Difference In Ventilator-free Days Research Articles

Effect of a Lower vs Higher Positive End-Expiratory Pressure Strategy on Ventilator-Free Days in ICU Patients Without ARDS

It is uncertain whether invasive ventilation can use lower positive end-expiratory pressure (PEEP) in critically ill patients without acute respiratory distress syndrome (ARDS). To determine whether a lower PEEP strategy is noninferior to a higher PEEP strategy regarding duration of mechanical ventilation at 28 days. Noninferiority randomized clinical trial conducted from October 26, 2017, through December 17, 2019, in 8 intensive care units (ICUs) in the Netherlands among 980 patients without ARDS expected not to be extubated within 24 hours after start of ventilation. Final follow-up was conducted in March 2020. Participants were randomized to receive invasive ventilation using either lower PEEP, consisting of the lowest PEEP level between 0 and 5 cm H2O (n = 476), or higher PEEP, consisting of a PEEP level of 8 cm H2O (n = 493). The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for the difference in ventilator-free days at day 28 of -10%. Secondary outcomes included ICU and hospital lengths of stay; ICU, hospital, and 28- and 90-day mortality; development of ARDS, pneumonia, pneumothorax, severe atelectasis, severe hypoxemia, or need for rescue therapies for hypoxemia; and days with use of vasopressors or sedation. Among 980 patients who were randomized, 969 (99%) completed the trial (median age, 66 [interquartile range {IQR}, 56-74] years; 246 [36%] women). At day 28, 476 patients in the lower PEEP group had a median of 18 ventilator-free days (IQR, 0-27 days) and 493 patients in the higher PEEP group had a median of 17 ventilator-free days (IQR, 0-27 days) (mean ratio, 1.04; 95% CI, 0.95-∞; P = .007 for noninferiority), and the lower boundary of the 95% CI was within the noninferiority margin. Occurrence of severe hypoxemia was 20.6% vs 17.6% (risk ratio, 1.17; 95% CI, 0.90-1.51; P = .99) and need for rescue strategy was 19.7% vs 14.6% (risk ratio, 1.35; 95% CI, 1.02-1.79; adjusted P = .54) in patients in the lower and higher PEEP groups, respectively. Mortality at 28 days was 38.4% vs 42.0% (hazard ratio, 0.89; 95% CI, 0.73-1.09; P = .99) in patients in the lower and higher PEEP groups, respectively. There were no statistically significant differences in other secondary outcomes. Among patients in the ICU without ARDS who were expected not to be extubated within 24 hours, a lower PEEP strategy was noninferior to a higher PEEP strategy with regard to the number of ventilator-free days at day 28. These findings support the use of lower PEEP in patients without ARDS. ClinicalTrials.gov Identifier: NCT03167580.

EFFECT OF COMBINATION TREATMENT APPROACH WITH EARLY INFUSION OF PARALYTICS, PRONING, AND LUNG PROTECTIVE VENTILATION ON MORTALITY IN PATIENTS WITH SEVERE ARDS: A SYSTEMIC REVIEW AND META-ANALYSIS

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Prone positioning with lung-protective ventilation (LPV) has been shown to confer a mortality benefit in severe acute respiratory distress syndrome (ARDS) (1). A recently published randomized controlled trial (RCT) failed to show a survival benefit with the use of paralytics (2). However, this study utilized far less prone positioning, and excluded patients who had prior administration of paralytics (2). The reviewers of this metanalysis raised the hypothesis that a combination of proning; paralytics; and LPV, improved mortality in patients with severe ARDS. The analysis was conducted to evaluate the effect of early combination treatment with: proning; infusion of paralytics and LPV versus individual modalities on 28-day mortality. METHODS: We conducted a literature search using PUBMED, MEDLINE, and EMBASE for studies published until August 2019. Our inclusion criteria were as follows; severe ARDS, defined as PaO2/FiO2 <150 with positive end expiratory pressure > 5, used LPV, continuous paralytics for at least 48 hours, and early proning (initiated within 12 hours) for at least 16 hours daily. The primary outcome of the study was 28-day mortality. Secondary outcomes included ventilator free days, intensive care unit (ICU) length of stay (LOS) and pneumothorax. A random effects model was used for analyzing pooled data. Methodologic qualities of the RCTs and overall body of evidence were evaluated using the ‘Effective Public Health Practice Project’ (EPHPP) quality assessment tool and meta-XL, respectively. RESULTS: Thirteen RCTs met the inclusion criteria. The risk of bias was low across all trials. Statistical analysis for 28-day mortality included 3,650 patients (1,844, 50.4%) in intervention group and (1,806, 49.6%) in the control group.The pooled effect size for 28-day mortality was 0.27 {95% confidence interval [CI], 0.19-0.34} in the intervention group compared to 0.34 {95% CI, 0.29-0.38} in the control group.There was significant heterogeneity with I2 of 93% vs 77% in both groups. Ventilator free days at 28-days were 11.67 {95% CI; 8.81-14.48} vs 7.8 {95% CI; 5.7-9.96}, and ICU LOS was 15.86 {95% CI; 10.92-20.79} vs 16.86 {95% CI; 8.08-25.63}. Pneumothorax incidence rates were 0.03 {95 % CI; 0.01-0.04} vs 0.029 {95% CI; 0.02-0.03} in the intervention and control group, respectively. Pooled performance estimates of mortality with subgroups could not be performed due to data limitations. CONCLUSIONS: Our metanalysis revealed a significant 28-day mortality difference between combination treatment versus LPV alone. There were also notable differences in ventilator free days and ICU LOS between study groups without increase in pneumothorax incidence. However, the heterogeneity between the included studies limits interpretation of these results. CLINICAL IMPLICATIONS: Future randomized controlled trials combining modalities will be useful to further evaluate potential mortality improvement in severe ARDS. DISCLOSURES: No relevant relationships by Noah Cook, source=Web Response No relevant relationships by Rajany Dy, source=Web Response No relevant relationships by Hafiz Mahboob, source=Web Response

Effect of Dexmedetomidine on duration of mechanical ventilation in septic patients: a systematic review and meta-analysis

BackgroundBecause of its analgesic and light sedative properties, the highly selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) has been suggested for the treatment of septic patients, but its effect on the duration of mechanical ventilation remains unclear. The present study was conducted to review the extant literature in DEX and determine its influence on ventilation time in adult septic patients.MethodsDatabases of PubMed, Cochrane, and EMBASE were applied till 20th January 2019 without language restriction. The searching strategy as following: sepsis OR septic AND mechanical ventilation AND dexmedetomidine. Two authors screened titles, abstracts, and even articles to meet the including criterion independently. In addition, references of related articles or reviews were also referred. Data was recorded in a table and analyzed using the software of Review Manager 5.0.ResultsFour studies with a total of 349 patients were included. Three trials with 267 patients revealed the effect of DEX on duration of mechanical ventilation, two trials with 264 patients on ventilator-free days and four trials with 334 patients on 28-day mortality. The analyzed results indicated that DEX was not associated with significantly different durations of mechanical ventilation (MD 0.65, 95% CI, − 0.13 to 1.42, P = 0.10). However, there were significant differences in ventilator-free days (MD 3.57, 95% CI, 0.26 to 6.89, P = 0.03) and 28-day mortality (RR 0.61, 95% CI, 0.49 to 0.94, P = 0.02) in the septic patients.ConclusionAdministration of DEX for sedation in septic patients was not associated with the duration of mechanical ventilation, but it increased the ventilator-free days and reduced 28-day mortality.

Validating plasminogen activator inhibitor-1 as a poor prognostic factor in sepsis.

Our previous report indicated that plasminogen activator inhibitor-1 (PAI-1) levels of ≥83ng/mL in patients with sepsis tended to be associated with disseminated intravascular coagulation (DIC), suppressed fibrinolysis, multiple organ dysfunction, and mortality. Therefore, the present study aimed to validate whether 83ng/mL was a useful cut-off value for using PAI-1 levels to predict a poor prognosis in sepsis. Patients with sepsis were included in this single-center retrospective study. The patients were classified as having high or low PAI-1 values (<83ng/mL versus ≥83ng/mL), and were compared in terms of their pre-DIC state, intensive care unit-free days, continuous renal replacement therapy-free days, ventilator-free days, catecholamine-free days, and 28-day survival rate. The high PAI-1 group included 61 patients (54%) and the low PAI-1 group included 52 patients (46%). The high PAI-1 group had significantly higher frequencies of a pre-DIC state within 1week (P=0.009). There was no significant difference in ventilator-free days. However, the high PAI-1 group had significantly lower values for intensive care unit-free days (P=0.01), continuous renal replacement therapy-free days (P=0.02), and catecholamine-free days (P=0.02). The high PAI-1 group also had a significantly lower 28-day survival rate based on the Kaplan-Meier analysis (log-rank, P=0.03). Patients with sepsis and PAI-1 levels of ≥83ng/mL had elevated risks of coagulopathy, organ failure, and mortality. Thus, these results suggest that 83ng/mL could be a useful cut-off value for prognostication based on PAI-1 levels in this setting.

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

PurposeThe CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).MethodsIn this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L).ResultsOverall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline.ConclusionsNo significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation.Trial registration: NCT01420744.

An Open Lung Strategy in the Management of Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

An open lung strategy (OLS) that includes positive end expiratory pressure and recruitment maneuvers during mechanical ventilation is probably an important treatment method in patients with acute respiratory distress syndrome (ARDS). However, the effect of OLS is unknown. We therefore hypothesized that patients with ARDS may benefit from OLS treatment. We identified relevant randomized controlled trials by searching through PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials updated to May 22, 2016. We performed a systematic review and meta-analysis to evaluate the effect of OLS in patients with ARDS. The primary outcome was mortality. A total of 15 randomized controlled trials involving 1,563 patients in OLS group and 1,571 patients in control group were included. Pooled analysis showed that there was significant difference in hospital mortality (relative risk [RR], 0.88; 95% CI, 0.80-0.97; P = 0.009), 28-day mortality (RR, 0.83; 95% CI, 0.71-0.96; P = 0.010), and intensive care unit (ICU) mortality (RR, 0.77; 95% CI, 0.65-0.92; P = 0.003) between the OLS group and control group, with no substantial heterogeneity. There was no significant difference in ventilator-free days at 28-day (mean difference [MD]; 3.32 d; 95% CI, -0.49 to 7.12; P = 0.09) and ICU length of stay (MD; 1.60 d; 95% CI, -2.99 to 6.20; P = 0.49) between OLS group and control group. Results from this systematic review and meta-analysis suggest that OLS during mechanical ventilation significantly reduces mortality among patients with ARDS.

Statin in the treatment of ALI/ARDS: a systematic review and Meta-analysis based on international databases

To confirm the effects of statin therapy on mortality of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). PubMed/Medline, Embase, Web of Science and Cochrane Central Register of Controlled Trials were searched for articles using the terms "acute lung injury", "ALI", "acute respiratory distress syndrome", "ARDS", "statin", "simvastatin" and "rosuvastatin" updated to November 17, 2015. Randomized controlled trial (RCT) or observational cohort studies investigating the effects of statin therapy on mortality in patients with ALI or ARDS were all identified, without date or language restriction. The control group was given conventional treatment, while the experimental group was treated with statins additionally. The primary outcome was in-hospital mortality. Meanwhile, ventilator-free day, intensive care unit (ICU)-free day, ICU length of stay (LOS) and ICU mortality were also analyzed. RevMan 5.2 and STATA 13 software were used for systematic review and Meta analysis, and funnel plot was used to analyze the publication bias. A total of five trials including three randomized controlled trials and two observational studies were included. Among 1 636 patients enrolled in the study, there were 739 patients in experimental group, and 897 in control group. It was shown by Meta analysis that there was no significant difference in in-hospital mortality between experimental group and control group [relative risk (RR) = 0.96, 95% confidence interval (95%CI) = 0.79-1.15, P = 0.63]. The subgroup analysis based on RCT and cohort study, or the subgroup analysis of different statins showed that there was no significant difference in in-hospital mortality between the experimental group and the control group (both P > 0.05). There were no significant differences in ventilator-free days [mean difference (MD) = 1.41, 95%CI = -0.32-3.13, P = 0.11], ICU-free days (MD = -0.23, 95%CI = -1.61-1.15, P = 0.75), ICU length of stay (MD = -1.03, 95%CI = -6.55-4.50, P = 0.72), or ICU mortality (RR = 0.88, 95%CI = 0.68-1.14, P = 0.33) between the experimental group and the control group. It was shown by funnel plot that there was no publication bias in in-hospital mortality. The systematic review and meta-analysis suggests that statin may not be associated with a significant reduction in mortality, ventilator-free day, ICU-free day and ICU length of stay in patients with ALI/ARDS.

The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis

Acute respiratory distress syndrome is associated with high mortality and morbidity. Inhaled nitric oxide has been used to improve oxygenation but its role remains controversial. Our primary objective in this systematic review was to examine the effects of inhaled nitric oxide administration on mortality in adults and children with acute respiratory distress syndrome. We included all randomised, controlled trials, irrespective of date of publication, blinding status, outcomes reported or language. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effect of inhaled nitric oxide. There was no statistically significant effect of inhaled nitric oxide on longest follow-up mortality (inhaled nitric oxide group 250/654 deaths (38.2%) vs. control group 221/589 deaths (37.5%; relative risk (95% CI) 1.04 (0.9-1.19)). We found a significant improvement in PaO2 /FI O2 ratio at 24 h (mean difference (95% CI) 15.91 (8.25-23.56)), but not at 48 h or 72 h, while four trials indicated improved oxygenation in the inhaled nitric oxide group at 96 h (mean difference (95% CI) 14.51 (3.64-25.38)). There were no statistically significant differences in ventilator-free days, duration of mechanical ventilation, resolution of multi-organ failure, quality of life, length of stay in intensive care unit or hospital, cost-benefit analysis and methaemoglobin and nitrogen dioxide levels. There was an increased risk of renal impairment (risk ratio (95% CI) 1.59 (1.17-2.16)) with inhaled nitric oxide. In conclusion, there is insufficient evidence to support inhaled nitric oxide in any category of critically ill patients with acute respiratory distress syndrome despite a transient improvement in oxygenation, since mortality is not reduced and it may induce renal impairment.

Improving Neurosurgical Outcomes in the Intensive Care Unit: Could Dexmedetomidine Make a Difference in Ventilator Free Days, Neurological Monitoring, and Outcomes?

Improving Neurosurgical Outcomes in the Intensive Care Unit: Could Dexmedetomidine Make a Difference in Ventilator Free Days, Neurological Monitoring, and Outcomes?

Clinical outcomes associated with high, intermediate, and low rates of failed extubation in an intensive care unit

PurposeExtubation failure is associated with adverse outcomes in mechanically ventilated patients, and it is believed that high rates of failed planned extubation (FPE) should be avoided. However, many believe that very low rates may also correlate with adverse outcomes if resulting from overly conservative weaning practices. We examined the relationship between the percentage of FPE (%FPE) and associated outcomes, with the aim of elucidating a favorable middle range. MethodsA total of 1395 extubations were analyzed in mechanically ventilated subjects. Monthly %FPE values were separated into tertiles. Ventilator-free days (VFDs), intensive care unit–free days (IFDs), and mortality were compared among tertiles. ResultsMonthly %FPE tertiles were as follows: low, less than 7%; intermediate, 7% to 15%; and high, greater than 15%. There were significant differences in VFDs and IFDs by tertile from low to high (VFDs: low, 11.8; intermediate, 12.1; high, 9.9 [P = .003]; IFDs: low, 10.5; intermediate, 10.7; high, 9.0 [P = .033]). Post hoc comparisons demonstrated significant differences between the middle and high tertiles for both VFDs and IFDs. ConclusionsAlthough exact rates may vary depending on setting, this suggests that a high %FPE (>15) should be avoided in the intensive care unit and that there may be an intermediate range where ventilator outcomes are optimized.

Enteral omega-3 fatty acid supplementation in adult patients with acute respiratory distress syndrome: a systematic review of randomized controlled trials with meta-analysis and trial sequential analysis

Controversy remains as to whether enteral supplementation of ω-3 fatty acids (FA) could improve outcomes in patients with acute respiratory distress syndrome (ARDS). Thus, we did a meta-analysis and aimed to investigate the benefit and harm of enteral ω-3 FA supplementation in adult patients with ARDS. Databases including PubMed, Embase, the Cochrane Register of Controlled Trials, and Google Scholar were searched to find relevant articles. Randomized controlled trials (RCTs) comparing enteral ω-3 FA supplementation with a control or placebo intervention in adult patients with ARDS were included. The primary outcome was all-cause 28-day mortality. We used the Cochrane Collaboration methodology. Seven RCTs with 955 adult patients qualified for inclusion, and all the selected trials were considered as at high risk of bias. The use of enteral ω-3 FA did not significantly reduce all-cause 28-day mortality [relative risk (RR), 0.90; 95 % confidence intervals (CI), 0.68-1.18; p = 0.44; I (2) = 31 %; random effects]. Trial sequential analysis indicated lack of firm evidence for a 20 % RR reduction in all-cause 28-day mortality. PaO2/FiO2 ratio was significantly increased in the ω-3 FA group on day 4 [weighted mean difference (WMD), 45.14; 95 % CI, 16.77-73.51; p = 0.002; I (2) = 86 %; random effects] and day 7 (WMD, 33.10; 95 % CI, 1.67-64.52; p = 0.04; I (2) = 88 %; random effects). Meta-analysis using a random effects model showed no significant differences in ventilator-free days (VFD) (WMD, 2.47 days; 95 % CI, -2.85 to 7.79; p = 0.36; I (2) = 91 %) or intensive care unit-free days (ICU) (WMD, 2.31 days; 95 % CI, -2.34 to 6.97; p = 0.33; I (2) = 89 %) between the two groups. Among patients with ARDS, enteral supplementation of ω-3 FA seemed ineffective regarding all-cause 28-day mortality, VFD, and ICU-free days. Routine use of enteral ω-3 FA cannot be recommended based on the available evidence.

Effect of type II diabetes mellitus on outcomes in patients with acute respiratory distress syndrome

PurposeThe acute respiratory distress syndrome (ARDS) is a life-threatening condition, whereas the presence of diabetes has been shown to be protective in its development. We undertook this study to assess the association of type II diabetes mellitus with clinical outcomes in patients with ARDS. Materials and MethodsWe retrospectively examined the medical records of consecutive series of patients with ARDS requiring mechanical ventilation from January 2008 to March 2011. Patients with type I diabetes were excluded from the study. Clinical outcomes such as ventilator-free days, mortality, length of stay in the hospital and intensive care unit (ICU), and reintubations were compared based on the presence of diabetes. Multivariate regression model was used to find if the presence of type II diabetes mellitus predicts ventilator-free days at day 28. ResultsTwo hundred forty-nine patients with ARDS were admitted to the ICU during the study period. Fifty (20%) subjects had type II diabetes mellitus. Differences in ventilator-free days, in-hospital mortality, reintubation rate, and length of stay in the hospital or ICU were not statistically significant between diabetic and nondiabetic patients with ARDS. Acute Physiologic and Chronic Health Evaluation II, ICU specialty, use of vasopressors, and the need for reintubation were predictors of ventilator-free days at day 28. The presence of type II diabetes mellitus and its adjustment by body mass index did not show association with ventilator-free days at day 28. ConclusionsThe presence of type II diabetes mellitus is not associated with clinical outcomes in ARDS, even when its presence is adjusted by body mass index.

The Effect of a Mechanical Ventilation Discontinuation Protocol in Patients with Simple and Difficult Weaning: Impact on Clinical Outcomes

We sought to determine whether the utilization of a respiratory therapist (RT) driven mechanical ventilation weaning protocol is associated with improvement in clinical outcomes in subjects with simple versus difficult weaning. This was a retrospective analysis of prospectively collected data obtained during a quality improvement project. We collected data on 803 consecutive mechanically ventilated patients admitted to the ICU of an academic tertiary care hospital. We compared an RT-driven weaning protocol to a physician-driven weaning strategy. Of the 803 patients, 651 with simple weaning and 131 with difficult weaning were included in the analysis. In the subjects with simple weaning, 514 (79%) were weaned with the RT-driven protocol. Among the difficult weaning subjects, 101(77.1%) were liberated with the RT-driven protocol. A multivariate analysis, which included Acute Physiology and Chronic Health Evaluation II, body mass index, and type of primary ICU team under which the subjects were admitted, revealed a significant difference in ventilator-free days at 28-days, which supports the RT-driven protocol over the physician-driven strategy. Specifically, the RT-driven protocol increased ventilator-free days by 20.92% and 68.2% among subjects with simple and difficult weaning, respectively. A multivariate analysis of ICU mortality and extubation failure found no significant difference between the RT-driven protocol and the physician-driven strategy. The RT-driven weaning protocol increased ventilator-free days among subjects with simple and difficult weaning, with no significant differences in ICU mortality or extubation failure.

A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury*

Despite recent advances in critical care and ventilator management, acute lung injury and acute respiratory distress syndrome continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor may be beneficial for patients with acute respiratory distress syndrome. To determine whether intravenous infusion of granulocyte-macrophage colony stimulating factor would improve clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome. A randomized, double-blind, placebo-controlled clinical trial of human recombinant granulocyte-macrophage colony stimulating factor vs. placebo. The primary outcome was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization. Secondary outcomes included mortality and organ failure-free days. Medical and surgical intensive care units at three academic medical centers. One hundred thirty individuals with acute lung injury of at least 3 days duration were enrolled, out of a planned cohort of 200 subjects. Patients were randomized to receive human recombinant granulocyte-macrophage colony stimulating factor (64 subjects, 250 μg/M) or placebo (66 subjects) by intravenous infusion daily for 14 days. Patients received mechanical ventilation using a lung-protective protocol. There was no difference in ventilator-free days between groups (10.7 ± 10.3 days placebo vs. 10.8 ± 10.5 days granulocyte-macrophage colony stimulating factor, p = .82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving granulocyte-macrophage colony stimulating factor (p = .31) and organ failure-free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days granulocyte-macrophage colony stimulating factor, p = .16) were not statistically significant. There were similar numbers of serious adverse events in each group. In a randomized phase II trial, granulocyte-macrophage colony stimulating factor treatment did not increase the number of ventilator-free days in patients with acute lung injury/acute respiratory distress syndrome. A larger trial would be required to determine whether treatment with granulocyte-macrophage colony stimulating factor might alter important clinical outcomes, such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov]).

APCAP - activated protein C in acute pancreatitis: a double-blind randomized human pilot trial

IntroductionPrevious human studies have shown low activity of protein C (APC) in severe acute pancreatitis (SAP). This, together with the findings in animal models, suggests that activated protein C (APC) may protect against pancreatic injury and ameliorate the disease. We, therefore, evaluated its effect on multiple organ dysfunction (MOD) measured by the SOFA (Sequential Organ Failure Assessment) and on organ-failure-free days, and the safety of APC in SAP.MethodsA prospective double blind randomized pilot study was use. The study occurred in one university hospital tertiary intensive care unit (ICU) with eight beds. The patients were chosen according to the following inclusion criteria: 1) Those admitted to the hospital < 96 h from the onset of pain, 2) Those who had a three-fold increase in serum amylase over normal upper range or/and in whom computed tomography (CT) verification of SAP was noted, 3) Those who had one or more organ dysfunction (OD), and 4) Those in whom less than 48 hours had passed since their first OD. Of a total of 215 adult patients with SAP screened between June 2003 and August 2007, 158 fulfilled the study inclusion criteria. After exclusions 32 patients were randomized to the study. The intervention consisted of APC (N = 16) administered intravenously for 96 hours with a dose of 24 μg/kg/hour or placebo (N = 16) with a similar infusion rate. The sample size for the study was calculated according to the primary end-point: the change in SOFA during study drug infusion (Days 0 and 5). Comparisons between the study groups were performed using patient-related changes and calculation of difference in means (DIM, 95% CIs) and regarding categorical variables with Fisher's exact test. For all comparisons P < 0.05 was considered significant.ResultsNo serious bleeding was detected clinically or by CT scans in either group. No significant difference in SOFA score change between the APC and placebo groups was found (difference in means (DIM) +2.3, 95% CI -0.7 to +5.3). Treatment with APC was associated with an increase in serum levels of both total and conjugated bilirubin. No differences in ventilator-free days, in renal replacement therapy-free days, in vasopressor-free days, or in days alive outside the hospital were detected.ConclusionsNo serious bleeding or differences in the evolution of MOD were detected between APC and the placebo. Instead we found an increase in serum bilirubin in the APC group compared to the placebo group in patients with SAP.Trial registrationClinicalTrials.gov NCT01017107.

Effects of Supervision by Attending Anesthesiologists on Complications of Emergency Tracheal Intubation

Emergent intubation is associated with a high complication rate. These intubations are often performed by resident physicians in teaching hospitals. The authors evaluated whether supervision by an anesthesia-trained intensivist decreases complications of emergent intubations. The authors performed a prospective cohort study in an Academic Tertiary Care Hospital. They enrolled 322 consecutive patients who required emergent intubation between November 1, 2006, and April 15, 2008. Emergency intubations are performed by anesthesia residents during their surgical intensive care unit rotation. An attending anesthesiologist was assigned to supervise these intubations at predetermined periods. A respiratory therapist assisted with airway management and ventilation. Information related to the intubation, detailing patient demographics, indication for intubation, attending anesthesiologist presence, medications used, and immediate complications, was recorded. Disposition and duration of mechanical ventilation were also recorded. There were no differences in demographics, clinical characteristics, or illness severity among patients intubated with and without attending supervision. Attending physician supervision was associated with a significant decrease in complications (6.1% vs. 21.7%; P = 0.0001). There was no difference in ventilator-free days or 30-day mortality. Supervision by an attending anesthesiologist was associated with a decreased incidence of complications during emergent intubations.

A critical appraisal of a randomized controlled trial: Willson et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury (JAMA 2005, 293: 470???476)

To evaluate the use of exogenous surfactant in pediatric acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in decreasing the duration of respiratory failure. A critical appraisal of a randomized controlled trial. This was a multiple-center, randomized, double-blinded, placebo-controlled trial evaluating the effect of calfactant via endotracheal tube in pediatric ALI/ARDS. The primary outcome was duration of respiratory failure measured by ventilator-free days at 28 days. Secondary outcomes included hospital course, adverse events, and failure of conventional mechanical ventilation (use of high-frequency oscillatory ventilation, inhaled nitric oxide, or extracorporeal membrane oxygenation). One hundred and fifty-two patients were enrolled and randomized with strict inclusion and exclusion criteria. Aside from the experimental interventions, the treatment and placebo groups were similar at baseline. Ventilator management guidelines were defined a priori. No significant difference in ventilator-free days was found, although the treatment group had a greater improvement in oxygenation. Mortality rate was significantly greater in the placebo group (relative risk, 1.9; 95% confidence interval, 1.1-3.2). However, when controlled for immunocompromised status, the statistical significance is lost. Subgroup analysis of infants showed a greater effect on mortality (relative risk, 3.3; 95% confidence interval, 1.1-10.5) and a significant difference in ventilator-free days (15.2 days vs. 7.0 days, p = .01) for the placebo group. No other differences in measured outcomes were seen. The treatment group had an increased rate of hypotension and transient hypoxia but not of airleaks or nosocomial pneumonias. This is a well-designed study with an appropriate intention-to-treat analysis, but it is underpowered, making it difficult to identify which patients with pediatric ALI/ARDS might benefit from calfactant. Given the uncertainty of the benefits, calfactant cannot be routinely recommended in pediatric ALI/ARDS.

Effect of Prone Positioning on Clinical Outcomes in Children With Acute Lung Injury

In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known. To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning. Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded. Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines. Ventilator-free days to day 28. The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, -0.2 days; 95% CI, -3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, -3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure-free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28. Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.

Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta-analysis.

We systematically reviewed randomized controlled trials examining inhaled nitric oxide (INO) for the treatment of acute respiratory distress syndrome or acute lung injury in children and adults. Qualitative assessments of identified trials were made, and metaanalyses were performed according to Cochrane methodology. Five randomized controlled trials (n = 535) met entry criteria. One study demonstrated significant improvement in oxygenation in the first 4 days of treatment, with no difference after this. There was no difference in ventilator-free days between treatment and placebo groups, and no specific dose of INO was more advantageous than any other. INO had no effect on mortality in trials without crossover of treatment failures to open-label INO (relative risk, 0.98; 95% confidence interval, 0.66-1.44). Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. Lack of data prevented assessment of all outcomes. If further trials assessing INO in acute respiratory distress syndrome or acute lung injury are to proceed, they should be stratified for primary etiology, incorporate other modalities that may affect outcome, and evaluate clinically relevant outcomes before any benefit of INO can be excluded.

Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults.

Acute hypoxemic respiratory failure affects all age groups and may result from a number of systemic diseases. It continues to be associated with high mortality and morbidity. Initial studies examining the effect of inhaled nitric oxide in respiratory failure demonstrated transient improvement in oxygenation but did not examine mortality or other significant morbidity outcomes. To systematically examine randomized controlled trials addressing the effect of inhaled nitric oxide, compared with placebo inhaled gas, on mortality and morbidity in patients with acute hypoxemic respiratory failure. Randomized controlled trials were identified from electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2002;MEDLINE (January 1966-August 2002); EMBASE (1980-March 2001); CINAHL (1982-July 2002), as well as from bibliographies of retrieved articles. Relevant journals and conference proceedings were hand searched and authors published in this field were contacted for knowledge of unpublished ongoing trials. Randomized controlled trials comparing inhaled nitric oxide with maximal conventional therapy and inhaled placebo, in either children or adults with acute hypoxemic respiratory failure. Qualitative assessment of each trial was made and analyses performed according to statistical methods in Review Manager MetaView 4.1. A sub-group analysis was performed to assess the impact of inhaled nitric oxide at varied doses. Five randomized controlled trials were evaluated, assessing 535 patients with acute hypoxemic respiratory failure (Age range not provided). Lack of data prevented assessment of all outcomes. There was no significant difference of nitric oxide on mortality in trials without cross-over (RR 0.98, 95%CI 0.66,1.44). Published evidence from one study demonstrated nitric oxide to transiently improve oxygenation in the first 72 hours of treatment. Limited data demonstrated no significant difference in ventilator-free days between treatment and placebo groups, and no specific dose of nitric oxide was significantly advantageous over another. Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. There were no significant complications directly attributable to this treatment. Nitric oxide did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation in patients with hypoxemic respiratory failure. Lack of data prevented assessment of other clinically relevant end points. If further trials comparing inhaled nitric oxide with an inhaled placebo are to proceed, they should be stratified for primary disease, assess the impact of other combined treatment modalities for respiratory failure, and must specifically evaluate clinically relevant outcomes, before any benefit of inhaled nitric oxide for respiratory failure can be excluded.