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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
16.  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
17.  A molecular characterization of spontaneous frameshift mutagenesis within the trpA gene of Escherichia coli 
DNA repair  2006;6(2):177-189.
Spontaneous frameshift mutations are an important source of genetic variation in all species and cause a large number of genetic disorders in humans. To enhance our understanding of the molecular mechanisms of frameshift mutagenesis, 583 spontaneous Trp+ revertants of two trpA frameshift alleles in Escherichia coli were isolated and DNA sequenced. In order to measure the contribution of methyl-directed mismatch repair to frameshift production, mutational spectra were constructed for both mismatch repair-proficient and repair-defective strains. The molecular origins of practically all of the frameshifts analyzed could be explained by one of six simple models based upon misalignment of the template or nascent DNA strands with or without misincoroporation of primer nucleotides during DNA replication. Most frameshifts occurred within mononucleotide runs as has been shown often in previous studies but the location of the 76 frameshift sites was usually outside of runs. Mismatch repair generally was most effective in preventing the occurrence of frameshifts within runs but there was much variation from site to site. Most frameshift sites outside of runs appear to be refractory to mismatch repair although the small number of occurrences at most of these sites make firm conclusions impossible. There was a dense pattern of reversion sites within the trpA DNA region where reversion events could occur, suggesting that, in general, most DNA sequences are capable of undergoing spontaneous mutational events during replication that can lead to small deletions and insertions. Many of these errors are likely to occur at low frequencies and be tolerated as events too costly to prevent or repair. These studies also revealed an unpredicted flexibility in the primary amino acid sequence of the trpA product, the α subunit of tryptophan synthase.
doi:10.1016/j.dnarep.2006.09.007
PMCID: PMC1804121  PMID: 17084112
18.  Blood conservation strategies to reduce the need for red blood cell transfusion in critically ill patients 
Anemia commonly affects critically ill patients. The causes are multifactorial and include acute blood loss, blood loss from diagnostic testing and blunted red blood cell production. Blood transfusions are frequently given to patients in intensive care units to treat low hemoglobin levels due to either acute blood loss or subacute anemia associated with critical illness. Although blood transfusion is a life-saving therapy, evidence suggests that it may be associated with an increased risk of morbidity and mortality. A number of blood conservation strategies exist that may mitigate anemia in hospital patients and limit the need for transfusion. These strategies include the use of hemostatic agents, hemoglobin substitutes and blood salvage techniques, the reduction of blood loss associated with diagnostic testing, the use of erythropoietin and the use of restrictive blood transfusion triggers. Strategies to reduce blood loss associated with diagnostic testing and the use of hemostatic agents and erythropoietin result in higher hemoglobin levels, but they have not been shown to reduce the need for blood transfusions or to improve clinical outcomes. Lowering the hemoglobin threshold at which blood is transfused will reduce the need for transfusions and is not associated with increased morbidity or mortality among most critically ill patients without active cardiac disease. Further research is needed to determine the potential roles for other blood conservation strategies.
doi:10.1503/cmaj.071298
PMCID: PMC2151112  PMID: 18166731
19.  A long-term follow-up study investigating health-related quality of life and resource use in survivors of severe sepsis: comparison of recombinant human activated protein C with standard care 
Critical Care  2007;11(6):R128.
Introduction
Recombinant human activated protein C (APC) therapy has been shown to reduce short-term mortality in patients with severe sepsis. However, survivors of sepsis may have long-term complications affecting health-related quality of life (HRQoL) and resource utilization. The objective of this study was to evaluate prospectively the effect of APC on long-term HRQoL and resource utilization compared with a nonrandomized control group that received standard care.
Methods
This was an observational cohort study at nine Canadian intensive care units. Patients with severe sepsis who survived to 28 days were recruited. Patients who received APC formed the treatment group and those that did not formed the standard care group. Patients who did not receive APC because of central nervous system bleeding risk were excluded from the standard care group. HRQoL (determined using the 36-item Short Form) and resource use were recorded at 28 days, and 3, 5 and 7 months.
Results
One hundred patients were enrolled (64 in the standard care group and 36 in the APC group), with 70 patients completing all follow-up visits. Over the 6 months of follow up, APC-treated patients exhibited statistically significantly better scores for the physical component score (P = 0.04) and trends toward improvements in physical functioning (P = 0.12), role physical (P = 0.10) and bodily pain (P = 0.14) as compared with standard care patients. Shorter hospital length of stay was observed for the APC group (36 days versus 48 days; P = 0.05).
Conclusion
These findings challenge earlier assumptions suggesting equivalent HRQoL and resource use in APC-treated and standard care patients who survive severe sepsis.
doi:10.1186/cc6195
PMCID: PMC2246225  PMID: 18072978
20.  Sex-and age-based differences in the delivery and outcomes of critical care 
Background
Previous studies have suggested that a patient's sex may influence the provision and outcomes of critical care. Our objective was to determine whether sex and age are associated with differences in admission practices, processes of care and clinical outcomes for critically ill patients.
Methods
We used a retrospective cohort of 466 792 patients, including 24 778 critically ill patients, admitted consecutively to adult hospitals in Ontario between Jan. 1, 2001, and Dec. 31, 2002. We measured associations between sex and age and admission to the intensive care unit (ICU); use of mechanical ventilation, dialysis or pulmonary artery catheterization; length of stay in the ICU and hospital; and death in the ICU, hospital and 1 year after admission.
Results
Of the 466 792 patients admitted to hospital, more were women than men (57.0% v. 43.0% for all admissions, p < 0.001; 50.1% v. 49.9% for nonobstetric admissions, p < 0.001). However, fewer women than men were admitted to ICUs (39.9% v. 60.1%, p < 0.001); this difference was most pronounced among older patients (age ≥ 50 years). After adjustment for admission diagnoses and comorbidities, older women were less likely than older men to receive care in an ICU setting (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.66–0.71). After adjustment for illness severity, older women were also less likely than older men to receive mechanical ventilation (OR 0.91, 95% CI 0.81– 0.97) or pulmonary artery catheterization (OR 0.80, 95% CI 0.73– 0.88). Despite older men and women having similar severity of illness on ICU admission, women received ICU care for a slightly shorter duration yet had a longer length of stay in hospital (mean 18.3 v. 16.9 days; p = 0.006). After adjustment for differences in comorbidities, source of admission, ICU admission diagnosis and illness severity, older women had a slightly greater risk of death in the ICU (hazard ratio 1.20, 95% CI 1.10–1.31) and in hospital (hazard ratio 1.08, 95% CI 1.00–1.16) than did older men.
Interpretation
Among patients 50 years or older, women appear less likely than men to be admitted to an ICU and to receive selected life-supporting treatments and more likely than men to die after critical illness. Differences in presentation of critical illness, decision-making or unmeasured confounding factors may contribute to these findings.
doi:10.1503/cmaj.071112
PMCID: PMC2096494  PMID: 18003954
21.  Multi-drug resistant Acinetobacter infections in critically injured Canadian forces soldiers 
Background
Military members, injured in Afghanistan or Iraq, have returned home with multi-drug resistant Acinetobacter baumannii infections. The source of these infections is unknown.
Methods
Retrospective study of all Canadian soldiers who were injured in Afghanistan and who required mechanical ventilation from January 1 2006 to September 1 2006. Patients who developed A. baumannii ventilator associated pneumonia (VAP) were identified. All A. baumannii isolates were retrieved for study patients and compared with A. baumannii isolates from environmental sources from the Kandahar military hospital using pulsed-field gel electrophoresis (PFGE).
Results
During the study period, six Canadian Forces (CF) soldiers were injured in Afghanistan, required mechanical ventilation and were repatriated to Canadian hospitals. Four of these patients developed A. baumannii VAP. A. baumannii was also isolated from one environmental source in Kandahar – a ventilator air intake filter. Patient isolates were genetically indistinguishable from each other and from the isolates cultured from the ventilator filter. These isolates were resistant to numerous classes of antimicrobials including the carbapenems.
Conclusion
These results suggest that the source of A. baumannii infection for these four patients was an environmental source in the military field hospital in Kandahar. A causal linkage, however, was not established with the ventilator. This study suggests that infection control efforts and further research should be focused on the military field hospital environment to prevent further multi-drug resistant A. baumannii infections in injured soldiers.
doi:10.1186/1471-2334-7-95
PMCID: PMC1988813  PMID: 17697345
22.  Behçet's disease 
doi:10.1503/cmaj.061136
PMCID: PMC1852859  PMID: 17452659

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