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1.  Factors Affecting Family Satisfaction with Inpatient End-of-Life Care 
PLoS ONE  2014;9(11):e110860.
Background
Little data exists addressing satisfaction with end-of-life care among hospitalized patients, as they and their family members are systematically excluded from routine satisfaction surveys. It is imperative that we closely examine patient and institution factors associated with quality end-of-life care and determine high-priority target areas for quality improvement.
Methods
Between September 1, 2010 and January 1, 2012 the Canadian Health care Evaluation Project (CANHELP) Bereavement Questionnaire was mailed to the next-of-kin of recently deceased inpatients to seek factors associated with satisfaction with end-of-life care. The primary outcome was the global rating of satisfaction. Secondary outcomes included rates of actual versus preferred location of death, associations between demographic factors and global satisfaction, and identification of targets for quality improvement.
Results
Response rate was 33% among 275 valid addresses. Overall, 67.4% of respondents were very or completely satisfied with the overall quality of care their relative received. However, 71.4% of respondents who thought their relative did not die in their preferred location favoured an out-of-hospital location of death. A common location of death was the intensive care unit (45.7%); however, this was not the preferred location of death for 47.6% of such patients. Multivariate Poisson regression analysis showed respondents who believed their relative died in their preferred location were 1.7 times more likely to be satisfied with the end-of-life care that was provided (p = 0.001). Items identified as high-priority targets for improvement included: relationships with, and characteristics of health care professionals; illness management; communication; and end-of-life decision-making.
Interpretation
Nearly three-quarters of recently deceased inpatients would have preferred an out-of-hospital death. Intensive care units were a common, but not preferred, location of in-hospital deaths. Family satisfaction with end-of-life care was strongly associated with their relative dying in their preferred location. Improved communication regarding end-of-life care preferences should be a high-priority quality improvement target.
doi:10.1371/journal.pone.0110860
PMCID: PMC4234251  PMID: 25401710
2.  Duration of antibiotic therapy for critically ill patients with bloodstream infections: A retrospective cohort study 
BACKGROUND:
The optimal duration of antibiotic treatment for bloodstream infections is unknown and understudied.
METHODS:
A retrospective cohort study of critically ill patients with bloodstream infections diagnosed in a tertiary care hospital between March 1, 2010 and March 31, 2011 was undertaken. The impact of patient, pathogen and infectious syndrome characteristics on selection of shorter (≤10 days) or longer (>10 days) treatment duration, and on the number of antibiotic-free days, was examined. The time profile of clinical response was evaluated over the first 14 days of treatment. Relapse, secondary infection and mortality rates were compared between those receiving shorter or longer treatment.
RESULTS:
Among 100 critically ill patients with bloodstream infection, the median duration of antibiotic treatment was 11 days, but was highly variable (interquartile range 4.5 to 17 days). Predictors of longer treatment (fewer antibiotic-free days) included foci with established requirements for prolonged treatment, underlying respiratory tract focus, and infection with Staphylococcus aureus or Pseudomonas species. Predictors of shorter treatment (more antibiotic-free days) included vascular catheter source and bacteremia with coagulase-negative staphylococci. Temperature improvements plateaued after the first week; white blood cell counts, multiple organ dysfunction scores and vasopressor dependence continued to decline into the second week. Among 72 patients who survived to 10 days, clinical outcomes were similar between those receiving shorter and longer treatment.
CONCLUSION:
Antibiotic treatment durations for patients with bloodstream infection are highly variable and often prolonged. A randomized trial is needed to determine the duration of treatment that will maximize cure while minimizing adverse consequences of antibiotics.
PMCID: PMC3852449  PMID: 24421823
Antibacterials; Antibiotic stewardship; Bacteremia; Bacterial infections; Critical care
3.  SodiUm SeleniTe Adminstration IN Cardiac Surgery (SUSTAIN CSX-trial): study design of an international multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients 
Trials  2014;15(1):339.
Background
Cardiac surgery has been shown to result in a significant decrease of the antioxidant selenium, which is associated with the development of multiorgan dysfunction and increased mortality. Thus, a large-scale study is needed to investigate the effect of perioperative selenium supplementation on the occurrence of postoperative organ dysfunction.
Methods/Design
We plan a prospective, randomized double-blind, multicenter controlled trial, which will be conducted in North and South America and in Europe. In this trial we will include 1,400 high-risk patients, who are most likely to benefit from selenium supplementation. This includes patients scheduled for non-emergent combined and/or complex procedures, or with a predicted operative mortality of ≥5% according to the EuroSCORE II. Eligible patients will be randomly assigned to either the treatment group (bolus infusion of 2,000 μg sodium selenite immediately prior to surgery, followed by an additional dosage of 2,000 μg at ICU admission, and a further daily supplementation of 1,000 μg up to 10 days or ICU discharge) or to the control group (placebo administration at the same time points).
The primary endpoint of this study is a composite of 'persistent organ dysfunction’ (POD) and/or death within 30 days from surgery (POD + death). POD is defined as any need for life-sustaining therapies (mechanical ventilation, vasopressor therapy, mechanical circulatory support, continuous renal replacement therapy, or new intermittent hemodialysis) at any time within 30 days from surgery.
Discussion
The SUSTAIN-CSX™ study is a multicenter trial to investigate the effect of a perioperative high dosage sodium selenite supplementation in high-risk cardiac surgical patients.
Trial registration
This trial was registered at Clinicaltrials.gov (identifier: NCT02002247) on 28 November 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-339) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-339
PMCID: PMC4247649  PMID: 25169040
Selenium; Inflammatory response; Oxidative stress; Antioxidant capacity; Myocardial ischemia/reperfusion; Postoperative organ failure
5.  Intracranial Pressure Monitoring in Severe Traumatic Brain Injury: Results from the American College of Surgeons Trauma Quality Improvement Program 
Journal of Neurotrauma  2013;30(20):1737-1746.
Abstract
Although existing guidelines support the utilization of intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI), the evidence suggesting benefit is limited. To evaluate the impact on outcome, we determined the relationship between ICP monitoring and mortality in centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). Data on 10,628 adults with severe TBI were derived from 155 TQIP centers over 2009–2011. Random-intercept multilevel modeling was used to evaluate the association between ICP monitoring and mortality after adjusting for important confounders. We evaluated this relationship at the patient level and at the institutional level. Overall mortality (n=3769) was 35%. Only 1874 (17.6%) patients underwent ICP monitoring, with a mortality of 32%. The adjusted odds ratio (OR) for mortality was 0.44 [95% confidence interval (CI), 0.31–0.63], when comparing patients with ICP monitoring to those without. It is plausible that patients receiving ICP monitoring were selected because of an anticipated favorable outcome. To overcome this limitation, we stratified hospitals into quartiles based on ICP monitoring utilization. Hospitals with higher rates of ICP monitoring use were associated with lower mortality: The adjusted OR of death was 0.52 (95% CI, 0.35–0.78) in the quartile of hospitals with highest use, compared to the lowest. ICP monitoring utilization rates explained only 9.9% of variation in mortality across centers. Results were comparable irrespective of the method of case-mix adjustment. In this observational study, ICP monitoring utilization was associated with lower mortality. However, variability in ICP monitoring rates contributed only modestly to variability in institutional mortality rates. Identifying other institutional practices that impact on mortality is an important area for future research.
doi:10.1089/neu.2012.2802
PMCID: PMC3796332  PMID: 23731257
head injury; intracranial pressure; multilevel analysis; traumatic brain injury
6.  Early observational research and registries during the 2009–2010 influenza A pandemic 
Critical care medicine  2010;38(4 0):e120-e132.
As a critical care community, we have an obligation to provide not only clinical care but also the research that guides initial and subsequent clinical responses during a pandemic. There are many challenges to conducting such research. The first is speed of response. However, given the near inevitability of certain events, for example, viral respiratory illness such as the 2009 pandemic, geographically circumscribed natural disasters, or acts of terror, many study and trial designs should be preplanned and modified quickly when specific events occur. Template case report forms should be available for modification and web entry; centralized research ethics boards and funders should have the opportunity to preview and advise on such research beforehand; and national and international research groups should be prepared to work together on common studies and trials for common challenges. We describe the early international critical care research response to the influenza A 2009 (H1N1) pandemic, including specifics of observational study case report form, registry, and clinical trial design, cooperation of international critical care research organizations, and the early results of these collaborations.
doi:10.1097/CCM.0b013e3181d20c77
PMCID: PMC3705715  PMID: 20101176
critical care; intensive care; registry; H1N1; influenza; pandemic
7.  Medication utilization patterns among type 2 diabetes patients initiating Exenatide BID or insulin glargine: a retrospective database study 
Background
Type 2 diabetes is a common and costly illness, associated with significant morbidity and mortality. Despite this, there is relatively little information on the ‘real-world’ medication utilization patterns for patients with type 2 diabetes initiating exenatide BID or glargine. The objective of this study was to evaluate the ‘real-world’ medication utilization patterns in patients with type 2 diabetes treated with exenatide BID (exenatide) versus insulin glargine (glargine).
Methods
Adult patients( ≥18 years of age) with type 2 diabetes who were new initiators of exenatide or glargine from October 1, 2006 through March 31, 2008 with continuous enrollment for the 12 months pre- and 18 months post-index period were selected from the MarketScan® Commercial and Medicare Databases. To control for selection bias, propensity score matching was used to complete a 1:1 match of glargine to exenatide patients. Key study outcomes (including the likelihood of overall treatment modification, discontinuation, switching, or intensification) were analyzed using survival analysis.
Results
A total of 9,197 exenatide- and 4,499 glargine-treated patients were selected. Propensity score matching resulted in 3,774 matched pairs with a mean age of 57 years and a mean Deyo Charlson Comorbidity Index score of 1.6; 54% of patients were males. The 18-month treatment intensification rates were 15.9% and 26.0% (p < 0.0001) and the discontinuation rates were 38.3% and 40.0% (p = 0.14) for exenatide and glargine, respectively. Alternatively, 14.9% of exenatide-treated patients switched therapies, compared to 10.0% of glargine-treated patients (p < 0.0001). Overall, glargine-treated patients were more likely to modify their treatment [hazard ratio (HR) = 1.33, p < 0.0001] with shorter mean time on treatment until modification (123 vs. 159 days, p < 0.0001). Compared to exenatide-treated patients, glargine-treated patients were more likely to discontinue [hazard ratio (HR) = 1.25, p < 0.0001] or intensify therapy (HR = 1.72, p < 0.0001) but less likely to switch (HR = 0.71, p < 0.0001) the index therapy.
Conclusions
Patients treated for type 2 diabetes with exenatide BID or insulin glargine differ in their adherence to therapy. Exenatide-treated patients were less likely to discontinue or modify treatment but more likely to switch therapy compared to glargine-treated patients.
doi:10.1186/1472-6823-13-20
PMCID: PMC3750447  PMID: 23799930
8.  Acute kidney injury among critically ill patients with pandemic H1N1 influenza A in Canada: cohort study 
BMC Nephrology  2013;14:123.
Background
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.
Methods
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.
Results
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.
Conclusion
The incidence of AKI and RRT utilization were high among Canadian patients with critical illness due to pH1N1.
doi:10.1186/1471-2369-14-123
PMCID: PMC3694036  PMID: 23763900
Acute kidney injury; Renal replacement therapy; Influenza; Critical illness; Mortality; Resource utilization
9.  Clinical and temporal patterns of severe pneumonia causing critical illness during Hajj 
BMC Infectious Diseases  2012;12:117.
Background
Pneumonia is a leading cause of hospitalization during Hajj and susceptibility and transmission may be exacerbated by extreme spatial and temporal crowding. We describe the number and temporal onset, co–morbidities, and outcomes of severe pneumonia causing critical illness among pilgrims.
Method
A cohort study of all critically ill Hajj patients, of over 40 nationalities, admitted to 15 hospitals in 2 cities in 2009 and 2010. Demographic, clinical, and laboratory data, and variables necessary for calculation of the Acute Physiology and Chronic Health Evaluation IV scores were collected.
Results
There were 452 patients (64.6% male) who developed critical illness. Pneumonia was the primary cause of critical illness in 123 (27.2%) of all intensive care unit (ICU) admissions during Hajj. Pneumonia was community (Hajj)–acquired in 66.7%, aspiration–related in 25.2%, nosocomial in 3.3%, and tuberculous in 4.9%. Pneumonia occurred most commonly in the second week of Hajj, 95 (77.2%) occurred between days 5–15 of Hajj, corresponding to the period of most extreme pilgrim density. Mechanical ventilation was performed in 69.1%. Median duration of ICU stay was 4 (interquartile range [IQR] 1–8) days and duration of ventilation 4 (IQR 3–6) days. Commonest preexisting co–morbidities included smoking (22.8%), diabetes (32.5%), and COPD (17.1%). Short–term mortality (during the 3–week period of Hajj) was 19.5%.
Conclusion
Pneumonia is a major cause of critical illness during Hajj and occurs amidst substantial crowding and pilgrim density. Increased efforts at prevention for at risk pilgrim prior to Hajj and further attention to spatial and physical crowding during Hajj may attenuate this risk.
doi:10.1186/1471-2334-12-117
PMCID: PMC3458962  PMID: 22591189
Respiratory tract infection; Pneumonia; Hajj; Co–morbidities; APACHE IV
10.  Economic analyses of venous thromboembolism prevention strategies in hospitalized patients: a systematic review 
Critical Care  2012;16(2):R43.
Introduction
Despite evidence-based guidelines for venous thromboembolism prevention, substantial variability is found in practice. Many economic evaluations of new drugs for thromboembolism prevention do not occur prospectively with efficacy studies and are sponsored by the manufacturers, raising the possibility of bias. We performed a systematic review of economic analyses of venous thromboembolism prevention in hospitalized patients to inform clinicians and policy makers about cost-effectiveness and the potential influence of sponsorship.
Methods
We searched MEDLINE, EMBASE, Cochrane Databases, ACP Journal Club, and Database of Abstracts of Reviews of Effects, from 1946 to September 2011. We extracted data on study characteristics, quality, costs, and efficacy.
Results
From 5,180 identified studies, 39 met eligibility and quality criteria. Each addressed pharmacologic prevention: low-molecular-weight heparins versus placebo (five), unfractionated heparin (12), warfarin (eight), one or another agents (five); fondaparinux versus enoxaparin (11); and rivaroxaban and dabigatran versus enoxaparin (two). Low-molecular-weight heparins were most economically attractive among most medical and surgical patients, whereas fondaparinux was favored for orthopedic patients. Fondaparinux was associated with increased bleeding events. Newer agents rivaroxaban and dabigatran may offer additional value. Of all economic evaluations, 64% were supported by manufacturers of a "new" agent. The new agent had a favorable outcome in 38 (97.4%) of 39 evaluations [95% confidence interval [CI] (86.5 to 99.9)]. Among studies supported by a pharmaceutical company, the sponsored medication was economically attractive in 24 (96.0%) of 25 [95% CI, 80.0 to 99.9)]. We could not detect a consistent bias in outcome based on sponsorship; however, only a minority of studies were unsponsored.
Conclusion
Low-molecular-weight heparins and fondaparinux are the most economically attractive drugs for venous thromboembolism prevention in hospitalized patients. Approximately two thirds of evaluations were supported by the manufacturer of the new agent; such drugs were likely to be reported as economically favorable.
doi:10.1186/cc11241
PMCID: PMC3964799
11.  Critical care resources in the Solomon Islands: a cross-sectional survey 
Background
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.
Methods
This study used a mixed methods approach, including a cross sectional survey of respondents' opinions regarding critical care needs, ethnographic information and qualitative data.
Results
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.
Conclusions
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.
doi:10.1186/1472-698X-12-1
PMCID: PMC3307438  PMID: 22376229
Critical care; Critical illness; Solomon Islands; Lower and middle income countries
12.  Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis 
Critical Care  2011;15(6):R267.
Introduction
The optimal duration of antibiotic therapy for bloodstream infections is unknown. Shorter durations of therapy have been demonstrated to be as effective as longer durations for many common infections; similar findings in bacteremia could enable hospitals to reduce antibiotic utilization, adverse events, resistance and costs.
Methods
A search of the MEDLINE, EMBASE and COCHRANE databases was conducted for the years 1947-2010. Controlled trials were identified that randomized patients to shorter versus longer durations of treatment for bacteremia, or the infectious foci most commonly causing bacteremia in critically ill patients (catheter-related bloodstream infections (CRBSI), intra-abdominal infections, pneumonia, pyelonephritis and skin and soft-tissue infections (SSTI)).
Results
Twenty-four eligible trials were identified, including one trial focusing exclusively on bacteremia, zero in catheter related bloodstream infection, three in intra-abdominal infection, six in pyelonephritis, thirteen in pneumonia and one in skin and soft tissue infection. Thirteen studies reported on 227 patients with bacteremia allocated to 'shorter' or 'longer' durations of treatment. Outcome data were available for 155 bacteremic patients: neonatal bacteremia (n = 66); intra-abdominal infection (40); pyelonephritis (9); and pneumonia (40). Among bacteremic patients receiving shorter (5-7 days) versus longer (7-21 days) antibiotic therapy, no significant difference was detected with respect to rates of clinical cure (45/52 versus 47/49, risk ratio 0.88, 95% confidence interval [CI] 0.77-1.01), microbiologic cure (28/28 versus 30/32, risk ratio 1.05, 95% CI 0.91-1.21), and survival (15/17 versus 26/29, risk ratio 0.97, 95% CI 0.76-1.23).
Conclusions
No significant differences in clinical cure, microbiologic cure and survival were detected among bacteremic patients receiving shorter versus longer duration antibiotic therapy. An adequately powered randomized trial of bacteremic patients is needed to confirm these findings.
doi:10.1186/cc10545
PMCID: PMC3388653  PMID: 22085732
13.  Disease-modifying drug initiation patterns in commercially insured multiple sclerosis patients: a retrospective cohort study 
BMC Neurology  2011;11:122.
Background
The goal of this research was to compare the demographics, clinical characteristics and treatment patterns for newly diagnosed multiple sclerosis (MS) patients in a commercial managed care population who received disease-modifying drug (DMD) therapy versus those not receiving DMD therapy.
Methods
A retrospective cohort study using US administrative healthcare claims identified individuals newly diagnosed with MS (no prior MS diagnosis 12 months prior using ICD-9-CM 340) and ≥ 18 years old during 2001-2007 to characterize them based on demographics, clinical characteristics, and pharmacologic therapy for one year prior to and a minimum of one year post-index. The index date was the first MS diagnosis occurring in the study period. Follow-up of subjects was done by ICD-9-CM code identification and not by actual chart review. Multivariate analyses were conducted to adjust for confounding variables.
Results
Patients were followed for an average of 35.7 ± 17.5 months after their index diagnosis. Forty-three percent (n = 4,462) of incident patients received treatment with at least one of the DMDs during the post-index period. Treated patients were primarily in the younger age categories of 18-44 years of age, with DMD therapy initiated an average of 5.3 ± 9.1 months after the index diagnosis. Once treatment was initiated, 27.7% discontinued DMD therapy after an average of 17.6 ± 14.6 months, and 16.5% had treatment gaps in excess of 60 days.
Conclusions
Nearly 60% of newly-diagnosed MS patients in this commercial managed care population remained untreated while over a quarter of treated patients stopped therapy and one-sixth experienced treatment gaps despite the risk of disease progression or a return of pre-treatment disease activity.
doi:10.1186/1471-2377-11-122
PMCID: PMC3204236  PMID: 21974973
14.  An Official American Thoracic Society Systematic Review: The Association between Health Insurance Status and Access, Care Delivery, and Outcomes for Patients Who Are Critically Ill 
Rationale: One in three Americans under 65 years of age does not have health insurance during some portion of each year. Patients who are critically ill and lack health insurance may be at particularly high risk of morbidity and mortality due to the high cost of intensive care.
Objectives: To systematically review the medical and nonmedical literature to determine whether differences in critical care access, delivery, and outcomes are associated with health insurance status.
Methods: Nine electronic databases (inception to 11 April 2008) were independently screened and abstracted in duplicate.
Measurements and Main Results: From 5,508 citations, 29 observational studies met eligibility criteria. Among the general U.S. population, patients who were uninsured were less likely to receive critical care services than those with insurance (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.55–0.56). Once admitted to the intensive care unit, patients who were uninsured had 8.5% (95% CI, 6.0–11.1) fewer procedures, were more likely to experience hospital discharge delays (OR 4.51; 95% CI, 1.46–13.93), and were more likely to have life support withdrawn (OR 2.80; 95% CI, 1.12–7.02). Lack of insurance may confer an independent risk of death for patients who are critically ill (OR 1.16; 95% CI, 1.01–1.33). Patients in managed care systems had 14.3% (95% CI, 11.5–17.2) fewer procedures in intensive care, but were also less likely to receive “potentially ineffective” care. Differences in unmeasured confounding factors may contribute to these findings.
Conclusions: Patients in the United States who are critically ill and do not have health insurance receive fewer critical care services and may experience worse clinical outcomes. Improving preexisting health care coverage, as opposed to solely delivering more critical care services, may be one mechanism to reduce such disparities.
doi:10.1164/rccm.200902-0281ST
PMCID: PMC3269233  PMID: 20430926
insurance; disparities; payer; critical care; intensive care; access; outcome; Medicare; managed care; Medicaid
15.  A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial 
Trials  2011;12:70.
Background
Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.
Methods/Design
A multi-national, pilot randomized controlled trial (RCT) of once daily enteral rosuvastatin versus matched placebo administered for 14 days for the treatment of critically ill patients with suspected, probable or confirmed H1N1 infection. We propose to randomize 80 critically ill adults with a moderate to high index of suspicion for H1N1 infection who require mechanical ventilation and have received antiviral therapy for ≤ 72 hours. Site investigators, research coordinators and clinical pharmacists will be blinded to treatment assignment. Only research pharmacy staff will be aware of treatment assignment. We propose several approaches to informed consent including a priori consent from the substitute decision maker (SDM), waived and deferred consent. The primary outcome of the CHAT trial is the proportion of eligible patients enrolled in the study. Secondary outcomes will evaluate adherence to medication administration regimens, the proportion of primary and secondary endpoints collected, the number of patients receiving open-label statins, consent withdrawals and the effect of approved consent models on recruitment rates.
Discussion
Several aspects of study design including the need to include central randomization, preserve allocation concealment, ensure study blinding compare to a matched placebo and the use novel consent models pose challenges to investigators conducting pandemic research. Moreover, study implementation requires that trial design be pragmatic and initiated in a short time period amidst uncertainty regarding the scope and duration of the pandemic.
Trial Registration Number
ISRCTN45190901
doi:10.1186/1745-6215-12-70
PMCID: PMC3068961  PMID: 21388549
16.  Utility and safety of draining pleural effusions in mechanically ventilated patients: a systematic review and meta-analysis 
Critical Care  2011;15(1):R46.
Introduction
Pleural effusions are frequently drained in mechanically ventilated patients but the benefits and risks of this procedure are not well established.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/cc10009
PMCID: PMC3221976  PMID: 21288334
17.  IMITATE: An intensive computer-based treatment for aphasia based on action observation and imitation 
Aphasiology  2010;24(4):449-465.
Background
Neurophysiological evidence from primates has demonstrated the presence of mirror neurons, with visual and motor properties, that discharge both when an action is performed and during observation of the same action. A similar system for observation-execution matching may also exist in humans. We postulate that behavioral stimulation of this parietal-frontal system may play an important role in motor learning for speech and thereby aid language recovery after stroke.
Aims
The purpose of this article is to describe the development of IMITATE, a computer-assisted system for aphasia therapy based on action observation and imitation. We also describe briefly the randomized controlled clinical trial that is currently underway to evaluate its efficacy and mechanism of action.
Methods and Procedures
IMITATE therapy consists of silent observation of audio-visually presented words and phrases spoken aloud by six different speakers, followed by a period during which the participant orally repeats the stimuli. We describe the rationale for the therapeutic features, stimulus selection, and delineation of treatment levels.
The clinical trial is a randomized single blind controlled trial in which participants receive two pre-treatment baseline assessments, six weeks apart, followed by either IMITATE or a control therapy. Both treatments are provided intensively (90 minutes per day). Treatment is followed by a post-treatment assessment, and a six-week follow-up assessment.
Outcomes & Results
Thus far, five participants have completed IMITATE. We expect the results of the randomized controlled trial to be available by late 2010.
Conclusions
IMITATE is a novel computer-assisted treatment for aphasia that is supported by theoretical rationales and previous human and primate data from neurobiology. The treatment is feasible, and preliminary behavioral data are emerging. However, the results will not be known until the clinical trial data are available to evaluate fully the efficacy of IMITATE and to inform theoretically about the mechanism of action and the role of a human mirror system in aphasia treatment.
doi:10.1080/02687030802714157
PMCID: PMC2882655  PMID: 20543997
18.  A patient with shortness of breath and bilateral pulmonary infiltrates 
Open Medicine  2010;4(4):e187-e192.
Eosinophilic disorders are rare and clinically challenging diagnoses. In part, the challenge comes from the fact that some classifications of eosinophilic diseases have been based on the site of eosinophilic infiltration whereas others have been based on the actual number of blood eosinophils present. We describe a 54-year-old woman who had a history of asthma and presented with shortness of breath and eosinophilia. The differential diagnosis is broad and includes infectious diseases, inflammatory conditions such as Churg–Strauss syndrome, and hematologic conditions such as hypereosinophilic syndrome. We describe the diagnostic challenges inherent in such a presentation and also the changing landscape of disease labels in light of our evolving ability to diagnose genetic abnormalities.
PMCID: PMC3090107  PMID: 21687339
19.  Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials 
Circulation  2008;117(16):2104-2113.
Background
Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events.
Methods and Results
We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID. From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16 070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen (P=0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events (P for interaction=0.034).
Conclusions
We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.
doi:10.1161/CIRCULATIONAHA.108.764530
PMCID: PMC2965408  PMID: 18378608
drugs; cardiovascular diseases; cyclooxygenase 2 inhibitors
20.  Oncoming tides in the Age(ing) of Aquarius 
Critical Care  2009;13(3):145.
The demographic shift in the age of most industrialized countries' populations is profoundly impacting all areas of healthcare, perhaps nowhere more so than critical care. As the proportion of elderly patients increases, so to will our consideration for admission of elderly patients to the intensive care unit (ICU). Whether explicitly acknowledged or not, intensivists routinely debate (both inwardly and outwardly) the benefit, utility, and patient-focused dignity of admitting very elderly patients to the ICU. Despite the apparent increase in demand for, and provision of critical care services to, the elderly, there are few data on the outcomes from these admissions, and how one might predict which elderly patients are most likely to derive benefit from the invasive and resource-intensive services provided in modern ICUs.
doi:10.1186/cc7791
PMCID: PMC2717410  PMID: 19490598
21.  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.
doi:10.1186/cc6984
PMCID: PMC2592728  PMID: 19014409
22.  A broken heart: Right-to-left shunt in the setting of normal cardiac pressures 
A patent foramen ovale (PFO) is a common structural cardiac variant occurring in approximately 30% of the general population. Patients are usually asymptomatic because the defect is flap-like and does not permit significant left-to-right shunting. However, pathological conditions that result in cardiac rotation or higher than normal right atrial pressures can reverse the normal left atrial to right atrial pressure gradient and cause a right-to-left shunt through a PFO. If the right-to-left shunt is persistent, systemic hypoxemia or paradoxical emboli may result. The present report describes a case of refractory hypoxemia in a critically ill patient with a PFO who had a right-to-left shunt with normal right-sided cardiac pressures.
PMCID: PMC2649639  PMID: 18340396
Heart diseases; Hypoxia; Shunts
23.  An innovative telemedicine knowledge translation program to improve quality of care in intensive care units: protocol for a cluster randomized pragmatic trial 
Background
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.
Discussion
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)
doi:10.1186/1748-5908-4-5
PMCID: PMC2649891  PMID: 19220893
25.  Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors 
Critical Care  2008;12(2):R32.
Background
Critically ill patients with renal insufficiency are predisposed to both deep vein thrombosis (DVT) and bleeding. The objective of the present study was to evaluate the prevalence, incidence and predictors of DVT and the incidence of bleeding in intensive care unit (ICU) patients with estimated creatinine clearance <30 ml/min.
Methods
In a multicenter, open-label, prospective cohort study of critically ill patients with severe acute or chronic renal insufficiency or dialysis receiving subcutaneous dalteparin 5,000 IU once daily, we estimated the prevalence of proximal DVT by screening compression venous ultrasound of the lower limbs within 48 hours of ICU admission. DVT incidence was assessed on twice-weekly ultrasound testing. We estimated the incidence of major and minor bleeding by daily clinical assessments. We used Cox proportional hazards regression to identify independent predictors of both DVT and major bleeding.
Results
Of 156 patients with a mean (standard deviation) creatinine clearance of 18.9 (6.5) ml/min, 18 had DVT or pulmonary embolism within 48 hours of ICU admission, died or were discharged before ultrasound testing – leaving 138 evaluable patients who received at least one dose of dalteparin. The median duration of dalteparin administration was 7 days (interquartile range, 4 to 12 days). DVT developed in seven patients (5.1%; 95% confidence interval, 2.5 to 10.1). The only independent risk factor for DVT was an elevated baseline Acute Physiology and Chronic Health Evaluation II score (hazard ratio for 10-point increase, 2.25; 95% confidence interval, 1.03 to 4.91). Major bleeding developed in 10 patients (7.2%; 95% confidence interval, 4.0 to 12.8), all with trough anti-activated factor X levels ≤ 0.18 IU/ml. Independent risk factors for major bleeding were aspirin use (hazard ratio, 6.30; 95% confidence interval, 1.35 to 29.4) and a high International Normalized Ratio (hazard ratio for 0.5-unit increase, 1.68; 95% confidence interval, 1.07 to 2.66).
Conclusion
In ICU patients with renal insufficiency, the incidence of DVT and major bleeding are considerable but appear related to patient comorbidities rather than to an inadequate or excessive anticoagulant from thromboprophylaxis with dalteparin.
Clinical Trial Registration
Number NCT00138099.
doi:10.1186/cc6810
PMCID: PMC2447552  PMID: 18315876

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