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.

OBJECTIVE: To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). DESIGN: Randomized, prospective, 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 prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. 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 prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of >300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. CONCLUSIONS: In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival.     

Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study

OBJECTIVE: To determine whether bovine surfactant given in cases of severe pediatric acute respiratory distress syndrome (ARDS) improves oxygenation. DESIGN: Single-center study with 19 patients, followed by a multicenter randomized comparison of surfactant with a standardized treatment algorithm. Primary endpoint PaO(2)/FIO(2) at 48 h, secondary endpoints: PaO(2)/FIO(2) at 2, 4, 12, and 24 h, survival, survival without rescue, days on ventilator, subgroups analyzed by analysis of variance to identify patients who might benefit from surfactant. SETTING: Multicenter study in 19 reference centers for ARDS. PATIENTS: Children after the 44th postconceptional week and under 14 years old, admitted for at least 4 h, ventilated for 12-120 h, and without heart failure or chronic lung disease. In the multicenter study 35 patients were recruited; 20 were randomized to the surfactant group and 15 to the nonsurfactant group. Decreasing recruitment of patients led to a preliminary end of this study. INTERVENTIONS: Administration of 100 mg/kg bovine surfactant intratracheally under continuous ventilation and PEEP, as soon as the PaO(2)/FIO(2) ratio dropped to less than 100 for 2 h (in the pilot study increments of 50 mg/kg as long as the PaO(2)/FIO(2) did not increase by 20%). A second equivalent dose within 48 h was permitted. RESULTS: In the pilot study the PaO(2)/FIO(2) increased by a mean of 100 at 48 h (n=19). A higher PaO(2)/FIO(2) ratio was observed in the surfactant group 2 h after the first dose (58 from baseline vs. 9), at 48 h there was a trend towards a higher ratio (38 from baseline vs. 22). The rate of rescue therapy was significantly lower in the surfactant group. Outcome criteria were not affected by a second surfactant dose (n=11). A significant difference in PaO(2)/FIO(2) in favor of surfactant at 48 h was found in the subgroup with an initial PaO(2)/FIO(2) ratio higher than 65 and in patients without pneumonia. CONCLUSIONS. Surfactant therapy in severe ARDS improves oxygenation immediately after administration. This improvement is sustained only in the subgroup of patients without pneumonia and that with an initial PaO(2)/FIO(2) ratio higher than 65     

The oxygenation variations related to prone positioning during mechanical ventilation: a clinical comparison between ARDS and non-ARDS hypoxemic patients

OBJECTIVES: To compare, in clinical practice, the oxygenation variations related to prone positioning (PP) during mechanical ventilation in ARDS and non-ARDS hypoxemic patients. DESIGN AND SETTING: Prospective observational study of data on consecutive patients treated with the same protocol in the intensive care unit (ICU) of a university hospital. PATIENTS: From May 1996 to December 1998, 226 PP periods without adjunction of nitric oxide (NO) inhalation and/or almitrine bismesylate infusion, performed in 59 mechanically ventilated hypoxemic patients (arterial oxygen tension/fractional inspired oxygen (PaO2/FIO2) ratio <300 mmHg) with no evidence of left ventricular failure, were included in this study. MEASUREMENTS: Arterial blood gas was measured before the PP, at 1 h from the beginning of the PP, at the end of the PP and 1 h after returning to the supine position. RESULTS: We analyzed 136 PP periods in 34 non-ARDS patients (60.2%) and 90 in 25 ARDS patients. The PP was repeated and the duration of the PP periods was: 10.6+/-0.22 h. The PP during the mechanical ventilation appeared to be safe and well tolerated. A PaO2/FIO2 ratio improvement at the end of the PP period, occurred for 196 periods (86.7%) with a mean PaO2/FIO2 ratio increase of +46.4+/-0.03% at the end of the PP periods compared to the baseline supine value. The PaO2/FIO2 ratio variations at 1 h after the start of the PP, at the end of the PP period and at 1 h after the return to supine were not different in ARDS or non-ARDS hypoxemic patients. The PaO2/FIO2 ratio improvement appeared to be more intense and more rapid in ARDS patients. CONCLUSIONS: In about 90% of periods, PP improved the PaO2/FIO2 ratio in patients with ARDS as well as in hypoxemic patients with non-ARDS. Studies are necessary to determine the impact of PP on survival and the mechanical ventilation duration in ARDS or non-ARDS hypoxemic patients.     

Acute respiratory distress syndrome in trauma patients: ICU mortality and prediction factors

OBJECTIVES: To study the factors that influence the intensive care unit (ICU) mortality of trauma patients who develop acute respiratory distress syndrome (ARDS) and to evaluate determinants of length of ICU stay among these patients. DESIGN: Study on a prospective cohort of 59 trauma patients that developed ARDS. SETTING: ICU of a referral trauma center. Fifty-nine patients were included during the study period from 1994 to 1997. METHODS: The dependent variables studied were the mortality and length of ICU stay. The main independent variables studied included the general severity score APACHE III, the revised trauma and injury severity scores (RTS, ISS), emergency treatment measures, the gas exchange index (PaO2/FIO2) recorded after the onset of ARDS and the development of multiple system organ failure (MSOF). Univariate and multivariate analyses were performed. RESULTS: The mean age of patients was 42.1 +/- 16.7 years, 49 patients (83 %) were male, the mean APACHE III score was 52.7 +/- 33.7 points, the ISS 28.5 +/- 11.4 points and the RTS 8.9 +/- 2.5 points. ICU length of stay was 28.5 +/- 24.5 days and the mortality rate 31.7 % (19 deaths). Mortality was associated with the following: PaO2/FIO2 ratio on the 3rd, 5th and 7th days post-ARDS; high volume of crystalloid/colloid infusion during resuscitation; the APACHE III score; and the development of MSOF According to the multivariate analysis, the mortality of these patients was correlated with the PaO2/FIO2 ratio on the 3rd day of ARDS, the APACHE III score and the development of MSOF. This analysis also showed days on mechanical ventilation to be the only variable that predicted ICU length of stay. CONCLUSIONS: The ICU mortality of trauma patients with ARDS is related to the APACHE III score, the gas exchange evolution as measured by the PaO2/FIO2 on the 3rd day and the progressive complications indicated by the onset of MSOF. The length of ICU stay of these patients is related to the number of days on mechanical ventilation.     

Comparison of the response to the prone position between pulmonary and extrapulmonary acute respiratory distress syndrome

OBJECTIVES: To determine whether the response to the prone position differs between acute respiratory distress syndrome (ARDS) resulting from a pulmonary cause (ARDSp) and that from an extrapulmonary cause (ARD-Sexp). DESIGN AND SETTING: Prospective observational study in a medical ICU of a university-affiliated hospital. SUBJECTS: A consecutive series of 31 patients with ARDSp and 16 with ARDSexp within 3 days of onset of ARDS. INTERVENTION: Prone position for at least 2 h. MEASUREMENTS AND RESULTS: In ARDSp, compared with the supine position (121 +/- 49 mmHg), PaO2/FIO2 was not increased after 0.5 h but was increased after 2 h in the prone position (158 +/- 60 mmHg). In ARDSexp, compared with the supine position (106 +/- 53 mmHg), PaO2/FIO2 was increased after 0.5 h (155 +/- 91 mmHg), but was not further changed after 2 h. Marked oxygenation response (increase in PaO2/FIO2 > 40% from baseline) after 0.5 h was 23% in ARDSp and 63% in ARDSexp, and that after 2 h was 29% and 63%, respectively. Static respiratory compliance decreased in the prone position in ARDSexp (30 +/- 11 ml/cmH2O at baseline, 27 +/- 11 after 0.5 h and 25 +/- 9 after 2 h) but not in ARDSp. Consolidation score as determined on the first chest radiography taken in the prone position decreased to a greater degree in ARDSexp (-2.4 +/- 4.1) than in ARDSp (0.3 +/- 4.1). CONCLUSION: Pulmonary ARDS and extrapulmonary ARDS in their early stages respond differently to the prone position with regard to the time course of oxygenation, respiratory mechanical behaviour, and radiographic change. These findings suggest that the early pathophysiology of ARDS differs according to the type of primary insult to the lung.     

Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response

OBJECTIVES: To examine the hypothesis that the response to inhaled prostacyclin (PGI2 on oxygenation and pulmonary hemodynamics may be related to different morphologic features that are supposed to be present in acute respiratory distress syndrome (ARDS) originating from pulmonary (primary ARDS [ARDS(PR)]) and from extrapulmonary disease (secondary ARDS [ARDS(SEC)]). DESIGN: Prospective, nonrandomized interventional study. SETTING: Multidisciplinary intensive care unit, secondary care center. PATIENTS: Fifteen consecutive, mechanically ventilated patients with ARDS and severe hypoxemia, defined as PaO2/FIO2 of <150 torr at the time of admission. INTERVENTIONS: After an initial stable period of at least 60 mins, patients received nebulized PGI2 in 15-min steps; the drug was titrated to find the dose with the best improvement of PaO2, starting with 2 ng/kg/min up to an allowed maximum dose of 40 ng/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood gas, gas exchange, and hemodynamic measurements were performed at the following time points: a) baseline; b) during the optimal or maximum dose of PGI2; and c) 1 hr after withdrawal of the drug. Patients underwent a computed tomographic (CT) scan using a basal CT section to compute the mean CT numbers and the density histogram. Patients were considered responders to PGI2 if an increase in PaO2 of > or =7.5 torr or an increase in PaO2/FIO2 ratio of > or =10% occurred. For the group as a whole, mean pulmonary artery pressure decreased from 32 +/- 1 to 29 +/- 1 mm Hg during PGI2 nebulization, whereas pulmonary vascular resistance decreased 1 hr after withdrawal of nebulization from 177 +/- 18 to 153 +/- 16 dyne x sec/cm5; oxygenation did not change significantly. Eight patients responded to PGI2 nebulization on oxygenation (all were in the ARDS(SEC) subgroup), whereas seven did not (all but one were in the ARDS(PR) subgroup). Among the physiologic variables examined to assess any difference between the two ARDS groups at time of PGI2 nebulization, there was a significant difference concerning the mean CT density number, which was -445 +/- 22 Hounsfield Units in the ARDS(SEC) group and -258 +/- 16 Hounsfield Units in the ARDS(PR) group. In patients presenting with an ARDS(PR), PGI2 induced a reduction in PaO2/FIO2 and a reduction in PaO2 from 87 +/- 2 to 79 +/- 2 torr, whereas in patients with an ARDS(SEC) there was an increase in PaO2/FIO2 and in PaO2 from 76 +/- 4 to 84 +/- torr with a decrease in mean pulmonary artery pressure. CONCLUSIONS: Based on the data from this study, the clinical recognition of the two types of the syndrome together with the CT number frequency distribution analysis may be associated with a prediction of the PGI2 nebulization response on oxygenation.     

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.

OBJECTIVES: Recent studies in animal models of sepsis-induced acute respiratory distress syndrome (ARDS) have shown that a low-carbohydrate, high-fat diet combining the anti-inflammatory and vasodilatory properties of eicosapentaenoic acid (EPA; fish oil), gamma-linolenic acid (GLA; borage oil) (EPA+GLA), and antioxidants improves lung microvascular permeability, oxygenation, and cardiopulmonary function and reduces proinflammatory eicosanoid synthesis and lung inflammation. These findings suggest that enteral nutrition with EPA+GLA and antioxidants may reduce pulmonary inflammation and may improve oxygenation and clinical outcomes in patients with ARDS. DESIGN: Prospective, multicentered, double-blind, randomized controlled trial. SETTING: Intensive care units of five academic and teaching hospitals in the United States. PATIENTS: We enrolled 146 patients with ARDS (as defined by the American-European Consensus Conference) caused by sepsis/pneumonia, trauma, or aspiration injury in the study. INTERVENTIONS: Patients meeting entry criteria were randomized and continuously tube-fed either EPA+GLA or an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure x 1.3 for at least 4-7 days. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were measured, and ventilator settings were recorded at baseline and study days 4 and 7 to enable calculation of PaO2/FIO2, a measure of gas exchange. Pulmonary neutrophil recruitment was assessed by measuring the number of neutrophils and the total cell count in bronchoalveolar lavage fluid at the same time points. Clinical outcomes were recorded. Baseline characteristics of 98 evaluable patients revealed that key demographic, physiologic, and ventilatory variables were similar at entry between both groups. Multiple bronchoalveolar lavages revealed significant decreases (approximately 2.5-fold) in the number of total cells and neutrophils per mL of recovered lavage fluid during the study with EPA+GLA compared with patients fed the control diet. Significant improvements in oxygenation (PaO2/FIO2) from baseline to study days 4 and 7 with lower ventilation variables (FIO2, positive end-expiratory pressure, and minute ventilation) occurred in patients fed EPA+GLA compared with controls. Patients fed EPA+GLA required significantly fewer days of ventilatory support (11 vs. 16.3 days; p = .011), and had a decreased length of stay in the intensive care unit (12.8 vs. 17.5 days; p = .016) compared with controls. Only four of 51 (8%) patients fed EPA+GLA vs. 13 of 47 (28%) control patients developed a new organ failure during the study (p = .015). CONCLUSIONS: The beneficial effects of the EPA+GLA diet on pulmonary neutrophil recruitment, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggest that this enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.     

Acute respiratory distress syndrome among trauma patients: trends in ICU mortality, risk factors, complications and resource utilization

OBJECTIVE: To evaluate trends in mortality and related factors among trauma patients who developed acute respiratory distress syndrome (ARDS). STUDY: Observational study based on data prospectively gathered in computerized trauma registry. SETTING: Trauma intensive care unit (ICU) of 48 beds in level I trauma center. PATIENTS: All trauma patients with ARDS admitted during 1985-87 (486, group 1 [G1]) and 1993-95 (552, group 2[G2]). METHODS: ARDS was defined by American-European Consensus Conference criteria and the need for 48 h or more on mechanical ventilation with FIO2 greater than 0.50 and PEEP of more than 5 cmH2O. Demographics, severity score, injury-admission delay time, first 24-h transfusion and septic and organ system failure complications were independent variables. ICU mortality was the dependent variable. ICU length of stay (LOS) and life support techniques were considered. Respiratory and renal support strategies were different in the two time periods. RESULTS: Mortality decreased over the period (G1: 29.2% vs G2: 21.4%, p < 0.04), in patients aged both over and under 65 years. Multivariate analysis showed mortality was related to age, severity and time period (G1 1.68-fold that in G2) and that the greater G1 mortality was related to more renal failure and hematologic failure/dysfunction. ICU LOS decreased from 31.7+/-26.7 days (G1) to 27.3+/-22 days (G2) (p < 0.003). CONCLUSIONS: Mortality among trauma patients with ARDS declined over the 8 years studied and was associated with less organ failure. This reduction was probably the result of new approaches to mechanical ventilation, renal failure replacement and vasoactive drug therapy.     

Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study.

OBJECTIVE: To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome (ARDS) in man. DESIGN: Randomized, 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 less than 250 torr) were treated with either the antioxidant N-acetylcysteine 150 mg/kg as a loading dose and then 20 mg/kg/hr, or with placebo for 6 days. 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 elucidated in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS.     

Is a short trial of prone positioning sufficient to predict the improvement in oxygenation in patients with acute respiratory distress syndrome?

OBJECTIVE: To determine whether a 1-h trial of prone positioning is sufficient to identify responders. DESIGN: Prospective clinical cohort study in a medico-surgical ICU in a teaching hospital. PATIENTS: 49 patients with acute respiratory distress syndrome. INTERVENTIONS: A 6-h period of prone positioning. MEASUREMENTS AND RESULTS: Baseline measurements (blood gas analysis and respiratory parameters) were evaluated in supine position just prior to turning the patients prone. Measurements were then repeated 1 h after the beginning of prone positioning (PP1h) and at the end of the 6-h period of prone positioning (PP6h). The last measurements were performed 1 h after repositioning the patients supine. Prone position induced an increase in the PaO2/FIO2 ratio (p < 0.001). A response (increase in PaO2/FIO2 ratio of at least 20 % at PP1h and/or at PP6h) was observed in 37 of 49 patients (76%). Twenty-seven of these patients (73%) were responders at PP1h while 10 (27%) were responders only at PP6h- In all, two-thirds of the patients were considered persistent responders. However, whereas the PaO2/FIO2 ratio decreased significantly 1 h after repositioning the fast responders supine, the PaO2/ FIO2 ratio remained unchanged after repositioning slow responders. CONCLUSIONS: A short-term trial of prone positioning does not appear a sufficient method to identify patients who would benefit from the postural treatment.     

Safety of granulocyte colony-stimulating factor (filgrastim) in intubated patients in the intensive care unit: interim analysis of a prospective, placebo-controlled, double-blind study

OBJECTIVE: To investigate the safety of the granulocyte colony-stimulating factor filgrastim in the prevention of nosocomial infections in intubated patients in the intensive care unit (ICU), with special emphasis on the possible deleterious effect on acute respiratory distress syndrome (ARDS) and the development of multiple organ dysfunction (MOD). DESIGN: Predetermined, interim analysis of a prospective, randomized, placebo-controlled, double-blind trial. SETTING: University hospital medical-surgical ICU. PATIENTS: A total of 59 consecutive ICU patients, aged >18 yrs, admitted to the ICU no more than 12 hrs before the study, intubated because of ventilatory insufficiency no more than 48 hrs before the study, expected to stay in the ICU for >48 hrs, and had informed consent from the next relative. INTERVENTIONS: Patients were randomized to receive either placebo or 300 microg of filgrastim subcutaneously once daily for 7 days. MEASUREMENTS AND MAIN RESULTS: No significant differences were found in the number of patients developing ARDS (2 of 20 in the placebo group vs. 0 of 22 in the filgrastim group), disseminated intravascular coagulation (3 of 27 vs. 3 of 29), acute renal failure (1 of 27 vs. 1 of 23), or change in MOD. Data analysis showed nosocomial infections in 11 of 29 patients in the placebo group and in 7 of 30 patients in the filgrastim group (p = .266). The median (range) length of ICU stay was 8 (1-34) days in the placebo group and 6 days (1-28) in the filgrastim group. The day 28 mortality rate was 17% (5 of 29) in the placebo group and 13% (4 of 30) in the filgrastim group. No drug-related adverse events occurred. CONCLUSION: Filgrastim is safe in intubated ICU patients, with no excess risk for development of ARDS or MOD.     

Chemically modified tetracycline 3 prevents acute respiratory distress syndrome in a porcine model of sepsis + ischemia/reperfusion-induced lung injury

Experimental pharmacotherapies for the acute respiratory distress syndrome (ARDS) have not met with success in the clinical realm. We hypothesized that chemically modified tetracycline 3 (CMT-3), an anti-inflammatory agent that blocks multiple proteases and cytokines, would prevent ARDS and injury in other organs in a clinically applicable, porcine model of inflammation-induced lung injury. Pigs (n = 15) were anesthetized and instrumented for monitoring. A "2-hit" injury was induced: (a) peritoneal sepsis-by placement of a fecal clot in the peritoneum, and (b) ischemia/reperfusion-by clamping the superior mesenteric artery for 30 min. Animals were randomized into two groups: CMT-3 group (n = 7) received CMT-3 (200 mg/kg); placebo group (n = 9) received the same dose of a CMT-3 vehicle (carboxymethylcellulose). Experiment duration was 48 h or until early mortality. Animals in both groups developed polymicrobial bacteremia. Chemically modified tetracycline 3 treatment prevented ARDS as indicated by PaO(2)/FIO(2) ratio, static compliance, and plateau airway pressure (P < 0.05 vs. placebo). It improved all histological lesions of ARDS (P < 0.05 vs. placebo). The placebo group developed severe ARDS, coagulopathy, and histological injury to the bowel. Chemically modified tetracycline 3 treatment prevented coagulopathy and protected against bowel injury. It significantly lowered plasma concentrations of interleukin 1β (IL-1β), tumor necrosis factor α, IL-6, IL-8, and IL-10. This study presents a clinically relevant model of lung injury in which CMT-3 treatment prevented the development of ARDS due in part to reduction of multiple plasma cytokines. Treatment of sepsis patients with CMT-3 could significantly reduce progression from sepsis into ARDS.     

Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome

OBJECTIVE: We investigated the efficacy of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome (ARDS) by post hoc analysis of a previously completed clinical trial. DESIGN: Retrospective analysis of a placebo-controlled, randomized, double-blind trial of low doses of corticosteroids in septic shock. SETTING: Nineteen intensive care units in France. PATIENTS: Among the 300 septic shock patients enrolled, we selected those meeting standard criteria for ARDS at inclusion. INTERVENTIONS: Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 microg of 9-alpha-fludrocortisone once a day. MEASUREMENTS AND MAIN RESULTS: There were 177 patients with ARDS (placebo, n = 92; corticosteroids, n = 85) including 129 (placebo, n = 67; corticosteroids, n = 62) nonresponders and 48 (placebo, n = 25; corticosteroids, n = 23) responders. In nonresponders, there were 50 deaths (75%) in the placebo group and 33 deaths (53%) in the steroid group (hazard ratio 0.57, 95% confidence interval 0.36-0.89, p = .013; relative risk 0.71, 95% confidence interval 0.54-0.94, p = .011). The number of days alive and off the ventilator was 2.6 +/- 6.6 in the placebo group and 5.7 +/- 8.6 in the steroid group (p = .006). There was no significant difference between groups in responders. There was no significant difference between groups in the two subsets of patients without ARDS. Adverse events rates were similar in the two groups. CONCLUSIONS: This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS.     

A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients

OBJECTIVES: To compare two levels of continuous cisatracurium-induced curarization in hypoxemic, ventilated patients. DESIGN AND SETTING: An open-labeled, multicenter, prospective, randomized study. PATIENTS: Hundred two patients with a ratio between arterial oxygen tension and inspired oxygen tension (PaO(2)/FIO(2)) less than 200 despite optimization of sedation and ventilation were randomized into group 1 (n=52) with an end point of no response at orbicularis oculi to train-of-four (TOF) stimulation or group 2 (n=50) with an end point of two responses. MEASUREMENTS AND RESULTS: The PaO(2)/FIO(2) and end-inspiratory plateau airway pressure (Pplat) were evaluated at baseline (before curarization) and at regular intervals once TOF end points had been attained for up to 2 h afterwards (T2 h). A decrease of 1 cmH(2)O or more of Pplat at T2 h compared to baseline was observed in 37% and 50% of the patients in groups 1 and 2, respectively (p=0.17). Time courses of PaO(2)/FIO(2) (mmHg) and Pplat (cmH(2)O) [mean (SD)] were equivalent in both groups, with a mild increase in PaO(2)/FIO(2) [p=0.0014; from 126 (33) to 141 (55) and from 134 (40) to 152 (52), respectively, in groups 1 and 2] and decrease in Pplat [p=0.016; from 29.1 (8.9) to 28.5 (8.8) and from 27.7 (7.5) to 26.6 (7.6)]. Median total durations of curarization were 28.9 h (3.1-219.7) in group 1 and 31.4 h (1.6-650.6) in group 2. Median cisatracurium infusion rates were 5.2 microg kg(-1) min(-1) (2.1-13.7) in group 1 and 3.6 microg kg(1) min(-1) (1.0-13.5) in group 2. The median delay to recovery from paralysis was shorter in group 2 (0.75 h vs 1.25 h; p=0.0008). CONCLUSION: When a prolonged curarization is decided upon in an ICU patient, a blockade at 2/4 at TOF at orbicularis oculi has similar effects on respiratory parameters as a blockade at 0/4, allowing a decrease in total administered doses and a shortening of the recovery of muscle strength after cessation of infusion.     

Safety of percutaneous dilational tracheostomy in patients ventilated with high positive end-expiratory pressure (PEEP)

OBJECTIVE: To assess the impact of bronchoscopically guided percutaneous dilational tracheostomy (PDT) on oxygenation in patients with severe respiratory failure ventilated with high positive end-expiratory pressure (PEEP). DESIGN: Prospective clinical study. SETTING: Anaesthesiological ICU, referral centre for acute respiratory distress syndrome (ARDS) therapy, university hospital. PATIENTS: Mechanically ventilated patients with indication for PDT. Two hundred three consecutive PDTs were performed in 198 patients on either high (>10 mbar, n=88) or low (相似文献   

Pediatric ARDS: effect of supine-prone postural changes on oxygenation

OBJECTIVE: To determine the effect of repeated prone positioning (supine-prone/prone-supine) on oxygenation in children suffering from ARDS. DESIGN: Single-center prospective case series. SETTING: University pediatric ICU. PATIENTS: Consecutive pediatric patients with severe ARDS (PaO(2)/FiO(2) <200, Murray score >2.5). INTERVENTIONS: Patients were treated as soon as possible with supine-prone/prone-supine positioning every 8 h until clinical improvement or death occurred. MEASUREMENTS AND RESULTS: Twenty-three patients who had ARDS (0.5-months to 12.6-years-old), were placed in the prone position within 56+/-109 h after the diagnosis of ARDS. Prone-supine/supine-prone postural changes were repeated every 8 h for 9.7+/-5.5 days. Changes in PaO(2)/FiO(2) ratio during supine-prone and prone-supine positioning were evaluated. A positive change was defined as an increase of 15% of baseline value. The patient was classified as a responder when the mean increase in the prone position was greater than 15%. There were 18 responders and five non-responders. The responders showed an increase in PaO(2)/FiO(2) ratio of 22%, from 91+/-33 to 112+/-43 (P <0.001), when they were placed from the supine to the prone position. Their PaO(2)/FiO(2) ratio dropped from 109+/- 37 to 94 +/-36, P = 0.011, when changed from the prone to supine position. The overall mortality rate in this series was 48% (11 patients), which was higher in the non-responders (80%) than in the responders (39%), although this difference was not statistically significant (P = 0.95). CONCLUSIONS: The prone position improves oxygenation in a significant proportion of children with ARDS. Although no statistically significant difference was found for the mortality rate, it was higher for the non-responders (80%) vs the responders (39%).     

Comparison of fixed dose versus train-of-four titration of cisatracurium in acute respiratory distress syndrome

PurposeTo compare the ventilatory and clinical outcomes associated with a fixed-dose cisatracurium infusion versus a titrated infusion strategy in patients with Acute Respiratory Distress Syndrome (ARDS).Materials and methodsSingle-center, retrospective, cohort study in a medical ICU of a tertiary care academic medical center. Adult patients ≥18 years old with a continuous infusion of cisatracurium for ≥12 h for treatment of ARDS were included. The primary outcome was the PaO2 /FiO2 ratio assessed at 24 and 48 h following cisatracurium initiation. Secondary outcomes included amount of average dose of drug administered, 28-day ventilator-free days, LOS, and hospital mortality.Results167 patients were included; median baseline PaO2/FiO2 was 97 (76–146), median SOFA score of 9 (7–11), and ICU mortality was 71/167 (43%). In a mixed-effects model, fixed dose and titrated cisatracurium associated with similar changes in PaO2/FiO2 assessed at 24 and 48 h (p = 0.316). Fixed-dose was associated with a >3-fold increase in drug exposure (average dose 6.4 (5.4–8.0) vs. 2.0 (1.5–2.8) mcg/kg/min; p < 0.001, respectively). No differences were observed in secondary clinical endpoints.ConclusionFixed-dose cisatracurium was associated with similar ventilatory and clinical outcomes compared to titrated strategy, yet it was associated with a 3-fold increase in dose administered.     

Titrating positive end-expiratory pressure therapy in patients with early, moderate arterial hypoxemia

A prospective randomized study to compare two physiologic end-points for titrating positive end-expiratory pressure (PEEP) was performed in patients with early, moderate arterial hypoxemia after surgery or trauma. All patients initially received 5 cm H2O of PEEP. In group 1 patients, PEEP was increased only if PaO2 decreased below 65 torr on an inspired oxygen fraction (FIO2) of 0.45. PEEP was then added in 2- to 3-cm H2O increments until PaO2 again was above 65 torr. Group 2 patients were treated with incremental PEEP until the PaO2/FIO2 ratio was greater than 300 or physiologic shunt (Qsp/Qt) was less than 0.20. All therapy other than PEEP was similar in the two groups. There were no statistically significant differences in entry PaO2 (mean 85 +/- 11 [SD] and 87 +/- 11 torr in groups 1 and 2, respectively), and Qsp/Qt was 0.22 in each group. Five (28%) of 18 patients in group 1 and 19 (95%) of 20 patients in group 2 received more than 5 cm H2O of PEEP. Between groups 1 and 2 there were no statistically significant differences in days intubated (3.4 +/- 3 vs. 5.3 +/- 5, respectively), ICU days (5.3 +/- 3 vs. 6.6 +/- 5), hospitalization days (26 +/- 24 vs. 28 +/- 24), incidence of pulmonary barotrauma (0/18 vs. 1/20), ICU mortality (22% vs. 20%), or overall mortality (33% vs. 25%). The number of blood gas analyses and cardiac output measurements, and the total hospital charges were also similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients.

Critically ill patients are commonly associated with systemic inflammatory response syndrome (SIRS) and are at a greater risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Under these conditions, large amounts of various cytokines are produced, which either directly or indirectly induce tissue injury and finally organ dysfunctions, through the activation of neutrophils and as a result of release of cytotoxic molecules, especially neutrophil elastase (NE). In the present study, we determined plasma neutrophil elastase-alpha-1 antitrypsin complex (NE-AT) and elastase digests of cross-linked fibrin (e-XDP) in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE-AT in the patients with ARDS, especially when the definition of SIRS was met. Among ALI/ARDS groups, plasma NE-AT, but not e-XDP, correlated significantly with the decrease in PaO(2)/FIO(2) ratio and the duration of ALI/ARDS. Furthermore, NE-AT, but not e-XDP, significantly increased in subgroups whose PaO(2)/FIO(2) ratio decreased by more than 20%. Such correlations and differences between the subgroups were not observed in the non-ALI patients. From these results, we speculate that NE-AT, but not e-XDP, may be predictive of progressive lung injury in the early stage of ALI and ARDS.     

Daily changes of the area of density in the dependent lung region – evaluation using transesophageal echocardiography

OBJECTIVE: To evaluate the daily changes of the area of density using transesophageal echocardiography (TEE) in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) patients. DESIGN: Retrospective observational study. SETTING: General ICU in a university hospital. PATIENTS: Fifteen patients with ARDS or ALI who underwent TEE examination for more than 5 days. MEASUREMENTS: Densities in the lower left lung region were observed through the descending aorta by TEE. Daily changes of the area of density were evaluated. The areas of density estimated by TEE were compared with those obtained by computed tomography (CT). The relation between the area of density and PaO(2)/FIO(2)was calculated. RESULTS: The area of density in the dependent lung region measured by TEE was 11.1+/-5.7 cm(2) (mean +/- SD) at the mid-esophageal position. The area of density in ARDS patients changed daily from 12.0+/-2.8 cm(2) to 8.5+/-6.7 cm(2).The areas of density evaluated using TEE in the left lung correlated significantly with those estimated using CT ( r=0.72, p<0.01). In addition, we found a significant correlation between PaO(2)/FIO(2) and the area of density estimated by TEE ( r=-0.53, p<0.05). CONCLUSION: Using TEE, we could evaluate daily changes of the area of density in the dependent lung region in the intensive care situation. The areas of density in ARDS patients changed from day to day following the changes of oxygenation.