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Rationale: Short-term follow-up in the Fluid and Catheter Treatment Trial (FACTT) suggested differential mortality by race with conservative fluid management, but no significant interaction.Objective: In a post hoc analysis of FACTT including 1-year follow-up, we sought to estimate long-term mortality by race and test for an interaction between fluids and race.Methods: We performed a post hoc analysis of FACTT and the Economic Analysis of Pulmonary Artery Catheters (EAPAC) study (which included 655 of the 1,000 FACTT patients with near-complete 1-year follow up). We fit a multistate Markov model to estimate 1-year mortality for all non-Hispanic black and white randomized FACTT subjects. The model estimated the distribution of time from randomization to hospital discharge or hospital death (available on all patients) and estimated the distribution of time from hospital discharge to death using data on patients after hospital discharge for patients in EAPAC. The 1-year mortality was found by combining these estimates.Results: Non-Hispanic black (n = 217, 25%) or white identified subjects (n = 641, 75%) were included. There was a significant interaction between race and fluid treatment (P = 0.012). One-year mortality was lower for black subjects assigned to conservative fluids (38 vs. 54%; mean mortality difference, 16%; 95% confidence interval, 2-30%; P = 0.027 between conservative and liberal). Conversely, 1-year mortality for white subjects was 35% versus 30% for conservative versus liberal arms (mean mortality difference, -4.8%; 95% confidence interval, -13% to 3%; P = 0.23).Conclusions: In our cohort, conservative fluid management may have improved 1-year mortality for non-Hispanic black patients with ARDS. However, we found no long-term benefit of conservative fluid management in white subjects. [ABSTRACT FROM AUTHOR]

Study Objective: To determine whether men with hypogonadism are at risk for hyperlipidemia.Design: Case-control study.Setting: Neuroendocrine clinical center of a referral-based university medical center.Patients: Consecutive sample of 18 men with testosterone deficiency who had prolactin-secreting pituitary adenomas, 15 men with acquired secondary hypogonadism and normal prolactin levels, and 33 normal male controls.Measurements and Main Results: We found a significant elevation in fasting cholesterol (6.23 +/- 0.28 mmol/L [mean +/- SE] compared with 5.17 +/- 0.13 mmol/L [241 +/- 11 mg/dL compared with 200 +/- 5 mg/dL], P less than 0.01), low density lipoprotein (LDL) cholesterol (4.11 +/- 0.23 mmol/L compared with 3.34 +/- 0.13 mmol/L [159 +/- 9 mg/dL compared with 129 +/- 5 mg/dL], P less than 0.05), and triglycerides (1.85 +/- 0.26 mmol/L compared with 1.11 +/- 0.07 mmol/L [164 +/- 23 mg/dL compared with 98 +/- 6 mg/dL], P less than 0.001) in men with hyperprolactinemia compared with controls. In the normoprolactinemic hypogonadal men, cholesterol (6.28 +/- 0.34 mmol/L [243 +/- 13 mg/dL], P less than 0.01), LDL cholesterol (4.34 +/- 0.34 mmol/L [168 +/- 13 mg/dL], P less than 0.01), and triglycerides (1.61 +/- 0.18 mmol/L [143 +/- 16 mg/dL], P less than 0.05) were also significantly higher than in the controls, and were the same as in the hyperprolactinemic men. High density lipoprotein (HDL) cholesterol did not differ among the three groups.Conclusions: Hypogonadism in men, with or without hyperprolactinemia, may be associated with elevation of fasting serum cholesterol, LDL cholesterol, and triglycerides compared with normal men. These data suggest that serum lipid levels should be evaluated in hypogonadal men. The presence of lipid abnormalities may affect the decision to treat testosterone deficiency in these patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Deployment of law enforcement operational canines (OpK9s) risks injuries to the animals. This study's aim was to assess the current status of states' OpK9 (veterinary Emergency Medical Services [VEMS]) laws and care protocols within the United States., Methods: Cross-sectional standardized review of state laws/regulations and OpK9 VEMS treatment protocols was undertaken. For each state and for the District of Columbia (DC), the presence of OpK9 legislation and/or care protocols was ascertained. Information was obtained through governmental records and from stakeholders (eg, state EMS medical directors and state veterinary boards).The main endpoints were proportions of states with OpK9 laws and/or treatment protocols. Proportions are reported with 95% confidence intervals (CIs). Fisher's exact test ( P <.05) assessed whether presence of an OpK9 law in a given jurisdiction was associated with presence of an OpK9 care protocol, and whether there was geographic variation (based on United States Census Bureau regions) in presence of OpK9 laws or protocols., Results: Of 51 jurisdictions, 20 (39.2%) had OpK9 legislation and 23 (45.1%) had state-wide protocols for EMS treatment of OpK9s. There was no association ( P = .991) between presence of legislation and presence of protocols. There was no association ( P = .144) between presence of legislation and region: Northeast 66.7% (95% CI, 29.9-92.5%), Midwest 50.0% (95% CI, 21.1-78.9%), South 29.4% (95% CI, 10.3-56.0%), and West 23.1% (95% CI, 5.0-53.8%). There was significant ( P = .001) regional variation in presence of state-wide OpK9 treatment protocols: Northeast 100.0% (95% CI, 66.4-100.0%), Midwest 16.7% (95% CI, 2.1-48.4%), South 47.1% (95% CI, 23.0-72.2%), and West 30.8% (95% CI, 9.1-61.4%)., Conclusion: There is substantial disparity with regard to presence of OpK9 legal and/or clinical guidance. National collaborative guidelines development is advisable to optimize and standardize care of OpK9s. Additional attention should be paid to educational and training programs to best utilize the limited available training budgets.

Objective: Early administration of tranexamic acid (TXA) has been shown to save lives in trauma patients, and some U.S. emergency medical systems (EMS) have begun providing this therapy prehospital. Treatment protocols vary from state to state: Some offer TXA broadly to major trauma patients, others reserve it for patients meeting vital sign criteria, and still others defer TXA entirely pending a hospital evaluation. The purpose of this study is to compare the avoidable mortality achievable under each of these strategies, and to report on the various approaches used by EMS., Methods: We used the National Center for Health Statistics Underlying Cause of Death data to identify a TXA-naïve population of trauma patients who died from 2007 to 2012 due to hemorrhage. We estimated the proportion of deaths where the patient was hypotensive or tachycardic using the National Trauma Data Bank. We used avoidable mortality risk ratios from the landmark CRASH 2 study to calculate lives saved had TXA been given within one hour of injury based on a clinician's gestalt the patient was at risk for significant hemorrhage; had it been reserved only for hypotensive or tachycardic patients; or had it been given between hours one to three of injury, considered here as a surrogate for deferring the question to the receiving hospital., Results: Had TXA been given within 1 hour of injury, an average of 3409 deaths per year could have been averted nationally. Had TXA been given between one and three hours after injury, 2236 deaths per year could have been averted. Had TXA only been given to either tachycardic or hypotensive trauma patients, 1371 deaths per year could have been averted. Had TXA only been given to hypotensive trauma patients, 616 deaths per year could have been averted. Similar trends are seen at the individual state level. A review of EMS practices found 15 statewide protocols that allow EMS providers to administer TXA for trauma., Conclusion: Providing early TXA to persons at risk of significant hemorrhage has the potential to prevent many deaths from trauma, yet most states do not offer it in statewide prehospital treatment protocols., (© 2022. The Author(s).)

Context: Anorexia nervosa (AN) is a psychiatric illness with considerable morbidity and no approved medical therapies. We have shown that relative androgen deficiency in AN is associated with greater depression and anxiety symptom severity., Objective: To determine whether low-dose testosterone therapy is an effective endocrine-targeted therapy for AN., Design: Double-blind, randomized, placebo-controlled trial., Setting: Clinical research center., Participants: Ninety women, 18 to 45 years, with AN and free testosterone levels below the median for healthy women., Intervention: Transdermal testosterone, 300 μg daily, or placebo patch for 24 weeks., Main Outcome Measures: Primary end point: body mass index (BMI). Secondary end points: depression symptom severity [Hamilton Depression Rating Scale (HAM-D)], anxiety symptom severity [Hamilton Anxiety Rating Scale (HAM-A)], and eating disorder psychopathology and behaviors., Results: Mean BMI increased by 0.0 ± 1.0 kg/m2 in the testosterone group and 0.5 ± 1.1 kg/m2 in the placebo group (P = 0.03) over 24 weeks. At 4 weeks, there was a trend toward a greater decrease in HAM-D score (P = 0.09) in the testosterone vs placebo group. At 24 weeks, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D: -2.9 ± 4.9 (testosterone) vs -3.0 ± 5.0 (placebo), P = 0.72; HAM-A: -4.5 ± 5.3 (testosterone) vs -4.3 ± 4.4 (placebo), P = 0.25]. There were no significant differences in eating disorder scores between groups. Testosterone therapy was safe and well tolerated with no increase in androgenic side effects compared with placebo., Conclusion: Low-dose testosterone therapy for 24 weeks was associated with less weight gain-and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms-compared with placebo in women with AN., (Copyright © 2019 Endocrine Society.)

Study Objective: Shared decisionmaking has been promoted as a method to increase the patient-centeredness of medical decisionmaking and decrease low-yield testing, but little is known about its medicolegal ramifications in the setting of an adverse outcome. We seek to determine whether the use of shared decisionmaking changes perceptions of fault and liability in the case of an adverse outcome., Methods: This was a randomized controlled simulation experiment conducted by survey, using clinical vignettes featuring no shared decisionmaking, brief shared decisionmaking, or thorough shared decisionmaking. Participants were adult US citizens recruited through an online crowd-sourcing platform. Participants were randomized to vignettes portraying 1 of 3 levels of shared decisionmaking. All other information given was identical, including the final clinical decision and the adverse outcome. The primary outcome was reported likelihood of pursuing legal action. Secondary outcomes included perceptions of fault, quality of care, and trust in physician., Results: We recruited 804 participants. Participants exposed to shared decisionmaking (brief and thorough) were 80% less likely to report a plan to contact a lawyer than those not exposed to shared decisionmaking (12% and 11% versus 41%; odds ratio 0.2; 95% confidence interval 0.12 to 0.31). Participants exposed to either level of shared decisionmaking reported higher trust, rated their physicians more highly, and were less likely to fault their physicians for the adverse outcome compared with those exposed to the no shared decisionmaking vignette., Conclusion: In the setting of an adverse outcome from a missed diagnosis, use of shared decisionmaking may affect patients' perceptions of fault and liability., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Low-tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined., Objectives: We observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design., Methods: We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure., Results: We included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1-7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0-2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power., Conclusions: Use of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.

Objective: To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database., Methods: We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted., Results: Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months., Conclusion: ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study., (© 2015 American Academy of Neurology.)

Objectives: In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols., Design: Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock., Setting: ICUs of Acute Respiratory Distress Syndrome Network participating hospitals., Patients: Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite., Interventions: Fluid management by protocol., Measurements and Main Results: Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite)., Conclusions: FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

Objective: To determine and compare outcomes with accepted benchmarks in burn care at 6 academic burn centers., Background: Since the 1960s, US morbidity and mortality rates have declined tremendously for burn patients, likely related to improvements in surgical and critical care treatment. We describe the baseline patient characteristics and well-defined outcomes for major burn injuries., Methods: We followed 300 adults and 241 children from 2003 to 2009 through hospitalization, using standard operating procedures developed at study onset. We created an extensive database on patient and injury characteristics, anatomic and physiological derangement, clinical treatment, and outcomes. These data were compared with existing benchmarks in burn care., Results: Study patients were critically injured, as demonstrated by mean % total body surface area (TBSA) (41.2 ± 18.3 for adults and 57.8 ± 18.2 for children) and presence of inhalation injury in 38% of the adults and 54.8% of the children. Mortality in adults was 14.1% for those younger than 55 years and 38.5% for those aged 55 years and older. Mortality in patients younger than 17 years was 7.9%. Overall, the multiple organ failure rate was 27%. When controlling for age and % TBSA, presence of inhalation injury continues to be significant., Conclusions: This study provides the current benchmark for major burn patients. Mortality rates, notwithstanding significant % TBSA and presence of inhalation injury, have significantly declined compared with previous benchmarks. Modern day surgical and medically intensive management has markedly improved to the point where we can expect patients younger than 55 years with severe burn injuries and inhalation injury to survive these devastating conditions.

Background:  International travel poses a risk of destination-specific illness and may contribute to the global spread of infectious diseases. Despite this, little is known about the health characteristics and pretravel healthcare of US international travelers, particularly those at higher risk of travel-associated illness., Methods:  We formed a national consortium (Global TravEpiNet) of 18 US clinics registered to administer yellow fever vaccination. We collected data regarding demographic and health characteristics, destinations, purpose of travel, and pretravel healthcare from 13235 international travelers who sought pretravel consultation at these sites from January 2009 through January 2011., Results:  The destinations and itineraries of Global TravEpiNet travelers differed from those of the overall population of US international travelers. The majority of Global TravEpiNet travelers were visiting low- or lower-middle-income countries, and Africa was the most frequently visited region. Seventy-five percent of travelers were visiting malaria-endemic countries, and 38% were visiting countries endemic for yellow fever. Fifty-nine percent of travelers reported ≥1 medical condition. Atovaquone/proguanil was the most commonly prescribed antimalarial drug, and most travelers received an antibiotic for self-treatment of travelers' diarrhea. Hepatitis A and typhoid were the most frequently administered vaccines., Conclusions:  Data from Global TravEpiNet provide insight into the characteristics and pretravel healthcare of US international travelers who are at increased risk of travel-associated illness due to itinerary, purpose of travel, or existing medical conditions. Improved understanding of this epidemiologically significant population may help target risk-reduction strategies and interventions to limit the spread of infections related to global travel.

Rationale: β₂-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies., Objectives: This clinical trial was designed to test the hypothesis that an aerosolized β₂-agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI)., Methods: We conducted a multicenter, randomized, placebo-controlled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days., Measurements and Main Results: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P = 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95%confidence interval for the difference,-4.0 to 14.7%;P = 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new 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 patients with ALI. Routine use of β₂-agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).

Background: Liver transplantation offers life-saving therapy for patients with decompensated liver disease or T2 hepatocellular carcinomas. In the United States, deceased donor livers are primarily allocated by Model for End-Stage Liver Disease (MELD) score within each of the country's more than 50 donation service areas (DSAs). Variation in DSA size, population, and organ availability have engendered concern that unequal access to deceased donor livers across DSAs contributes to geographic variability in outcome., Methods: To determine the extent to which DSA variability in organ availability correlated with combined waitlist and posttransplant mortality, we analyzed retrospectively national waitlist and posttransplant data for a 7-year period after implementation of the current MELD-based allocation system., Results: Marked variation among DSAs was evident in death rate (3.3-fold), transplant rate (20-fold), and mean transplant MELD (>10 points). Death rate correlated with organ availability was assessed by transplant rate and transplant MELD. DSAs with low organ availability included the country's largest cities, had more new listings per capita, larger waitlists, more transplant centers per DSA, and a higher proportion of black and Asian patients. DSAs of organ shortage were also characterized by more frequent dual listing at another transplant center, more living donor liver transplants, and increased average length of the transplant admission., Conclusions: Geographic differences in deceased donor organ availability contribute to variation in overall death rate of liver transplant patients, shape the clinical practice of transplant, and influence the resources consumed per transplant. Geographic variation in organ access results primarily from rates of listing rather than donation. Our findings highlight the need to restructure organ distribution areas to achieve equal access to deceased donor livers for transplantation in the United States.

Context: To ensure interpretability and replicability of clinical experiments, methods must be adequately explicit and should elicit the same decision from different clinicians who comply with the study protocol., Objective: The objective of this study was to determine whether clinician compliance with protocol recommendations exceeds 90%., Design: We developed an adequately explicit computerized protocol (eProtocol-insulin) for managing critically ill adult patient blood glucose. We monitored clinician compliance with eProtocol-insulin recommendations in four intensive care units in four hospitals and compared blood glucose distributions with those of a simple clinical guideline at one hospital and a paper-based protocol at another. All protocols and the guideline used intravenous insulin and 80 to 110 mg/dL (4.4-6.1 mmol/L) blood glucose targets., Setting: The setting for this study was four academic hospital intensive care units., Patients: This study included critically ill adults requiring intravenous insulin., Intervention: Intervention used in this study was a bedside computerized protocol for managing blood glucose., Main Outcome Measure: The main outcome measure was clinician compliance with eProtocol-insulin recommendations., Results: The number of patients was 31 to 458 and the number of blood glucose measurements was 2,226 to 19,925 among the four intensive care units. Clinician compliance with eProtocol-insulin recommendations was 91% to 98%. Blood glucose distributions were similar in the four hospitals (generalized linear model p = .18). Compared with the simple guideline, eProtocol-insulin glucose measurements within target increased from 21% to 39%, and mean blood glucose decreased from 142 to 115 mg/dL (generalized linear model p < .001). Compared with the paper-based protocol, eProtocol-insulin glucose measurements within target increased from 28% to 42%, and mean blood glucose decreased from 134 to 116 mg/dL (generalized linear model p = .001)., Conclusions: The 91% to 98% clinician compliance indicates eProtocol-insulin is an exportable instrument that can establish a replicable experimental method for clinical trials of blood glucose management in critically ill adults. Control of blood glucose was better with eProtocol-insulin than with a simple clinical guideline or a paper-based protocol.

Objective: Trials of potential new therapies in acute lung injury are difficult and expensive to conduct. This article is designed to determine the utility, behavior, and statistical properties of a new primary end point for such trials, ventilator-free days, defined as days alive and free from mechanical ventilation. Describing the nuances of this outcome measure is particularly important because using it, while ignoring mortality, could result in misleading conclusions., Design: To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial. To determine the appropriate test statistic for the new measure and derive a formula for power. To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement. To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses., Setting: Intensive care units., Patients: Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference., Main Results: The proposed model fit the clinical data. Ventilator-free days were improved by lower tidal volume ventilation, but the improvement was mostly caused by the improved mortality rate, so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality. Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score. On the other hand, if patients are divided into two groups on the basis of the lung injury score, both the duration of ventilation and mortality are lower in the low lung injury score group. A trial of a treatment that had a similar clinical effect would have a large increase in power, allowing for a reduction in the required sample size., Conclusions: Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality. It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days. This would be especially true if the treatment were also required to produce a nominal improvement in mortality.