the outcome variables examined . We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit The effects of massive steroids on pulmonary function  after hypovolemic shock were tested in 114 injured patients who received an average of 13 transfusions , 760 ml plasma , and 11.7 L crystalloid solution ; by r and om selection , 54 patients received  methylprednisolone ( 1 g in operating room plus 3,578 mg average during the next three days ) . The patients who received steroids had a significant increase in central venous pressure and a decrease in arterial oxygen tension ( PaO2 ) compared with control patients . The inspired oxygen concentration was similar for both groups ; the FiO2/PO2 , therefore , was significantly deranged ( p= ≤ 0.05 ) in steroid patients ( 0.45 ± 0.05 SE vs 0.37 ± 0.02 SE ) . The patients who received steroids had an insignificantly increased pulmonary shunt ( 25 vs 22 % ) , number of days on a volume ventilator ( 5.1 vs 3.0 days ) , and number of deaths ( seven vs two ) . Massive steroids neither prevent nor ameliorate pulmonary failure after shock ; indeed , steroids may aggravate pulmonary failure after At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as Levels of thromboxane B2 ( TxB2 ) , the stable metabolite of thromboxine 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 r and omized prospect i ve 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 > 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 OBJECTIVE No means exist for predicting the acute respiratory distress syndrome ( ARDS ) , which complicates sepsis , trauma , and a variety of clinical disorders . Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response , and thereby lead to the development of ARDS , we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients . DESIGN Part I : A prospect i ve , single-blind trial . Part II : A prospect i ve , r and omized , double-blind trial . SETTING General intensive therapy units in five university teaching hospitals . SUBJECTS Part I : Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values , followed by 30 patients admitted with onset of sepsis , trauma , or development of ARDS ( within 24 hrs of admission ) over a 1-yr period . Part II : Eight patients admitted with sepsis syndrome over a 2-month period . INTERVENTIONS Part II : Patients were r and omized to receive the substituted methylxanthine , lisofylline ( CT1501R ) , or an identically presented placebo . MEASUREMENTS AND MAIN RESULTS We measured the serum free fatty acid concentrations in the 39 healthy control subjects , and then we prospect ively examined the serum free fatty acid concentrations in 30 age-matched patients in sample s obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS . We then prospect ively studied eight septic , at-risk patients who were matched for age , Acute Physiology and Chronic Health Evaluation II scores , Multiple Organ Failure index , and Glasgow Coma Score , in a double-blind , placebo-controlled , pilot study . These patients included four patients who received no treatment and four patients who received lisofylline , a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and /or trauma . The calculated ratios of serum free fatty acids ( Le . , the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate , C16:0 ) increased and predicted the development of ARDS in at-risk patients . Serum sample s from the 30 patients , obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS , had significantly increased mean acyl chain ratios ( 1.42 + /- 0.35 [ SD ] ) compared with healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from 13 patients with sepsis or trauma who did not develop ARDS ( group A [ at-risk , non-pre-ARDS ] ) also had increased acyl ratios ( 1.23 + /- 0.27 ) compared with sera from healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from seven patients who subsequently developed ARDS ( group B [ at-risk , pre-ARDS ] ) had higher acyl ratios ( 1.70 + /- 0.21 ) than group A at-risk patients who did not develop ARDS ( 1.23 + /- 0.27 ; p < .01 ) or healthy control subjects ( 0.86 + /- 0.25 ; p < .001 ) . Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios ( 1.80 + /- 0.75 ) , which exceeded values for healthy control subjects ( p < .001 ) and group A at-risk patients without ARDS ( p = .01 ) , but were not significantly different then group B at-risk , pre-ARDS patients ( p = .17 ) . Prospect i ve study of eight septic , at-risk patients demonstrated significantly ( p < .05 ) increased serum acyl ratios in the four untreated patients ( findings consistent with the first study ) but a significantly ( p = .02 ) reduced ratio in the four at-risk patients treated with lisofyline . CONCLUSIONS Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients , and identify those patients likely to develop ARDS . Thus , the serum acyl ratio may not only prospect ively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS , but may also lead to new insights about the pathogenesis of ARDS This study assessed the safety and efficacy of filgrastim ( r-metHuG-CSF [ recombinant human methionine granulocyte colony-stimulating factor ] ) , when combined with intravenous ( IV ) antibiotics , in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia ( CAP ) . Four hundred eighty patients were r and omized to receive placebo ( n=243 ) or filgrastim 300 microg/day ( n=237 ) , in addition to st and ard therapy . Treatment with study drug was continued for 10 days , until the peak white blood cell ( WBC ) count reached 75x109/L , until discharge from the hospital , until death , or until IV antibiotics were discontinued . Study -related observations continued through day 29 . Filgrastim increased WBC counts ( baseline median , 13.3x109/L ; median peak , 43 . 8x109/L ) . The 2 treatment groups were not statistically different with respect to the study end points ; however , there was a trend toward reduction of mortality in patients with pneumococcal bacteremia . Although further studies will be required to vali date this observation , filgrastim was safe and well tolerated when administered to patients with multilobar CAP OBJECTIVE Platelet-activating factor ( PAF ) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome . One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase ( PAF-AH ) . Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients , the present study was conducted to determine whether treatment with recombinant human PAF-AH ( rPAF-AH , Pafase ) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality . DESIGN A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Thirty-three medical and surgical intensive care units located in the United States . PATIENTS A total of 127 patients with severe sepsis , but without established acute respiratory distress syndrome , were enrolled in the study . R and omization occurred within 12 hrs of the onset of severe sepsis . Patients then received 1.0 mg/kg rPAF-AH ( n = 45 ) , 5.0 mg/kg rPAF-AH ( n = 39 ) , or placebo ( n = 43 ) administered intravenously , once daily , for five consecutive days . MEASUREMENTS AND MAIN RESULTS Demographic and baseline clinical characteristics of the three treatment groups were similar , except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH . There were no treatment-related deaths , and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients . There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups . However , 28-day all-cause mortality was 21 % in the 1.0 mg/kg rPAF-AH group , 28 % in the 5.0 mg/kg rPAF-AH group , and 44 % in the placebo group ( overall chi-square p = .07 ; 1.0 mg/kg rPAF-AH vs. placebo , p = .03 ) . A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group ( p = .11 ) . CONCLUSION The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis
BACKGROUND Multiple pharmacologic treatments have been studied for acute lung injury ( ALI ) and acute respiratory distress syndrome ( ARDS ) .
OBJECTIVES Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS .