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1.  Corticosteroid therapy in critical illness due to seasonal and pandemic influenza 
Corticosteroids are a powerful class of drugs used to treat several chronic and acute conditions; however, they may be harmful to a subset of critically ill intensive care unit patients with specific conditions. Therefore, understanding the clinical triggers for corticosteroid use in this environment is a quality of care issue. Accordingly, this study used a seasonal influenza outbreak in two Canadian cities to explore the variables associated with corticosteroid use in the intensive care unit.
Survey data suggest that Canadian intensivists administer corticosteroids to critically ill patients primarily in response to airway obstruction, perceived risk for adrenal insufficiency and hemodynamic instability.
To describe variables independently associated with systemic corticosteroid therapy during an influenza outbreak.
The present analysis was retrospective cohort study involving critically ill patients with influenza in two Canadian cities. Hospital records were reviewed for critically ill patients treated in the intensive care units (ICUs) of eight hospitals in Canada during the 2008 to 2009 and 2009 to 2010 influenza outbreaks. Abstracted data included demographic information, symptoms at disease onset, chronic comorbidities and baseline illness severity scores. Corticosteroid use data were extracted for every ICU day and expressed as hydrocortisone dose equivalent in mg. Multivariable regression models were constructed to identify variables independently associated with corticosteroid therapy in the ICU.
The study cohort included 90 patients with a mean (± SD) age of 55.0±17.3 years and Acute Physiology and Chronic Health Evaluation II score of 19.8±8.3. Patients in 2009 to 2010 were younger with more severe lung injury but similar exposure to corticosteroids. Overall, 54% of patients received corticosteroids at a mean daily dose of 343±330 mg of hydrocortisone for 8.5±4.8 days. Variables independently associated with corticosteroid therapy in the ICU were history of airway obstruction (OR 4.8 [95% CI 1.6 to 14.9]) and hemodynamic instability (OR 4.6 [95% CI 1.2 to 17.8]).
Observational data revealed that hemodynamic instability and airway obstruction were associated with corticosteroid therapy in the critical care setting, similar to a recent survey of stated practice. Efforts to determine the effects of corticosteroids in the ICU for these specific clinical situations are warranted.
PMCID: PMC4596649  PMID: 26436911
Cohort study; Corticosteroids; Critical illness; Influenza; Intensive care unit; Pandemic H1N1; Seasonal influenza
3.  The influence of statin exposure on inflammatory markers in patients with early bacterial infection: pilot prospective cohort study 
BMC Anesthesiology  2014;14:106.
In the context of infection, progressive illness resulting in acute organ dysfunction is thought to be secondary to inflammatory response. Our aims were to determine risk factors for progressive illness following infection in a low-risk hospitalised cohort, including the impact of prior stain therapy.
We performed a prospective observational cohort study on two adult acute medical wards of a single tertiary academic hospital. We screened drug prescription charts of all adult acute medical admissions for inclusion criteria of inpatient administration of antibiotics for more than 24 hours for a microbiologically confirmed or clinically suspected infection. Patients were followed until admission to a high dependency unit (HDU) or intensive care unit (ICU), discharge from hospital, or to a maximum of 10 days. Outcomes were evolution of systemic inflammatory response syndrome (SIRS) criteria, white cell count and C-reactive protein measurements, and adverse clinical outcomes. We constructed multivariable models accounting for repeated within-patient measurements to determine associations between a priori selected predictors (days since admission, age, gender, Charlson score, prior statin exposure) and selected outcomes.
We enrolled 209 patients; 27.8% were statin users and the commonest infection was pneumonia (51.0%). Most (88.0%) had at least 1 SIRS criterion on admission, and 76 (37.3%) manifested additional SIRS criteria over time. Risks of admission to HDU/ICU (3.3%) and of 30-day mortality (5.7%) were low. The proportion of patients with at least 1 SIRS criterion, mean CRP, and mean WBC all decreased over time. Multivariable regression models identified days since hospital admission as the only variable associated with daily presence of SIRS criteria, WCC, or CRP (adjusted OR <1 and p < 0.0001 in all analyses). Statin exposure was not a significant predictor.
This cohort of ward patients treated for infection had a low risk of clinical deterioration, inflammatory markers improved over time, and statin exposure was not associated with any outcome. Future larger studies may identify risk factors for progression of illness in this population and plausible surrogate endpoints for evaluation in clinical trials.
PMCID: PMC4256798  PMID: 25484622
Sepsis; Biomarkers; Surrogate end-points; Progression of illness
4.  Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study 
Critical Care  2014;18(6):624.
In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).
We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.
In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 μmol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.
In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0624-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4255668  PMID: 25407408
5.  Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review 
Critical Care  2014;18(5):518.
The understanding of coagulopathies in trauma has increased interest in thromboelastography (TEG®) and thromboelastometry (ROTEM®), which promptly evaluate the entire clotting process and may guide blood product therapy. Our objective was to review the evidence for their role in diagnosing early coagulopathies, guiding blood transfusion, and reducing mortality in injured patients.
We considered observational studies and randomized controlled trials (MEDLINE, EMBASE, and Cochrane databases) to February 2014 that examined TEG®/ROTEM® in adult trauma patients. We extracted data on demographics, diagnosis of early coagulopathies, blood transfusion, and mortality. We assessed methodologic quality by using the Newcastle-Ottawa scale (NOS) for observational studies and QUADAS-2 tool for diagnostic accuracy studies.
Fifty-five studies (12,489 patients) met inclusion criteria, including 38 prospective cohort studies, 15 retrospective cohort studies, two before-after studies, and no randomized trials. Methodologic quality was moderate (mean NOS score, 6.07; standard deviation, 0.49). With QUADAS-2, only three of 47 studies (6.4%) had a low risk of bias in all domains (patient selection, index test, reference standard and flow and timing); 37 of 47 studies (78.8%) had low concerns regarding applicability. Studies investigated TEG®/ROTEM® for diagnosis of early coagulopathies (n = 40) or for associations with blood-product transfusion (n = 25) or mortality (n = 24). Most (n = 52) were single-center studies. Techniques examined included rapid TEG® (n =12), ROTEM® (n = 18), TEG® (n = 23), or both TEG® and rapid TEG® (n = 2). Many TEG®/ROTEM® measurements were associated with early coagulopathies, including some (hypercoagulability, hyperfibrinolysis, platelet dysfunction) not assessed by routine screening coagulation tests. Standard measures of diagnostic accuracy were inconsistently reported. Many abnormalities predicted the need for massive transfusion and death, but predictive performance was not consistently superior to routine tests. One observational study suggested that a ROTEM®-based transfusion algorithm reduced blood-product transfusion, but TEG®/ROTEM®-based resuscitation was not associated with lower mortality in most studies.
Limited evidence from observational data suggest that TEG®/ROTEM® tests diagnose early trauma coagulopathy and may predict blood-product transfusion and mortality in trauma. Effects on blood-product transfusion, mortality, and other patient-important outcomes remain unproven in randomized trials.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0518-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4206701  PMID: 25261079
6.  Inter-hospital transfers and outcomes of critically ill patients with severe acute kidney injury: a multicenter cohort study 
Critical Care  2014;18(5):513.
Patients with severe acute kidney injury (AKI) who are hospitalized at centers that do not provide renal replacement therapy (RRT) are frequently subjected to inter-hospital transfer for the provision of RRT. It is unclear whether such transfers are associated with worse patient outcomes as compared with the receipt of initial care in a center that provides RRT. This study examined the relationship between inter-hospital transfer and 30-day mortality among critically ill patients with AKI who received RRT.
We conducted a retrospective cohort study of all critically ill patients who commenced RRT for AKI at two academic hospitals in Toronto, Canada. The exposure of interest was inter-hospital transfer for the administration of RRT. We evaluated the relationship between transfer status and 30-day mortality (primary outcome) and RRT dependence at 30 days following RRT initiation (secondary outcome), by using multivariate logistic regression with adjustment for patient demographics, clinical factors, biochemical indices, and severity of illness.
Of 370 patients who underwent RRT for AKI, 82 (22.2%) were transferred for this purpose from another hospital. Compared with non-transferred patients who started RRT, transferred patients were younger (61 ± 15 versus 65 ± 15 years, P = 0.03) and had a higher serum creatinine concentration at RRT initiation (474 ± 295 versus 365 ± 169 μmol/L, P = 0.002). Inter-hospital transfer was not associated with mortality (adjusted odds ratio 0.61, 95% confidence interval 0.33 to 1.12) or RRT-dependence (adjusted odds ratio 1.64, 95% confidence interval 0.70 to 3.81) at 30 days.
Within the limitations of this observational study and the potential for residual confounding, inter-hospital transfer of critically ill patients with AKI was not associated with a higher risk of death or dialysis dependence 30 days after the initiation of acute RRT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0513-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4189586  PMID: 25228166
7.  Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRT-AKI): study protocol for a randomized controlled trial 
Trials  2013;14:320.
Acute kidney injury is a common and devastating complication of critical illness, for which renal replacement therapy is frequently needed to manage severe cases. While a recent systematic review suggested that “earlier” initiation of renal replacement therapy improves survival, completed trials are limited due to small size, single-centre status, and use of variable definitions to define “early” renal replacement therapy initiation.
This is an open-label pilot randomized controlled trial. One hundred critically ill patients with severe acute kidney injury will be randomly allocated 1:1 to receive “accelerated” initiation of renal replacement therapy or “standard” initiation at 12 centers across Canada. In the accelerated arm, participants will have a venous catheter placed and renal replacement therapy will be initiated within 12 hours of fulfilling eligibility. In the standard initiation arm, participants will be monitored over 7 days to identify indications for renal replacement therapy. For participants in the standard arm with persistent acute kidney injury, defined as a serum creatinine not declining >50% from the value at the time of eligibility, the initiation of RRT will be discouraged unless one or more of the following criteria are fulfilled: serum potassium ≥6.0 mmol/L; serum bicarbonate ≤10 mmol/L; severe respiratory failure (PaO2/FiO2<200) or persisting acute kidney injury for ≥72 hours after fulfilling eligibility. The inclusion criteria are designed to identify a population of critically ill adults with severe acute kidney injury who are likely to need renal replacement therapy during their hospitalization, but not immediately. The primary outcome is protocol adherence (>90%). Secondary outcomes include measures of feasibility (proportion of eligible patients enrolled in the trial, proportion of enrolled patients followed to 90 days for assessment of vital status and the need for renal replacement therapy) and safety (occurrence of adverse events).
The optimal timing of renal replacement therapy initiation in patients with severe acute kidney injury remains uncertain, representing an important knowledge gap and a priority for high-quality research. This pilot trial is necessary to establish protocol feasibility, confirm the safety of participants and obtain estimated events rates for design of a large definitive trial.
Trial registration number
PMCID: PMC3851593  PMID: 24093950
Acute kidney injury; Critical illness; Dialysis; Hemodialysis; Renal replacement therapy; Critical care
8.  Acute refractory hypoxemia after chest trauma reversed by high-frequency oscillatory ventilation: a case report 
Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart–lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies.
Case presentation
We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient.
High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy.
PMCID: PMC3726508  PMID: 23855954
9.  Acute kidney injury among critically ill patients with pandemic H1N1 influenza A in Canada: cohort study 
BMC Nephrology  2013;14:123.
Canada’s pandemic H1N1 influenza A (pH1N1) outbreak led to a high burden of critical illness. Our objective was to describe the incidence of AKI (acute kidney injury) in these patients and risk factors for AKI, renal replacement therapy (RRT), and mortality.
From a prospective cohort of critically ill adults with confirmed or probable pH1N1 (16 April 2009–12 April 2010), we abstracted data on demographics, co-morbidities, acute physiology, AKI (defined by RIFLE criteria for Injury or Failure), treatments in the intensive care unit, and clinical outcomes. Univariable and multivariable logistic regression analyses were used to evaluate the associations between clinical characteristics and the outcomes of AKI, RRT, and hospital mortality.
We included 562 patients with pH1N1-related critical illness (479 [85.2%] confirmed, 83 [14.8%] probable]: mean age 48.0 years, 53.4% female, and 13.3% aboriginal. Common co-morbidities included obesity, diabetes, and chronic obstructive pulmonary disease. AKI occurred in 60.9%, with RIFLE categories of Injury (23.0%) and Failure (37.9%). Independent predictors of AKI included obesity (OR 2.94; 95%CI, 1.75-4.91), chronic kidney disease (OR 4.50; 95%CI, 1.46-13.82), APACHE II score (OR per 1-unit increase 1.06; 95%CI, 1.03-1.09), and PaO2/FiO2 ratio (OR per 10-unit increase 0.98; 95%CI, 0.95-1.00). Of patients with AKI, 24.9% (85/342) received RRT and 25.8% (85/329) died. Independent predictors of RRT were obesity (OR 2.25; 95% CI, 1.14-4.44), day 1 mechanical ventilation (OR 4.09; 95% CI, 1.21-13.84), APACHE II score (OR per 1-unit increase 1.07; 95% CI, 1.03-1.12), and day 1 creatinine (OR per 10 μmol/L increase, 1.06; 95%CI, 1.03-1.10). Development of AKI was not independently associated with hospital mortality.
The incidence of AKI and RRT utilization were high among Canadian patients with critical illness due to pH1N1.
PMCID: PMC3694036  PMID: 23763900
Acute kidney injury; Renal replacement therapy; Influenza; Critical illness; Mortality; Resource utilization
10.  Co-enrollment of critically ill patients into multiple studies: patterns, predictors and consequences 
Critical Care  2013;17(1):R1.
Research on co-enrollment practices and their impact are limited in the ICU setting. The objectives of this study were: 1) to describe patterns and predictors of co-enrollment of patients in a thromboprophylaxis trial, and 2) to examine the consequences of co-enrollment on clinical and trial outcomes.
In an observational analysis of an international thromboprophylaxis trial in 67 ICUs, we examined the co-enrollment of critically ill medical-surgical patients into more than one study, and examined the clinical and trial outcomes among co-enrolled and non-co-enrolled patients.
Among 3,746 patients enrolled in PROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial), 713 (19.0%) were co-enrolled in at least one other study (53.6% in a randomized trial, 37.0% in an observational study and 9.4% in both). Six factors independently associated with co-enrollment (all P < 0.001) were illness severity (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.19 to 1.53 for each 10-point Acute Physiology and Chronic Health Evaluation (APACHE) II score increase), substitute decision-makers providing consent, rather than patients (OR 3.31, 2.03 to 5.41), experience of persons inviting consent (OR 2.67, 1.74 to 4.11 for persons with > 10 years' experience compared to persons with none), center size (all ORs > 10 for ICUs with > 15 beds), affiliation with trials groups (OR 5.59, 3.49 to 8.95), and main trial rather than pilot phase (all ORs > 8 for recruitment year beyond the pilot). Co-enrollment did not influence clinical or trial outcomes or risk of adverse events.
Co-enrollment was strongly associated with features of the patients, research personnel, setting and study. Co-enrollment had no impact on trial results, and appeared safe, acceptable and feasible. Transparent reporting, scholarly discourse, ethical analysis and further research are needed on the complex topic of co-enrollment during critical illness.
PMCID: PMC4056073  PMID: 23298553
11.  Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI) - a pilot randomized controlled trial of hemofiltration versus hemodialysis: a Canadian Critical Care Trials Group project 
Critical Care  2012;16(5):R205.
Among critically ill patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT), the effect of convective (via continuous venovenous hemofiltration [CVVH]) versus diffusive (via continuous venovenous hemodialysis [CVVHD]) solute clearance on clinical outcomes is unclear. Our objective was to evaluate the feasibility of comparing these two modes in a randomized trial.
This was a multicenter open-label parallel-group pilot randomized trial of CVVH versus CVVHD. Using concealed allocation, we randomized critically ill adults with AKI and hemodynamic instability to CVVH or CVVHD, with a prescribed small solute clearance of 35 mL/kg/hour in both arms. The primary outcome was trial feasibility, defined by randomization of >25% of eligible patients, delivery of >75% of the prescribed CRRT dose, and follow-up of >95% of patients to 60 days. A secondary analysis using a mixed-effects model examined the impact of therapy on illness severity, defined by sequential organ failure assessment (SOFA) score, over the first week.
We randomized 78 patients (mean age 61.5 years; 39% women; 23% with chronic kidney disease; 82% with sepsis). Baseline SOFA scores (mean 15.9, SD 3.2) were similar between groups. We recruited 55% of eligible patients, delivered >80% of the prescribed dose in each arm, and achieved 100% follow-up. SOFA tended to decline more over the first week in CVVH recipients (-0.8, 95% CI -2.1, +0.5) driven by a reduction in vasopressor requirements. Mortality (54% CVVH; 55% CVVHD) and dialysis dependence in survivors (24% CVVH; 19% CVVHD) at 60 days were similar.
Our results suggest that a large trial comparing CVVH to CVVHD would be feasible. There is a trend toward improved vasopressor requirements among CVVH-treated patients over the first week of treatment.
Trial Registration NCT00675818
PMCID: PMC3682309  PMID: 23095370
12.  Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis 
Critical Care  2012;16(4):R146.
The objective of this systematic review and meta-analysis was to determine the effect of renal replacement therapy (RRT), delivered as hemofiltration vs. hemodialysis, on clinical outcomes in patients with acute kidney injury (AKI).
MEDLINE, EMBASE and CENTRAL databases and conference abstracts were searched to June 2012 for parallel-group or crossover randomized and quasi-randomized controlled trials (RCTs) evaluating hemofiltration vs. hemodialysis in patients with AKI. Two authors independently selected studies and abstracted data on study quality and outcomes. Additional information was obtained from trial authors. We pooled data using random-effects models.
Of 6,657 citations, 19 RCTs (10 parallel-group and 9 crossover) met inclusion criteria. Sixteen trials used continuous RRT. Study quality was variable. The primary analysis included three parallel-group trials comparing similar doses of hemofiltration and hemodialysis; sensitivity analyses included trials comparing combined hemofiltration-hemodialysis or dissimilar doses. We found no effect of hemofiltration on mortality (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.73 to 1.25, P = 0.76; three trials, n = 121 (primary analysis); RR 1.10, 95% CI 0.88 to 1.38, P = 0.38; eight trials, n = 540 (sensitivity analysis)) or other clinical outcomes (RRT dependence in survivors, vasopressor use, organ dysfunction) compared to hemodialysis. Hemofiltration appeared to shorten time to filter failure (mean difference (MD) -7 hours, 95% CI (-19,+5), P = 0.24; two trials, n = 50 (primary analysis); MD -5 hours, 95% CI (-10, -1), P = 0.01; three trials, n = 113 (including combined hemofiltration-hemodialysis trials comparing similar doses); MD -6 hours, 95% CI (-10, -1), P = 0.02; five trials, n = 383 (sensitivity analysis)). Data primarily from crossover RCTs suggested that hemofiltration increased clearance of medium to larger molecules, including inflammatory cytokines, compared to hemodialysis, although almost no studies measured changes in serum concentrations. Meta-analyses were based on very limited data.
Data from small RCTs do not suggest beneficial clinical outcomes from hemofiltration, but confidence intervals were wide. Hemofiltration may increase clearance of medium to larger molecules. Larger trials are required to evaluate effects on clinical outcomes.
PMCID: PMC3580734  PMID: 22867021
13.  The effect of telemedicine in critically ill patients: systematic review and meta-analysis 
Critical Care  2012;16(4):R127.
Telemedicine extends intensivists' reach to critically ill patients cared for by other physicians. Our objective was to evaluate the impact of telemedicine on patients' outcomes.
We searched electronic databases through April 2012, bibliographies of included trials, and indexes and conference proceedings in two journals (2001 to 2012). We selected controlled trials or observational studies of critically ill adults or children, examining the effects of telemedicine on mortality. Two authors independently selected studies and extracted data on outcomes (mortality and length of stay in the intensive care unit (ICU) and hospital) and methodologic quality. We used random-effects meta-analytic models unadjusted for case mix or cluster effects and quantified between-study heterogeneity by using I2 (the percentage of total variability across studies attributable to heterogeneity rather than to chance).
Of 865 citations, 11 observational studies met selection criteria. Overall quality was moderate (mean score on Newcastle-Ottawa scale, 5.1/9; range, 3 to 9). Meta-analyses showed that telemedicine, compared with standard care, is associated with lower ICU mortality (risk ratio (RR) 0.79; 95% confidence interval (CI), 0.65 to 0.96; nine studies, n = 23,526; I2 = 70%) and hospital mortality (RR, 0.83; 95% CI, 0.73 to 0.94; nine studies, n = 47,943; I2 = 72%). Interventions with continuous patient-data monitoring, with or without alerts, reduced ICU mortality (RR, 0.78; 95% CI, 0.64 to 0.95; six studies, n = 21,384; I2 = 74%) versus those with remote intensivist consultation only (RR, 0.64; 95% CI, 0.20 to 2.07; three studies, n = 2,142; I2 = 71%), but effects were statistically similar (interaction P = 0.74). Effects were also similar in higher (RR, 0.83; 95% CI, 0.68 to 1.02) versus lower (RR, 0.69; 95% CI, 0.40 to 1.19; interaction, P = 0.53) quality studies. Reductions in ICU and hospital length of stay were statistically significant (weighted mean difference (telemedicine-control), -0.62 days; 95% CI, -1.21 to -0.04 days and -1.26 days; 95% CI, -2.49 to -0.03 days, respectively; I2 > 90% for both).
Telemedicine was associated with lower ICU and hospital mortality among critically ill patients, although effects varied among studies and may be overestimated in nonrandomized designs. The optimal telemedicine technology configuration and dose tailored to ICU organization and case mix remain unclear.
PMCID: PMC3580710  PMID: 22809335
14.  Routine chest x-rays in intensive care units: a systematic review and meta-analysis 
Critical Care  2012;16(2):R68.
Chest x-rays (CXRs) are the most frequent radiological tests performed in the intensive care unit (ICU). However, the utility of performing daily routine CXRs is unclear.
We searched Medline and Embase (1948 to March 2011) for randomized and quasi-randomized controlled trials (RCTs) and before-after observational studies comparing a strategy of routine CXRs to a more restrictive approach with CXRs performed to investigate clinical changes among critically ill adults or children. In duplicate, we extracted data on the CXR strategy, study quality and clinical outcomes (ICU and hospital mortality; duration of mechanical ventilation and ICU and hospital stay).
Nine studies (39,358 CXRs; 9,611 patients) were included in the meta-analysis. Three trials (N = 870) of moderate to good quality provided information on the safety of a restrictive routine CXR strategy; only one trial systematically assessed for missed findings. Pooled data from trials showed no evidence of effect of a restrictive approach on ICU mortality (risk ratio [RR] 1.04, 95% confidence interval [CI] 0.84 to 1.28, P = 0.72; two trials, N = 776), hospital mortality (RR 0.98, 95% CI 0.68 to 1.41, P = 0.91; two trials, N = 259), ICU length of stay (weighted mean difference [WMD] -0.86 days, 95% CI -2.38 to 0.66 days, P = 0.27; three trials, N = 870), hospital length of stay (WMD -2.50 days, 95% CI -6.62 to 1.61 days, P = 0.23; two trials, N = 259), or duration of mechanical ventilation (WMD -0.30 days, 95% CI -1.48 to 0.89 days, P = 0.62; three trials, N = 705). Adding data from six observational studies, one of which systematically screened for missed findings, gave similar results.
This meta-analysis did not detect any harm associated with a restrictive chest radiograph strategy. However, confidence intervals were wide and harm was not rigorously assessed. Therefore, the safety of abandoning routine CXRs in patients admitted to the ICU remains uncertain.
PMCID: PMC3681397  PMID: 22541022
15.  Critical care resources in the Solomon Islands: a cross-sectional survey 
There are minimal data available on critical care case-mix, care processes and outcomes in lower and middle income countries (LMICs). The objectives of this paper were to gather data in the Solomon Islands in order to gain a better understanding of common presentations of critical illness, available hospital resources, and what resources would be helpful in improving the care of these patients in the future.
This study used a mixed methods approach, including a cross sectional survey of respondents' opinions regarding critical care needs, ethnographic information and qualitative data.
The four most common conditions leading to critical illness in the Solomon Islands are malaria, diseases of the respiratory system including pneumonia and influenza, diabetes mellitus and tuberculosis. Complications of surgery and trauma less frequently result in critical illness. Respondents emphasised the need for basic critical care resources in LMICs, including equipment such as oximeters and oxygen concentrators; greater access to medications and blood products; laboratory services; staff education; and the need for at least one national critical care facility.
A large degree of critical illness in LMICs is likely due to inadequate resources for primary prevention and healthcare; however, for patients who fall through the net of prevention, there may be simple therapies and context-appropriate resources to mitigate the high burden of morbidity and mortality. Emphasis should be on the development and acquisition of simple and inexpensive tools rather than complicated equipment, to prevent critical care from unduly diverting resources away from other important parts of the health system.
PMCID: PMC3307438  PMID: 22376229
Critical care; Critical illness; Solomon Islands; Lower and middle income countries
16.  Does intensive insulin therapy really reduce mortality in critically ill surgical patients? A reanalysis of meta-analytic data 
Critical Care  2010;14(5):324.
Two recent systematic reviews evaluating intensive insulin therapy (IIT) in critically ill patients grouped randomized controlled trials (RCTs) by type of intensive care unit (ICU). The more recent review found that IIT reduced mortality in patients admitted to a surgical ICU, but not in those admitted to medical ICUs or mixed medical-surgical ICUs, or in all patients combined. Our objective was to determine whether IIT saves lives in critically ill surgical patients regardless of the type of ICU. Pooling mortality data from surgical and medical subgroups in mixed-ICU RCTs (16 trials) with RCTs conducted exclusively in surgical ICUs (five trials) and in medical ICUs (five trials), respectively, showed no effect of IIT in the subgroups of surgical patients (risk ratio = 0.85, 95% confidence interval (CI) = 0.69 to 1.04, P = 0.11; I2 = 51%, 95% CI = 1 to 75%) or of medical patients (risk ratio = 1.02, 95% CI = 0.95 to 1.09, P = 0.61; I2 = 0%, 95% CI = 0 to 41%). There was no differential effect between subgroups (interaction P = 0.10). There was statistical heterogeneity in the surgical subgroup, with some trials demonstrating significant benefit and others demonstrating significant harm, but no surgical subgroup consistently benefited from IIT. Such a reanalysis suggests that IIT does not reduce mortality in critically ill surgical patients or medical patients. Further insights may come from individual patient data meta-analyses or from future large multicenter RCTs in more narrowly defined subgroups of surgical patients.
PMCID: PMC3219247  PMID: 21062514
17.  Statins do not prevent acute organ failure in ventilated ICU patients: single-centre retrospective cohort study 
Critical Care  2011;15(1):R74.
Observational studies suggest statin therapy reduces incident sepsis, but few studies have examined the impact on new organ failure. We tested the hypothesis that statin therapy, administered for standard clinical indications to ventilated intensive care unit patients, prevents acute organ failure without harming the liver.
We performed a retrospective, single-centre cohort study in a tertiary mixed medical/surgical intensive care unit. Mechanically ventilated patients without nonrespiratory organ failure within 24 hours after admission were assessed (during the first 15 days) for new acute organ failure (defined as Sequential Organ Failure Assessment (SOFA) score 3 or 4), liver failure (defined as new hepatic SOFA ≥3, or a 1.5 times increase of bilirubin from baseline to a value ≥20 mmol/l), and alanine transferase (ALT) > 165 IU/l. The effect of statin administration was explored in generalised linear mixed models.
A total of 1,397 patients were included. Two hundred and nineteen patients received a median (interquartile range) of three (two, eight) statin doses. Patients receiving statins were older (67.4 vs. 55.5 years, P < 0.0001), less likely female (25.1% vs. 37.9%, P = 0.0003) and sicker (Acute Physiology and Chronic Health Evaluation (APACHE) II score 20.3 vs. 17.8, P < 0.0001). Considering outcome events at least 1 day after statin administration, statin patients were equally likely to develop acute organ failure (28.4% vs. 22.3%, P = 0.29) and hepatic failure (9.5% vs. 7.6%, P = 0.34), but were more likely to experience an ALT increase to > 165 IU/l ((11.2% vs. 4.8%, P = 0.0005). Multivariable analysis showed that APACHE II score (odds ratio (OR) = 1.05 per point; 95% confidence interval (CI) = 1.03 to 1.07) and APACHE II admission category (P < 0.0001), but not statin administration (OR = 1.21; 95% CI = 0.92 to 1.62), were significantly associated with acute organ failure occurring on or after the day of first statin administration. Statin administration was not associated with liver impairment (OR = 1.08; 95% CI = 0.66 to 1.77) but was associated with a rise in ALT > 165 IU/l (OR = 2.25; 95% CI = 1.32 to 3.84), along with APACHE II score (P = 0.016) and admission ALT (P = 0.0001).
Concurrent statin therapy does not appear to protect against the development of new acute organ failure in critically ill, ventilated patients. The lack of effect may be due to residual confounding, a relatively low number of doses received, or an absence of true effect. Randomised controlled trials are needed to confirm a protective effect.
PMCID: PMC3222007  PMID: 21356051
18.  Utility and safety of draining pleural effusions in mechanically ventilated patients: a systematic review and meta-analysis 
Critical Care  2011;15(1):R46.
Pleural effusions are frequently drained in mechanically ventilated patients but the benefits and risks of this procedure are not well established.
We performed a literature search of multiple databases (MEDLINE, EMBASE, HEALTHSTAR, CINAHL) up to April 2010 to identify studies reporting clinical or physiological outcomes of mechanically ventilated critically ill patients who underwent drainage of pleural effusions. Studies were adjudicated for inclusion independently and in duplicate. Data on duration of ventilation and other clinical outcomes, oxygenation and lung mechanics, and adverse events were abstracted in duplicate independently.
Nineteen observational studies (N = 1,124) met selection criteria. The mean PaO2:FiO2 ratio improved by 18% (95% confidence interval (CI) 5% to 33%, I2 = 53.7%, five studies including 118 patients) after effusion drainage. Reported complication rates were low for pneumothorax (20 events in 14 studies including 965 patients; pooled mean 3.4%, 95% CI 1.7 to 6.5%, I2 = 52.5%) and hemothorax (4 events in 10 studies including 721 patients; pooled mean 1.6%, 95% CI 0.8 to 3.3%, I2 = 0%). The use of ultrasound guidance (either real-time or for site marking) was not associated with a statistically significant reduction in the risk of pneumothorax (OR = 0.32; 95% CI 0.08 to 1.19). Studies did not report duration of ventilation, length of stay in the intensive care unit or hospital, or mortality.
Drainage of pleural effusions in mechanically ventilated patients appears to improve oxygenation and is safe. We found no data to either support or refute claims of beneficial effects on clinically important outcomes such as duration of ventilation or length of stay.
PMCID: PMC3221976  PMID: 21288334
19.  Statin research in critical illness: hampered by poor trial design? 
Critical Care  2009;13(6):1015.
Statin therapy may prevent an excessive inflammatory response after cardiopulmonary bypass for cardiac surgery. In a recent issue of Critical Care, Morgan and colleagues present data from a well-conducted systematic review and meta-analysis of randomised controlled trials using inflammatory markers as primary outcome measure. They find that pre-operative statin therapy, compared with placebo, may reduce various post-operative markers of systemic inflammation (IL-6, IL-8, C-reactive protein, tumour necrosis factor-alpha). Their ability to make definitive conclusions is limited, however, by the suboptimal methodological quality of the primary studies. Their review suggests that ICU researchers should focus on developing valid surrogate markers and use these to accurately describe the mechanisms and effectiveness of novel therapies before proceeding to large pragmatic trials using mortality as primary outcome.
PMCID: PMC2811942  PMID: 20017899
20.  Clinical review: Critical care in the global context – disparities in burden of illness, access, and economics 
Critical Care  2008;12(5):225.
World health care expenditures exceed US $4 trillion. However, there is marked variation in global health care spending, from upwards of US $7,000 per capita in the US to under US $25 per capita in most of sub-Saharan Africa. In developed countries, care of the critically ill comprises a large proportion of health care spending; however, in developing countries, with a greater burden of both illness and critical illness, there is little infrastructure to provide care for these patients. There is sparse research to inform the needs of critically ill patients, but often basic requirements such as trained personnel, medications, oxygen, diagnostic and therapeutic equipment, reliable power supply, and safe transportation are unavailable. Why should this be a focus of intensivists of the developed world? Nearly all of those dying in developing countries would be our patients without the accident of latitude. Tailored to the needs of the region, the provision of critical care has a role, even in the context of limited preventive and primary care. Internationally and locally driven solutions are needed. We can help by recognizing the '10/90 gap' that is pervasive within global health care and our profession by educating ourselves of needs, contacting and collaborating with colleagues in the developing world, and advocating that our professional societies and funding agencies consider an increasingly global perspective in education and research.
PMCID: PMC2592728  PMID: 19014409
21.  Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2) 
Trials  2009;10:49.
Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit.
We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.
Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases.
A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.
PMCID: PMC2723099  PMID: 19580665
22.  An innovative telemedicine knowledge translation program to improve quality of care in intensive care units: protocol for a cluster randomized pragmatic trial 
There are challenges to timely adoption of, and ongoing adherence to, evidence-based practices known to improve patient care in the intensive care unit (ICU). Quality improvement initiatives using a collaborative network approach may increase the use of such practices. Our objective is to evaluate the effectiveness of a novel knowledge translation program for increasing the proportion of patients who appropriately receive the following six evidence-based care practices: venous thromboembolism prophylaxis; ventilator-associated pneumonia prevention; spontaneous breathing trials; catheter-related bloodstream infection prevention; decubitus ulcer prevention; and early enteral nutrition.
Methods and design
We will conduct a pragmatic cluster randomized active control trial in 15 community ICUs and one academic ICU in Ontario, Canada. The intervention is a multifaceted videoconferenced educational and problem-solving forum to organize knowledge translation strategies, including comparative audit and feedback, educational sessions from content experts, and dissemination of algorithms. Fifteen individual ICUs (clusters) will be randomized to receive quality improvement interventions targeting one of the best practices during each of six study phases. Each phase lasts four months during the first study year and three months during the second. At the end of each study phase, ICUs are assigned to an intervention for a best practice not yet received according to a random schedule. The primary analysis will use patient-level process-of-care data to measure the intervention's effect on rates of adoption and adherence of each best practice in the targeted ICU clusters versus controls.
This study design evaluates a new system for knowledge translation and quality improvement across six common ICU problems. All participating ICUs receive quality improvement initiatives during every study phase, improving buy-in. This study design could be considered for other quality improvement interventions and in other care settings.
Trial Registration
This trial is registered with (ID #: NCT00332982)
PMCID: PMC2649891  PMID: 19220893
23.  Rosiglitazone: can meta-analysis accurately estimate excess cardiovascular risk given the available data? Re-analysis of randomized trials using various methodologic approaches 
BMC Research Notes  2009;2:5.
A recent and provocative meta-analysis, based on few outcome events, suggested that rosiglitazone increased cardiovascular mortality and myocardial infarction. However, results of meta-analyses of trials with sparse events, often performed when examining uncommon adverse effects due to common therapies, can vary substantially depending on methodologic decisions. The objective of this study was to assess the robustness of the rosiglitazone results by using alternative reasonable methodologic approaches and by analyzing additional related outcomes.
In duplicate and independently, we abstracted all myocardial and cerebrovascular ischemic events from all randomized controlled trials listed on the manufacturer's web site meeting inclusion criteria of the original meta-analysis (at least 24 weeks of rosiglitazone exposure in the intervention group and any control group without rosiglitazone). We performed meta-analyses of these data under different methodologic conditions. An unconfounded comparison that includes only trials (or arms of trials) in which medications apart from rosiglitazone are identical suggests higher risks than previously reported, making even the risk of cardiovascular death statistically significant. Alternatively, meta-analysis that includes all trials comparing a treatment arm receiving rosiglitazone to any control arm without rosiglitazone (as in the original meta-analysis) but also including trials with no events in both the rosiglitazone and control arms (not incorporated in the original meta-analysis), shows adverse but non-statistically significant effects of rosiglitazone on myocardial infarction and cardiovascular mortality. Rosiglitazone appears to have inconsistent effects on a wider range of cardiovascular outcomes. It increases the risk of a broad range of myocardial ischemic events (not just myocardial infarction). However, its effect on cerebrovascular ischemic events suggests benefit, although far from statistically significant.
We have shown that alternative reasonable methodological approaches to the rosiglitazone meta-analysis can yield increased or decreased risks that are either statistically significant or not significant at the p = 0.05 level for both myocardial infarction and cardiovascular death. Completion of ongoing trials may help to generate more accurate estimates of rosiglitazone's effect on cardiovascular outcomes. However, given that almost all point estimates suggest harm rather than benefit and the availability of alternative agents, the use of rosiglitazone may greatly decline prior to more definitive safety data being generated.
PMCID: PMC2649945  PMID: 19134216
24.  The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: A simulation study 
Meta-analysis of continuous outcomes traditionally uses mean difference (MD) or standardized mean difference (SMD; mean difference in pooled standard deviation (SD) units). We recently used an alternative ratio of mean values (RoM) method, calculating RoM for each study and estimating its variance by the delta method. SMD and RoM allow pooling of outcomes expressed in different units and comparisons of effect sizes across interventions, but RoM interpretation does not require knowledge of the pooled SD, a quantity generally unknown to clinicians.
Objectives and methods
To evaluate performance characteristics of MD, SMD and RoM using simulated data sets and representative parameters.
MD was relatively bias-free. SMD exhibited bias (~5%) towards no effect in scenarios with few patients per trial (n = 10). RoM was bias-free except for some scenarios with broad distributions (SD 70% of mean value) and medium-to-large effect sizes (0.5–0.8 pooled SD units), for which bias ranged from -4 to 2% (negative sign denotes bias towards no effect). Coverage was as expected for all effect measures in all scenarios with minimal bias. RoM scenarios with bias towards no effect exceeding 1.5% demonstrated lower coverage of the 95% confidence interval than MD (89–92% vs. 92–94%). Statistical power was similar. Compared to MD, simulated heterogeneity estimates for SMD and RoM were lower in scenarios with bias because of decreased weighting of extreme values. Otherwise, heterogeneity was similar among methods.
Simulation suggests that RoM exhibits comparable performance characteristics to MD and SMD. Favourable statistical properties and potentially simplified clinical interpretation justify the ratio of means method as an option for pooling continuous outcomes.
PMCID: PMC2430201  PMID: 18492289
25.  Survey of information technology in Intensive Care Units in Ontario, Canada 
The Intensive Care Unit (ICU) is a data-rich environment where information technology (IT) may enhance patient care. We surveyed ICUs in the province of Ontario, Canada, to determine the availability, implementation and variability of information systems.
A self-administered internet-based survey was completed by ICU directors between May and October 2006. We measured the spectrum of ICU clinical data accessible electronically, the availability of decision support tools, the availability of electronic imaging systems for radiology, the use of electronic order entry and medication administration systems, and the availability of hardware and wireless or mobile systems. We used Fisher's Exact tests to compare IT availability and Classification and Regression Trees (CART) to estimate the optimal cut-point for the number of computers per ICU bed.
We obtained responses from 50 hospitals (68.5% of institutions with level 3 ICUs), of which 21 (42%) were university-affiliated. The majority electronically accessed laboratory data and imaging reports (92%) and used picture archiving and communication systems (PACS) (76%). Other computing functions were less prevalent (medication administration records 46%, physician or nursing notes 26%; medication order entry 22%). No association was noted between IT availability and ICU size or university affiliation. Sites used clinical information systems from15 different vendors and 8 different PACS systems were in use. Half of the respondents described the number of computers available as insufficient. Wireless networks and mobile computing systems were used in 23 ICUs (46%).
Ontario ICUs demontrate a high prevalence of the use of basic information technology systems. However, implementation of the more complex and potentially more beneficial applications is low. The wide variation in vendors utilized may impair information exchange, interoperability and uniform data collection.
PMCID: PMC2233621  PMID: 18218117

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