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Objective: To compare elderly (? 80 yr), older (65–79 yr), and younger (< 65 yr) ICU admissions in Scotland in relation to trends in admission rates, regional variation in admissions, ICU treatment intensity, and ICU and 1-year mortality. Design: National 5-year cohort study of ICU first admissions (January 1, 2005, to December 31, 2009). Setting: All admissions to ICUs and combined units (level 2/3 care) in Scotland captured by the Scottish Intensive Care Society Audit Group database, linked with hospital discharge data and death records. Patients: A total of 40,142 patients: 3,865 were 80 years old or older (9.6%), 13,904 (34.6%) were 65–79 years old; and 22,373 were younger than 65 years (55.7%). Interventions: None. Measurements and Main Results: Between 2005 and 2009, elderly admission rates decreased from 36.6/10,000 (95% CI, 34.0–39.2) in 2005 to 28.7/10,000 (95% CI, 26.5–30.9) in 2009 (p < 0.001; relative decrease, 22.0%); older admission rates also decreased, but less steeply (31.1 [95% CI, 29.9–32.2] to 26.1 [95% CI, 25.1–27.1] per 10,000 population; p < 0.001; relative decrease, 16.1%). Rates were static for younger patients. Restricted to mechanically ventilated elderly patients, rates ranged from 13.9 to 30.1/10,000 between healthboard administrative regions (p < 0.001). Emergency surgical diagnoses were more prevalent for elderly patients (elderly, 39.8%; older, 25.1%; younger, 20.3%; p < 0.001). Subgroup analyses limited to pneumonia admissions (elderly, n = 242; older, n = 1,226; younger, n = 1,836) indicated similar acute physiology scores, but fewer preexisting comorbidities among elderly patients (p = 0.007), who received a shorter duration of organ support and ICU stay. Mortality rates were higher in elderly patients at ICU discharge (elderly, 26.5%; older, 25.0%; younger, 17.0%; p < 0.001; confounder adjusted odds ratio elderly vs younger, 2.33 [95% CI, 2.11–2.58]; p < 0.001). Differences persisted at 1 year (elderly, 52.2%; older, 43.8%; younger, 27.6%; adjusted odds ratio elderly vs younger, 3.72 [95% CI, 3.42–4.06]; p < 0.001). Conclusions: In Scotland, elderly and older ICU admission rates are decreasing, with regional geographic variation. Although limited by an absence of a measure of frailty, patient characteristics and treatment intensity suggest selection of less comorbid elderly patients, indicating possible rationing based on chronologic age.

Objectives: To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator-associated condition definitions identify patients with worse outcomes. Design: Retrospective cohort study and a matched cohort analysis. Setting: Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals. Patients: Children 18 years old or younger ventilated for at least 1 day. Interventions: None. Measurements and Main Results: We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7?cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1–1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7–3.4) to 6.8 (2.9–16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs. Conclusions: Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions.

Objective: Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Forty-six adult female sheep. Interventions: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 ?g]/kg/min) when mean arterial pressure remained less than 70?mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70–80?mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. Measurements and Main Results: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals. Conclusions: In this clinically relevant model, selepressin, a selective V1A receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Objective: The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome. Design: A prospective, multicenter, pilot, randomized controlled trial. Setting: A network of 20 multidisciplinary ICUs. Patients: Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study. Interventions: At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2?0.5, positive end-expiratory pressure ?10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight. Measurements and Main Results: From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher’s exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol. Barotrauma rate was similar in both groups. Conclusions: In patients with established acute respiratory distress syndrome, open lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma. This pilot study supports the need for a large, multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome.

Objectives: There is a marked propensity for patients with acetaminophen-induced acute liver failure to develop sepsis, which may culminate in multiple organ failure and death. Toll-like receptors sense pathogens and induce inflammatory responses, but whether this is protective or detrimental in acetaminophen-induced acute liver failure remains unknown. Design, Setting, and Patients: We assessed Toll-like receptor expression on circulating neutrophils and their function in 24 patients with acetaminophen-induced acute liver failure and compared with 10 healthy controls. Interventions: Neutrophil Toll-like receptor 2, -4, and -9 expression and cytokine production and function were studied ex vivo at baseline and following stimulation with lipopolysaccharide, oligodeoxynucleotides, ammonium chloride, and interleukin-8. To examine the influence of acetaminophen-induced acute liver failure plasma and endogenous DNA on Toll-like receptors-9 expression, healthy neutrophils were incubated with acetaminophen-induced acute liver failure plasma with and without deoxyribonuclease-I. Measurements and Main Results: Circulating neutrophil Toll-like receptor 9 expression was increased in acetaminophen-induced acute liver failure on day 1 compared with healthy controls (p = 0.0002), whereas Toll-like receptor 4 expression was decreased compared with healthy controls (p < 0.0001). Toll-like receptor 2 expression was unchanged. Neutrophil phagocytic activity was decreased, and spontaneous oxidative burst increased in all patients with acetaminophen-induced acute liver failure compared with healthy controls (p < 0.0001). Neutrophil Toll-like receptor 9 expression correlated with plasma interleukin-8 and peak ammonia concentration (r = 0.6; p < 0.05) and increased with severity of hepatic encephalopathy (grade 0–2 vs 3/4) and systemic inflammatory response syndrome score (0–1 vs 2–4) (p < 0.05). Those patients with advanced hepatic encephalopathy (grade 3/4) or high systemic inflammatory response syndrome score (2–4) on day 1 had higher neutrophil Toll-like receptor 9 expression, arterial ammonia concentration, and plasma interleukin-8 associated with neutrophil exhaustion. Healthy neutrophil Toll-like receptor 9 expression increased upon stimulation with acetaminophen-induced acute liver failure plasma, which was abrogated by preincubation with deoxyribonuclease-I. Intracellular Toll-like receptor 9 was induced by costimulation with interleukin-8 and ammonia. Conclusion: These data point to neutrophil Toll-like receptor 9 expression in acetaminophen-induced acute liver failure being mediated both by circulating endogenous DNA as well as ammonia and interleukin-8 in a synergistic manner inducing systemic inflammation, neutrophil exhaustion, and exacerbating hepatic encephalopathy.

Objective: To identify whether delays in rapid response team activation contributed to worse patient outcomes (mortality and morbidity). Design: Retrospective observational cohort study including all rapid response team activations in 2012. Setting: Tertiary academic medical center. Patients: All those 18 years old or older who had a rapid response team call activated. Vital sign data were abstracted from individual patient electronic medical records for the 24 hours before the rapid response team activation took place. Patients were considered to have a delayed rapid response team activation if more than 1 hour passed between the first appearance in the record of an abnormal vital sign meeting rapid response team criteria and the activation of an rapid response team. Interventions: None. Measurements and Main Results: A total of 1,725 patients were included in the analysis. Data were compared between those who had a delayed rapid response team activation and those who did not. Fifty seven percent patients met the definition of delayed rapid response team activation. Patients in high-frequency physiologic monitored environments were more likely to experience delay than their floor counterparts. In the no-delay group, the most common reasons for rapid response team activation were tachycardia/bradycardia at 29% (217/748), respiratory distress/low SpO2 at 28% (213/748), and altered level of consciousness at 23% (170/748) compared with respiratory distress/low SpO2 at 43% (423/977), tachycardia/bradycardia at 33% (327/977), and hypotension at 27% (261/977) in the delayed group. The group with no delay had a higher proportion of rapid response team calls between 8:00 and 16:00, whereas those with delay had a higher proportion of calls between midnight and 08:00. The delayed group had higher hospital mortality (15% vs 8%; adjusted odds ratio, 1.6; p = 0.005); 30-day mortality (20% vs 13%; adjusted odds ratio, 1.4; p = 0.02); and hospital length of stay (7 vs 6 d; relative prolongation, 1.10; p = 0.02) compared with the no-delay group. Conclusions: Delays in rapid response team activation occur frequently and are independently associated with worse patient mortality and morbidity outcomes.

Objective: To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design: Prospective cohort study. Setting: Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients: Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay. Measurements and Main Results: We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 ?g/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92?kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35?L/hr (95% CI, 32–39?L/hr), 55?L/hr (95% CI, 42–68?L/hr), 203?L (95% CI, 140–266?L), and 523?L (95% CI, 428–618?L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included. Conclusions: In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients.

Objective: To evaluate the independent association between low peak admission plasma creatinine concentrations and in-hospital mortality in patients requiring critical care in Australia and New Zealand. Design: Multicenter, binational, retrospective cohort study. Setting: Data were extracted from the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation adult patient database. Patients: All available records for the period 2000 to 2013 were utilized. The following exclusion criteria were applied: all readmission episodes (within the same hospital stay), missing in-hospital mortality, admission post kidney transplantation, chronic renal replacement therapy (hemodialysis or peritoneal dialysis), and missing peak plasma creatinine concentration. Demographic, anthropometric, admission, illness severity, laboratory, and outcome data were then extracted. Patients were categorized on the basis of their peak (maximum) plasma creatinine concentration recorded in the first 24 hours of ICU admission. Illness severity–adjusted associations with in-hospital mortality relative to a reference category of 70–79 ?mol/L were then determined using multivariate logistic regression. Interventions: Nil. Measurements and Main Results: Data pertaining to 1,250,449 admissions were available for the study period. Following exclusions, 1,045,718 patients were included. Regression analysis identified that peak plasma creatinine concentrations less than 60 ?mol/L measured in the first 24 hours after ICU admission imply a steadily increasing adjusted in-hospital mortality risk. In cases where this value is markedly low (< 30 ?mol/L), the adjusted odds of dying in-hospital is over two-fold higher than the reference category and exceeds the risk implied with elevated (? 180 ?mol/L) values. This finding was also independent of anthropometric data. Conclusions: In a large heterogenous cohort of critically ill patients, low admission peak plasma creatinine concentrations are independently associated with increased risk-adjusted in-hospital mortality. Further research should now focus on the potential mechanisms underpinning this finding, such as a low skeletal muscle mass and/or fluid overload.

Objectives: As interactions of each organ system have been conceptually known to play an important role during life-threatening conditions, we quantitatively evaluated the organ system interactions in critically ill patients and examined the difference in the organ system network structure between the survivors and the nonsurvivors. Design: Prospective observational study. Settings: An ICU of a university hospital. Patients: Two hundred and eighty-two patients who were admitted to the ICU. Interventions: Blood samples were obtained at ICU admission. Measurements and Main Results: We analyzed the associations among nine representative laboratory variables of each organ system using network analysis. We compared the network structure of the variables in the 40 nonsurvivors with that in the 40 survivors. Their baseline characteristics, including the degree of organ dysfunction, were matched using propensity score matching method. Network structure was quantitatively evaluated using edge (significant correlation among variables evaluated by the p value), weight (connective strength of edge evaluated by coefficient), and cluster (group with tight connection evaluated by edge betweenness). The number of edges among the nine variables was significantly fewer for the nonsurvivors than for the severity-matched survivors (3 vs 12; p = 0.035). The mean weight of edges was significantly smaller for the nonsurvivors (0.055 vs 0.119; p = 0.007). The nine laboratory variables for the nonsurvivors were divided into a significantly larger number of clusters (7 vs 2; p = 0.001). Statistical conclusions were preserved with Bonferroni multiple comparison procedure. These findings were consistently observed in comparison of the 40 nonsurvivors with all the survivors. Conclusions: This study, as a preliminary proof-of-concept, quantitatively demonstrated a more disrupted network structure of organ systems in the nonsurvivors compared with that in the survivors. These observations suggest the necessity of assessment for organ system interactions to evaluate critically ill patients.

Objective: Global lung stress varies considerably with low tidal volume ventilation for acute respiratory distress syndrome. High stress despite low tidal volumes may worsen lung injury and increase risk of death. No widely available parameter exists to assess global lung stress. We aimed to determine whether the volume delivered during a recruitment maneuver (VRM) is inversely associated with lung stress and mortality in acute respiratory distress syndrome. Design: Substudy of an acute respiratory distress syndrome clinical trial on esophageal pressure-guided positive end-expiratory pressure titration. Setting: U.S. academic medical center. Patients: Forty-two patients with acute respiratory distress syndrome in whom airflow, airway pressure, and esophageal pressure were recorded during the recruitment maneuver. Interventions: A single recruitment maneuver was performed before initiating protocol-directed ventilator management. Recruitment maneuvers consisted of a 30-second breath hold at 40?cm H2O airway pressure under heavy sedation or paralysis. VRM was calculated by integrating the flow-time waveform during the maneuver. End-inspiratory stress was defined as the transpulmonary (airway minus esophageal) pressure during end-inspiratory pause of a tidal breath and tidal stress as the transpulmonary pressure difference between end-inspiratory and end-expiratory pauses. Measurements and Main Results: VRM ranged between 7.4 and 34.7?mL/kg predicted body weight. Lower VRM predicted high end-inspiratory and tidal lung stress (end-inspiratory: ? = –0.449; 95% CI, –0.664 to –0.234; p < 0.001; tidal: ? = –0.267; 95% CI, –0.423 to –0.111; p = 0.001). After adjusting for PaO2/FIO2 and either driving pressure, tidal volume, or plateau pressure and positive end-expiratory pressure, VRM remained independently associated with both end-inspiratory and tidal stress. In unadjusted analysis, low VRM predicted increased risk of death (odds ratio, 0.85; 95% CI, 0.72–1.00; p = 0.026). VRM remained significantly associated with mortality after adjusting for study arm (odds ratio, 0.84; 95% CI, 0.71–1.00; p = 0.022). Conclusions: Low VRM independently predicts high lung stress and may predict risk of death in patients with acute respiratory distress syndrome.

Objective: To determine the association between anxiety during critical illness and symptoms of anxiety and depression over 6 months after ICU discharge in survivors of intensive care treatment. Design: Longitudinal study. Setting: One closed mixed ICU in an adult tertiary hospital in Brisbane, Australia. Patients: Participants (n = 141) were adults (? 8 yr), admitted to ICU for at least 24 hours, able to communicate either verbally or nonverbally, understand English, and open their eyes spontaneously or in response to voice. Interventions: None. Measurements and Main Results: The outcomes of symptoms of anxiety and depression over 6 months after ICU discharge were assessed using the Hospital Anxiety Depression Scale. The primary variable of interest was anxiety during critical illness. Two components of anxiety (state and trait) were assessed during critical illness using the Faces Anxiety Scale and the trait component of the State-Trait Anxiety Inventory. Perceived social support, cognitive functioning, and posttraumatic stress symptoms were also assessed using standardized instruments. Clinical and demographic data were obtained from patients and medical records. Participants were followed up in hospital wards and at 3 and 6 months after ICU discharge. During ICU treatment, 81 of the 141 participants (57%) reported moderate to severe levels of state anxiety. Of the 92 participants who completed the surveys at the 6-month follow-up, 26 participants (28%) reported symptoms of anxiety and 21 (23%) symptoms of depression. Symptoms of anxiety and depression were strongly correlated in this cohort of survivors. Trait anxiety was significantly associated with both anxiety and depression symptoms over time; however, state anxiety was not associated with either outcome. Participants who reported post-ICU memories of intra-ICU anxiety were significantly more anxious during recovery over 6 months. Cognitive functioning and posttraumatic stress symptoms were both significantly associated with anxiety and depression symptoms over time. Conclusion: Symptoms of anxiety and depression are a significant issue for general ICU survivors. Trait anxiety was significantly associated with adverse emotional outcomes over 6 months after ICU discharge. There was also a significant relationship between post-ICU memories of intra-ICU anxiety and anxiety during recovery. Interventions to reduce anxiety during critical illness need to be considered and evaluated for their longer term benefits for survivors of critical illness.

Objectives: In the first days after cardiac arrest, accurate prognostication is challenging. Serum biomarkers are a potentially attractive adjunct for prognostication and risk stratification. Our primary objective in this exploratory study was to identify novel early serum biomarkers that predict survival after cardiac arrest earlier than currently possible. Design: Prospective, observational study. Setting: A single academic medical center. Subjects: Adult subjects who sustained cardiac arrest with return of spontaneous circulation. Intervention: None. Measurements and Main Results: We obtained blood samples from each subject at enrollment, 6, 12, 24, 48, and 72 hours after return of spontaneous circulation. We measured the serum levels of novel biomarkers, including neutrophil gelatinase–associated lipocalin, high-mobility group protein B1, intracellular cell adhesion molecule-1, and leptin, as well as previously characterized biomarkers, including neuron-specific enolase and S100B protein. Our primary outcome of interest was survival-to-hospital discharge. We compared biomarker concentrations at each time point between survivors and nonsurvivors and used logistic regression to test the unadjusted associations of baseline clinical characteristics and enrollment biomarker levels with survival. Finally, we constructed a series of adjusted models to explore the independent association of each enrollment biomarker level with survival. A total of 86 subjects were enrolled. Enrollment levels of high-mobility group protein B1, neutrophil gelatinase–associated lipocalin, and S100B were higher in nonsurvivors than survivors. Enrollment leptin, neuron-specific enolase, and intracellular cell adhesion molecule-1 levels did not differ between nonsurvivors and survivors. The discriminatory power of enrollment neutrophil gelatinase–associated lipocalin level was the greatest (c-statistic, 0.78 [95% CI, 0.66–0.90]) and remained stable across all time points. In our adjusted models, enrollment neutrophil gelatinase–associated lipocalin level was independently associated with survival even after controlling for the development of acute kidney injury, and its addition to clinical models improved overall predictive accuracy. Conclusions: Serum neutrophil gelatinase–associated lipocalin levels are strongly predictive of survival-to-hospital discharge after cardiac arrest.

Objective: The prevalence, clinical characteristics, and outcomes of critically ill, nonintubated patients with evidence of the acute respiratory distress syndrome remain inadequately characterized. Design: Secondary analysis of a prospective observational cohort study. Setting: Vanderbilt University Medical Center. Patients: Among adult patients enrolled in a large, multi-ICU prospective cohort study between the years of 2006 and 2011, we studied intubated and nonintubated patients with acute respiratory distress syndrome as defined by acute hypoxemia (PaO2/FIO2 ? 300 or SpO2/FIO2 ? 315) and bilateral radiographic opacities not explained by cardiac failure. We excluded patients not committed to full respiratory support. Interventions: None. Measurements and Main Results: Of 457 patients with acute respiratory distress syndrome, 106 (23%) were not intubated at the time of meeting all other acute respiratory distress syndrome criteria. Nonintubated patients had lower morbidity and severity of illness than intubated patients; however, mortality at 60 days was the same (36%) in both groups (p = 0.91). Of the 106 nonintubated patients, 36 (34%) required intubation within the subsequent 3 days of follow-up; this late-intubation subgroup had significantly higher 60-day mortality (56%) when compared with the both early intubation group (36%, P<0.03) and patients never requiring intubation (26%; p = 0.002). Increased mortality in the late intubation group persisted at 2-year follow-up. Adjustment for baseline clinical and demographic differences did not change the results. Conclusions: A substantial proportion of critically ill adults with acute respiratory distress syndrome were not intubated in their initial days of intensive care, and many were never intubated. Late intubation was associated with increased mortality. Criteria defining the acute respiratory distress syndrome prior to need for positive pressure ventilation are required so that these patients can be enrolled in clinical studies and to facilitate early recognition and treatment of acute respiratory distress syndrome.

Objectives: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. Design: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. Setting: Randomized clinical trials involving patients in an acute or nonacute care setting. Subjects and Interventions: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. Measurements and Main Results: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72–9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. Conclusions: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.