A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome

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, randomized, double-blind, placebo-controlled clinical study. SETTING: Thirty-one hospitals in six European countries. PATIENTS: One hundred two patients with ARDS. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h. 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.     

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.     

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.     

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     

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.     

Stability of the arterial/alveolar oxygen partial pressure ratio. Effects of low ventilation/perfusion regions.

The alveolar-arterial oxygen partial pressure difference (AaDO2) and the arterial/alveolar oxygen partial pressure ratio (a/APO2) were compared for stability when inspired oxygen concentration (FIO2) changed. The analysis was based on a three-compartment lung model and experimental results in 10 patients with respiratory failure receiving assisted ventilation. It was found that a/APO2 was more stable than AaDO2 and more useful for: (1) comparing gas exchange in patients receiving different levels of FIO2, (2) following gas exchange in the same patient as FIO2 is changed, and (3) estimating the PaO2 expected at a given level of FIO2 if blood gas data are available at another level. However, areas with low ventilation/perfusion (V/Q) ratios may cause sudden changes in a/PO2 at certain critical values of PAO2. Most stable is a/APO2 and, therefore, most useful at FIO2 levels greater than 0.3, and PaO2 levels less than 100 torr.     

Time required for partial pressure of arterial oxygen equilibration during mechanical ventilation after a step change in fractional inspired oxygen concentration

OBJECTIVE: To determine the time required for the partial pressure of arterial oxygen (PaO2) to reach equilibrium after a 0.20 increment or decrement in fractional inspired oxygen concentration (FIO2) during mechanical ventilation. SETTING: A multi-disciplinary ICU in a university hospital. PATIENTS AND METHODS: Twenty-five adult, non-COPD patients with stable blood gas values (PaO2/FIO2 > or = 180 on the day of the study) on pressure-controlled ventilation (PCV). Following a baseline PaO2 (PaO2b) measurement at FIO2 = 0.35, the FIO2 was increased to 0.55 for 30 min and then decreased to 0.35 without any other change in ventilatory parameters. Sequential blood gas measurements were performed at 3, 5, 7, 9, 11, 15, 20, 25 and 30 min in both periods. The PaO2 values measured at the 30th min after a step change in FIO2 (FIO2 = 0.55, PaO2[55] and FIO2 = 0.35, PaO2[35]) were accepted as representative of the equilibrium values for PaO2. Each patient's rise and fall in PaO2 over time, PaO2(t), were fitted to the following respective exponential equations: PaO2b + (PaO2[55]-PaO2b)(1-e-kt) and PaO2[55] + (PaO2[35]-PaO2[55])(e-kt) where "t" refers to time, PaO2[55] and PaO2[35] are the final PaO2 values obtained at a new FIO2 of 0.55 and 0.35, after a 0.20 increment and decrement in FIO2, respectively. Time constant "k" was determined by a non-linear fitting curve and 90% oxygenation times were defined as the time required to reach 90% of the final equilibrated PaO2 calculated by using the non-linear fitting curves. RESULTS: Time constant values for the rise and fall periods were 1.01 +/- 0.71 min-1, 0.69 +/- 0.42 min-1, respectively, and 90% oxygenation times for rises and falls in PaO2 periods were 4.2 +/- 4.1 min-1 and 5.5 +/- 4.8 min-1, respectively. There was no significant difference between the rise and fall periods for the two parameters (p > 0.05). CONCLUSION: We conclude that in stable patients ventilated with PCV, after a step change in FIO2 of 0.20, 5-10 min will be adequate for obtaining a blood gas sample to measure a PaO2 that will be representative of the equilibrium PaO2 value.     

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.     

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.     

The impact of endotracheal suctioning on gas exchange and hemodynamics during lung-protective ventilation in acute respiratory distress syndrome

OBJECTIVE: To evaluate the respiratory and hemodynamic effects of open suctioning (OS) versus closed suctioning (CS) during pressure-control (PC) and volume-control (VC) ventilation, using a lung-protective ventilation strategy in an animal model of acute respiratory distress syndrome (ARDS). SETTING: Animal laboratory in a university hospital. DESIGN: Randomized cross-over evaluation. ANIMALS: Eight female Dorset sheep. INTERVENTIONS: Lung lavage was used to simulate ARDS. We applied VC and PC mechanical ventilation with a tidal volume of 6 mL/kg and positive end-expiratory pressure (PEEP), adjusted based on a table of PEEP versus fraction of inspired oxygen (FIO2). Suctioning was performed for 10 s with a suction pressure of -100 mm Hg, during both OS and CS. OS and CS were randomly performed with each animal. Hemodynamics and arterial blood gases were recorded before, during, and after endotracheal suctioning. RESULTS: The PaO2/FIO2 ratios before suctioning were similar in all groups, as were the PEEP and FIO2. PaO2/FIO2 was lower after OS than after CS/VC or CS/PC. There was no post-suctioning difference in oxygenation between CS/VC and CS/PC. PaCO2 recorded 10 min after suctioning was greater than the presuctioning value, in all groups. Intrapulmonary shunt fraction increased between baseline and 10 min post-suctioning with OS and CS/VC, but did not significantly increase with CS/PC. There were no significant changes in hemodynamics pre-suctioning versus post-suctioning with OS, CS/VC, or CS/PC. CONCLUSION: PaO2/FIO2) was better maintained during CS with both VC and PC modes during lung-protective ventilation for ARDS, as compared with OS, and shunt fraction post-suctioning changed least with PC.     

Adapting prognostic respiratory variables of ARDS in children to small-scale community needs

PURPOSE: The clinical literature on the incidence and subsequent mortality of adult respiratory distress syndrome (ARDS) has come primarily from the experiences of large tertiary referral centers, particularly in Western Europe and North America. Consequently, very little has been published on the incidence, management, and outcome of ARDS in smaller community-based intensive care units. We aimed to delineate early clinical respiratory predictors of death in children with ARDS on the modest scale of a community hospital. MATERIALS AND METHODS: A retrospective chart review of children with ARDS needing conventional mechanical ventilation admitted to our pediatric intensive care unit from 1984 to 1997. The diagnosis of ARDS was based on acute onset of diffuse, bilateral pulmonary infiltrates of noncardiac origin and severe hypoxemia defined by partial pressure of oxygen <200 mm Hg during positive end-expiratory pressure (PEEP) of 6 cm H2O or greater for a minimum of 24 hours. Demographic, clinical, and physiological data including PaO2/ FIO2, A-aDo2, and ventilation index were retrieved. RESULTS: Fifty-six children with ARDS aged 8 +/- 5.5 years (range, 50 days to 21 years) were identified. The mortality rate was 50%. Early predictors of death included the peak inspiratory pressure (PIP), ventilation index, and PEEP on the third day after diagnosis: Nonsurvivors had significantly higher PIP (35.3 +/- 10.5 cm H2O vs 44.4 +/- 10.7 cm H2O, P < .001), PEEP (8 +/- 2.8 cm H2O vs 10.7.0 +/- 3.5 cm H2O, P < .01), and ventilation index (49.14 +/- 20.4 mm Hg x cm H2O/minute vs 61.6 +/- 51.1 mm Hg cm H2O/minute) than survivors. In contrast, PAO2/FIO2 and A-a DO2 were capable of predicting outcome by day 5 and thereafter. CONCLUSIONS: A small-scale mortality outcome for ARDS is comparable to large tertiary referral institutions. The PIP, PEEP, and ventilation index are valuable for predicting outcome in ARDS by the third day of conventional therapy. The development of a local risk profile may assist in decision-making of early application of supportive therapies in this population.     

Acute respiratory distress syndrome in children with malignancy--can we predict outcome?

PURPOSE: The purpose of this study was to delineate early respiratory predictors of mortality in children with hemato-oncology malignancy who developed acute respiratory distress syndrome (ARDS). Materials and Methods: We conducted a retrospective chart review of children with malignant and ARDS who needed mechanical ventilation and were admitted to a pediatric intensive care unit from January 1987 to January 1997. RESULTS: Seventeen children with ARDS and malignancy aged 10.5 +/- 5.1 years were identified. Six of the 17 children (35.3%) survived. Sepsis syndrome was present in 70.6% of all the children. Peak inspiratory pressure, positive end-expiratory pressure (PEEP), and ventilation index values could distinguish outcome by day 3. A significant relationship between respiratory data and outcome related to efficiency of oxygenation, as determined by PaO(2)/FIO(2) and P(A-a)O(2), was present from day 8 after onset of mechanical ventilation. CONCLUSIONS: Peak inspiratory pressure, PEEP, and ventilation index values could distinguish survivors from nonsurvivors by day 3. This may assist in early application of supportive nonconventional therapies in children with malignancy 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.     

Treatment with N-acetylcysteine during acute respiratory distress syndrome: A randomized, double-blind, placebo-controlled clinical study

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 ≤ 200 mm Hg), we tested the hypothesis that treatment with intravenous NAC may be beneficial.

Respiratory dysfunction was graded daily according to the need for mechanical ventilation and Fio₂ and to the evolution of the lung injury score (LIS) and the Pao₂/Fi0₂ ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course.

NAC and placebo groups (22 and 20 patients, respectively) were comparable for demographic characteristics, ARDS categories, severity of illness (simplified acute physiology score [SAPS II]) LIS and Pao₂/Fio₂ ratio. Mortality rate was 32% for the NAC and 25% for the placebo group (difference not significant). At admission (day 1), 91% of patients in the NAC and 95% in the placebo group required ventilatory support; at days 2, 3, 5, and 7 after admission, the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1. Moreover, there were no differences between the two groups at the same observation days. In both groups, the Fio₂ was significantly lower and the Pao₂/Fio₂ ratio was significantly higher than the initial values during the evolution (Fio₂ at day 3, P < .01 for NAC and P < .05 for placebo; Pao₂/Fio₂ at day 3: P < .01 for NAC and P < .02 for placebo), but this improvement was similar for both groups and, moreover, the between-group comparison was never significantly different at the various collection days. The LIS decreased significantly in NAC group between days 1 and 3 (2.23 ± 0.62 v 1.76 ± 0.17; P < .05), whereas no changes were observed in the placebo group; at day 5, there was a significant difference between the two groups (1.53 ± 0.21 for the NAC v 2.15 ± 0.19 for the placebo group; P < .05). In the prevalent sepsis category (10 patients in the NAC and 9 in the placebo group), the mortality rate, the need of ventilatory support, the intensive care unit stay, and the Pao₂/Fio₂ evolution did not differ significantly in both subgroups.

In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases, intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support oxygenation nor reduced the need for ventilatory support.     

First do no harm: surrogate endpoints and the lesson of β-agonists in acute lung injury

EXPANDED ABSTRACT: CITATION: Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, Moss M, Schoenfeld D, Steingrub J, Thompson BT: Randomized, placebo-controlled clinical trial of an aerosolized β-agonist for treatment of acute lung injury. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Am J Respir Crit Care Med 2011, 184:561-568. BACKGROUND: β2-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies of acute lung injury (ALI). METHODS: Objective: To determine whether an aerosolized β2-agonist would improve clinical outcomes in patients with ALI.Design: Multi-center, phase III randomized, placebo-controlled clinical trial.Setting: 33 hospitals participating National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.Subjects: Patients who were intubated and receiving mechanical ventilation, had bilateral infiltrates consistent with edema on frontal chest radiograph, had a ratio of PaO2 to FIO2 (fraction of inspired oxygen) of 300 or less, and not had clinical evidence of left atrial hypertension. A maximum enrolment of 1,000 patients was planned.Intervention: Patients were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days.Outcomes: The primary outcome variable was ventilator-free days (VFD). Secondary outcome measures included mortality before hospital discharge on day 60 and day 90, the number of intensive care unit (ICU)-free days and the number of organ failure-free days. RESULTS: There were 282 patients enrolled before the trial was stopped for futility after the second interim analysis. The VFDs difference with albuterol treatment was unfavourable by -2.2 days, well past the futility boundary of -0.4 VFDs. VFDs were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 days, respectively; 95% confidence interval for the difference, -4.7 to 0.3 days; P = 0.087). Rates of death before hospital discharge and the number of organ failure-free days were also not significantly different between the two groups. The number of ICU-free days was lower in the albuterol group in comparison with the placebo group (means of 13.5 and 16.2 days respectively; 95% confidence intervals for the mean difference, -4.9 to -0.4 days; P = 0.023). Overall, heart rates were significantly higher in the albuterol group by approximately 5 beats/minute in the first 2 days after randomization (P < 0.05), but rates of new onset atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. CONCLUSIONS: These results suggest that aerosolized albuterol does not improve clinical outcomes in ALI patients. Routine use of β2 agonist therapy in mechanically ventilated ALI patients cannot be recommended.     

The development of ventilator-associated pneumonia does not change aspects of mechanical ventilation

OBJECTIVE: To evaluate whether the development of ventilator-associated pneumonia (VAP) is associated with changes in ventilation parameters. DESIGN: Matched case-control study. SETTING: Mixed intensive care unit of a university hospital. PATIENTS: From a large database we selected 33 patients with VAP, diagnosed with quantitative cultures of bronchoscopically obtained specimens. In addition, 33 other mechanically ventilated patients who did not develop VAP were selected (controls). Patients with VAP and controls were matched on seven variables representing severity of illness: duration of ventilation until matching, diagnosis on admission, renal function, liver function, preceding infection, preceding surgery and immunosuppressive therapy. Each patient with VAP was matched to a single control. Variables regarding type and mode of ventilation and interpretation of chest radiographs were not included in the matching procedure. MEASUREMENTS AND RESULTS: Characteristics of mechanical ventilation (mode of ventilation, tidal volume, expired minute ventilation, peak airway pressures, mean airway pressures, level of positive end-expiratory pressure, arterial oxygen tension(PaO2)/fractional inspired oxygen (FIO2) ratio), were compared on the day of diagnosis of VAP (or matching for controls) and 2 and 4 days before. Although there was a significant difference in PaO2/FIO2 ratios between cases and controls on the day of diagnosis of VAP, the change in PaO2/FIO2 ratios during the days of study were not statistically different between patients developing VAP and controls. No significant differences were found for any of the other variables of ventilation at any of the three time points studied, nor were there significant differences in changes of these parameters within individual patients. CONCLUSIONS: Characteristics and parameters of mechanical ventilation are not influenced by the development of VAP. It is, therefore, unlikely that these variables are useful in the diagnostic work-up of VAP.     

High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation

OBJECTIVES: To evaluate the results of treatment of severe acute respiratory distress syndrome (ARDS) with extracorporeal membrane oxygenation (ECMO), minimal sedation, and pressure supported ventilation. DESIGN AND SETTING: Observational study in a tertiary referral center, Intensive Care Unit, Astrid Lindgren Children's Hospital at Karolinska Hospital, Stockholm, Sweden. SUBJECTS AND METHODS: Seventeen adult patients with ARDS were treated with venovenous or venoarterial ECMO after failure of conventional therapy. The Murray score of pulmonary injury averaged 3.5 (3.0-4.0) and the mean PaO2/FIO2 ratio was 46 (31-65). A standard ECMO circuit with nonheparinized surfaces was used. The patients were minimally sedated and received pressure-supported ventilation. High inspiratory pressures were avoided and arterial saturation as low as 70% was accepted on venovenous bypass. RESULTS: In one patient a stable bypass could not be established. Among the remaining 16 patients 13 survived (total survival rate 76%) after 3-52 days (mean 15) on bypass. Major surgical procedures were performed in several patients. The cause of death in the three nonsurvivors was intracranial complications leading to total cerebral infarction. CONCLUSION: A high survival rate can be obtained in adult patients with severe ARDS using ECMO and pressure-supported ventilation with minimal sedation. Surgical complications are amenable to surgical treatment during ECMO. Bleeding problems can generally be controlled but require immediate and aggressive approach. It is difficult or impossible to decide when a lung disease is irreversible, and prolonged ECMO treatment may be successful even in the absence of any detectable lung function.     

Prospective evaluation of combined high-frequency ventilation in post-traumatic patients with adult respiratory distress syndrome refractory to optimized conventional ventilatory management

This study explores the value of combined high-frequency ventilation (CHFV) in a prospective clinical trial of 35 patients suffering from severe post-traumatic and/or septic adult respiratory distress syndrome (ARDS) who were refractory to conventional controlled mechanical ventilatory (CMV) support. The severity of ARDS was quantified by lung mechanics and gas exchange variables and the patients were classified on clinical grounds as well as on the basis of their respiratory index/pulmonary shunt relationship [RI/(Qsp/Qt)]. During the same time period as the CHFV study, data from these patients were compared to those from 88 ARDS patients who had quantitatively similar degrees of respiratory insufficiency, but who were treated only with controlled mechanical ventilation (CMV). The use of CHFV in the 35 CMV refractory patients resulted in an increase in expired tidal volume (VTE) by reducing the CMV inspired tidal volume (VTI) while increasing the volume component derived from high-frequency ventilation (HFV). This procedure appeared to reveal potentially salvageable ARDS patients who were refractory to CMV. In these patients, CHFV significantly reduced pulmonary mean airway pressure (Paw). The RI also decreased significantly and it was possible to reduce significantly the FIO2. In surviving ARDS patients treated with CHFV, an improvement in blood gases at reduced FIO2, without decreased cardiac output, was produced. The CHFV technique was used for less than or equal to 25 days and resulted in 23% survival of patients who were clinically and physiologically indistinguishable from the patients in the ARDS nonsurvivor group who were treated by CMV only. In surviving CHFV patients the decrease in Paw permitted a sustained, or increased, cardiac output with a rise in the oxygen delivery/oxygen consumption ratio, thus allowing for a higher PaO2 for any given level of pulmonary shunt.     

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.     

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.