Neill K. J. Adhikari

Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review.

RATIONALE It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing. OBJECTIVES To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality. METHODS We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models. MEASUREMENTS AND MAIN RESULTS Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled weighted mortality was 44.3% (95% confidence interval [CI], 41.8-46.9). Mortality decreased with time in observational studies conducted before 1994; no temporal associations with mortality were demonstrated in RCTs (any time) or observational studies (after 1994). Pooled mortality from 1994 to 2006 was 44.0% (95% CI, 40.1-47.5) for observational studies, and 36.2% (95% CI, 32.1-40.5) for RCTs. Meta-regression identified study type (observational versus RCT, odds ratio, 1.36; 95% CI, 1.08-1.73) and patient age (odds ratio per additional 10 yr, 1.27; 95% CI, 1.07-1.50) as the only factors associated with mortality. CONCLUSIONS A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies.

A guide for the design and conduct of self-administered surveys of clinicians

Survey research is an important form of scientific inquiry[1][1] that merits rigorous design and analysis.[2][2] The aim of a survey is to gather reliable and unbiased data from a representative sample of respondents.[3][3] Increasingly, investigators administer questionnaires to clinicians about

Critical care and the global burden of critical illness in adults

Summary Critical care has evolved from treatment of poliomyelitis victims with respiratory failure in an intensive care unit to treatment of severely ill patients irrespective of location or specific technology. Population-based studies in the developed world suggest that the burden of critical illness is higher than generally appreciated and will increase as the population ages. Critical care capacity has long been needed in the developing world, and efforts to improve the care of the critically ill in these settings are starting to occur. Expansion of critical care to handle the consequences of an ageing population, natural disasters, conflict, inadequate primary care, and higher-risk medical therapies will be challenged by high costs at a time of economic constraint. To meet this challenge, investigators in this discipline will need to measure the global burden of critical illness and available critical-care resources, and develop both preventive and therapeutic interventions that are generalisable across countries.

Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations

RATIONALE Reducing the global burden of sepsis, a recognized global health challenge, requires comprehensive data on the incidence and mortality on a global scale. OBJECTIVES To estimate the worldwide incidence and mortality of sepsis and identify knowledge gaps based on available evidence from observational studies. METHODS We systematically searched 15 international citation databases for population-level estimates of sepsis incidence rates and fatality in adult populations using consensus criteria and published in the last 36 years. MEASUREMENTS AND MAIN RESULTS The search yielded 1,553 reports from 1979 to 2015, of which 45 met our criteria. A total of 27 studies from seven high-income countries provided data for metaanalysis. For these countries, the population incidence rate was 288 (95% confidence interval [CI], 215-386; τ = 0.55) for hospital-treated sepsis cases and 148 (95% CI, 98-226; τ = 0.99) for hospital-treated severe sepsis cases per 100,000 person-years. Restricted to the last decade, the incidence rate was 437 (95% CI, 334-571; τ = 0.38) for sepsis and 270 (95% CI, 176-412; τ = 0.60) for severe sepsis cases per 100,000 person-years. Hospital mortality was 17% for sepsis and 26% for severe sepsis during this period. There were no population-level sepsis incidence estimates from lower-income countries, which limits the prediction of global cases and deaths. However, a tentative extrapolation from high-income country data suggests global estimates of 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually. CONCLUSIONS Population-level epidemiologic data for sepsis are scarce and nonexistent for low- and middle-income countries. Our analyses underline the urgent need to implement global strategies to measure sepsis morbidity and mortality, particularly in low- and middle-income countries.

Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis

Objective To review the literature on the use of inhaled nitric oxide to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and to summarise the effects of nitric oxide, compared with placebo or usual care without nitric oxide, in adults and children with ALI or ARDS. Design Systematic review and meta-analysis. Data sources Medline, CINAHL, Embase, and CENTRAL (to October 2006), proceedings from four conferences, and additional information from authors of 10 trials. Review methods Two reviewers independently selected parallel group randomised controlled trials comparing nitric oxide with control and extracted data related to study methods, clinical and physiological outcomes, and adverse events. Main outcome measures Mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, adverse events. Results 12 trials randomly assigning 1237 patients met inclusion criteria. Overall methodological quality was good. Using random effects models, we found no significant effect of nitric oxide on hospital mortality (risk ratio 1.10, 95% confidence interval 0.94 to 1.30), duration of ventilation, or ventilator-free days. On day one of treatment, nitric oxide increased the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) (13%, 4% to 23%) and decreased the oxygenation index (14%, 2% to 25%). Some evidence suggested that improvements in oxygenation persisted until day four. There was no effect on mean pulmonary arterial pressure. Patients receiving nitric oxide had an increased risk of developing renal dysfunction (1.50, 1.11 to 2.02). Conclusions Nitric oxide is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm. We do not recommend its routine use in these severely ill patients.

Sepsis: a roadmap for future research

Sepsis is a common and lethal syndrome: although outcomes have improved, mortality remains high. No specific anti-sepsis treatments exist; as such, management of patients relies mainly on early recognition allowing correct therapeutic measures to be started rapidly, including administration of appropriate antibiotics, source control measures when necessary, and resuscitation with intravenous fluids and vasoactive drugs when needed. Although substantial developments have been made in the understanding of the basic pathogenesis of sepsis and the complex interplay of host, pathogen, and environment that affect the incidence and course of the disease, sepsis has stubbornly resisted all efforts to successfully develop and then deploy new and improved treatments. Existing models of clinical research seem increasingly unlikely to produce new therapies that will result in a step change in clinical outcomes. In this Commission, we set out our understanding of the clinical epidemiology and management of sepsis and then ask how the present approaches might be challenged to develop a new roadmap for future research.

Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data

BackgroundMeta-analysis handles randomized trials with no outcome events in both treatment and control arms inconsistently, including them when risk difference (RD) is the effect measure but excluding them when relative risk (RR) or odds ratio (OR) are used. This study examined the influence of such trials on pooled treatment effects.MethodsAnalysis with and without zero total event trials of three illustrative published meta-analyses with a range of proportions of zero total event trials, treatment effects, and heterogeneity using inverse variance weighting and random effects that incorporates between-study heterogeneity.ResultsIncluding zero total event trials in meta-analyses moves the pooled estimate of treatment effect closer to nil, decreases its confidence interval and decreases between-study heterogeneity. For RR and OR, inclusion of such trials causes small changes, even when they comprise the large majority of included trials. For RD, the changes are more substantial, and in extreme cases can eliminate a statistically significant effect estimate.ConclusionTo include all relevant data regardless of effect measure chosen, reviewers should also include zero total event trials when calculating pooled estimates using OR and RR.

High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis

Objective To determine clinical and physiological effects of high frequency oscillation compared with conventional ventilation in patients with acute lung injury/acute respiratory distress syndrome (ARDS). Design Systematic review and meta-analysis. Data sources Electronic databases to March 2010, conference proceedings, bibliographies, and primary investigators. Study selection Randomised controlled trials of high frequency oscillation compared with conventional ventilation in adults or children with acute lung injury/ARDS. Data selection Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. Analyses used random effects models. Results Eight randomised controlled trials (n=419 patients) were included; almost all patients had ARDS. Methodological quality was good. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16-24% higher in patients receiving high frequency oscillation. There were no significant differences in oxygenation index because mean airway pressure rose by 22-33% in patients receiving high frequency oscillation (P≤0.01). In patients randomised to high frequency oscillation, mortality was significantly reduced (risk ratio 0.77, 95% confidence interval 0.61 to 0.98, P=0.03; six trials, 365 patients, 160 deaths), and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) resulting in discontinuation of assigned therapy was less likely (0.67, 0.46 to 0.99, P=0.04; five trials, 337 patients, 73 events). Other risks were similar. There was substantial heterogeneity between trials for physiological (I2=21-95%) but not clinical (I2=0%) outcomes. Pooled results were based on few events for most clinical outcomes. Conclusion High frequency oscillation might improve survival and is unlikely to cause harm. As ongoing large multicentre trials will not be completed for several years, these data help clinicians who currently use or are considering this technique for patients with ARDS.

Sex-and age-based differences in the delivery and outcomes of critical care.

Background: Previous studies have suggested that a patients sex may influence the provision and outcomes of critical care. Our objective was to determine whether sex and age are associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients. Methods: We used a retrospective cohort of 466 792 patients, including 24 778 critically ill patients, admitted consecutively to adult hospitals in Ontario between Jan. 1, 2001, and Dec. 31, 2002. We measured associations between sex and age and admission to the intensive care unit (ICU); use of mechanical ventilation, dialysis or pulmonary artery catheterization; length of stay in the ICU and hospital; and death in the ICU, hospital and 1 year after admission. Results: Of the 466 792 patients admitted to hospital, more were women than men (57.0% v. 43.0% for all admissions, p < 0.001; 50.1% v. 49.9% for nonobstetric admissions, p < 0.001). However, fewer women than men were admitted to ICUs (39.9% v. 60.1%, p < 0.001); this difference was most pronounced among older patients (age ≥ 50 years). After adjustment for admission diagnoses and comorbidities, older women were less likely than older men to receive care in an ICU setting (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.66–0.71). After adjustment for illness severity, older women were also less likely than older men to receive mechanical ventilation (OR 0.91, 95% CI 0.81–0.97) or pulmonary artery catheterization (OR 0.80, 95% CI 0.73–0.88). Despite older men and women having similar severity of illness on ICU admission, women received ICU care for a slightly shorter duration yet had a longer length of stay in hospital (mean 18.3 v. 16.9 days; p = 0.006). After adjustment for differences in comorbidities, source of admission, ICU admission diagnosis and illness severity, older women had a slightly greater risk of death in the ICU (hazard ratio 1.20, 95% CI 1.10–1.31) and in hospital (hazard ratio 1.08, 95% CI 1.00–1.16) than did older men. Interpretation: Among patients 50 years or older, women appear less likely than men to be admitted to an ICU and to receive selected life-supporting treatments and more likely than men to die after critical illness. Differences in presentation of critical illness, decision-making or unmeasured confounding factors may contribute to these findings.

A multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial.

CONTEXT Evidence-based practices improve intensive care unit (ICU) outcomes, but eligible patients may not receive them. Community hospitals treat most critically ill patients but may have few resources dedicated to quality improvement. OBJECTIVE To determine the effectiveness of a multicenter quality improvement program to increase delivery of 6 evidence-based ICU practices. DESIGN, SETTING, AND PARTICIPANTS Pragmatic cluster-randomized trial among 15 community hospital ICUs in Ontario, Canada. A total of 9269 admissions occurred during the trial (November 2005 to October 2006) and 7141 admissions during a decay-monitoring period (December 2006 to August 2007). INTERVENTION We implemented a videoconference-based forum including audit and feedback, expert-led educational sessions, and dissemination of algorithms to sequentially improve delivery of 6 practices. We randomized ICUs into 2 groups. Each group received this intervention, targeting a new practice every 4 months, while acting as control for the other group, in which a different practice was targeted in the same period. MAIN MEASURE OUTCOMES: The primary outcome was the summary ratio of odds ratios (ORs) for improvement in adoption (determined by daily data collection) of all 6 practices during the trial in intervention vs control ICUs. RESULTS Overall, adoption of the targeted practices was greater in intervention ICUs than in controls (summary ratio of ORs, 2.79; 95% confidence interval [CI], 1.00-7.74). Improved delivery in intervention ICUs was greatest for semirecumbent positioning to prevent ventilator-associated pneumonia (90.0% of patient-days in last month vs 50.0% in first month; OR, 6.35; 95% CI, 1.85-21.79) and precautions to prevent catheter-related bloodstream infection (70.0% of patients receiving central lines vs 10.6%; OR, 30.06; 95% CI, 11.00-82.17). Adoption of other practices, many with high baseline adherence, changed little. CONCLUSION In a collaborative network of community ICUs, a multifaceted quality improvement intervention improved adoption of care practices. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00332982.