Treatment of Ebola-related critical illness.

PURPOSE: To explore contemporary clincial case management of patients with Ebola virus disease. METHODS: A narrative review from a clinical perspective of clinical features, diagnostic tests, treatments and outcomes of patients with Ebola virus disease. RESULTS: Substantial advances have been made in the care of patients with Ebola virus disease (EVD), precipitated by the unprecedented extent of the 2014-2016 outbreak. There has been improved point-of-care diagnostics, improved characterization of the clinical course of EVD, improved patient-optimized standards of care, evaluation of effective anti-Ebola therapies, administration of effective vaccines, and development of innovative Ebola treatment units. A better understanding of the Ebola virus disease clinical syndrome has led to the appreciation of a central role for critical care clinicians-over 50% of patients have life-threatening complications, including hypotension, severe electrolyte imbalance, acute kidney injury, metabolic acidosis and respiratory failure. Accordingly, patients often require critical care interventions such as monitoring of vital signs, intravenous fluid resuscitation, intravenous vasoactive medications, frequent diagnostic laboratory testing, renal replacement therapy, oxygen and occasionally mechanical ventilation. CONCLUSION: With advanced training and adherence to infection prevention and control practices, clinical interventions, including critical care, are feasible and safe to perform in critically ill patients. With specific anti-Ebola medications, most patients can survive Ebola virus infection.

Clinical and echocardiographic predictors of embolism in infective endocarditis: systematic review and meta-analysis.

OBJECTIVES: Prediction of embolic events (EEs) in infective endocarditis (IE) could inform clinical decisions, such as surgical timing. We conducted a systematic review to more precisely define associations between risk factors and EEs. METHODS: We searched two bibliographic databases (1994-2018) for observational studies that reported EEs in IE patients and considered clinical, microbiological or echocardiographic risk factors. Studies that did not use Duke criteria or only investigated a subset of IE patients were excluded. Study quality was assessed using the Newcastle-Ottawa scale. A pooled risk ratio (RR) for each risk factor was estimated using random-effects models; statistical heterogeneity was estimated using I2. RESULTS: Of 3862 unique citations, 47 cohort studies (11 215 IE cases) were included; 54 risk factors were analysed in at least two studies, with nine studies reporting other individual factors. Most studies were of high methodological quality. Major predictors of EEs were intravenous drug use (RR 1.69, 95% CI 1.32-2.17; I2 = 46%), Staphylococcus aureus infection (RR 1.64, 95% CI 1.45-1.86, I2 = 32%), mitral valve vegetation (RR 1.24, 95% CI 1.11-1.37, I2 = 30%), and vegetation size >10 mm (RR 1.87, 95% CI 1.57-2.21, I2 = 48%). EE risk was also higher with human immunodeficiency virus, chronic liver disease, elevated C-reactive protein, Staphylococcus spp. infection, vegetation presence, and multiple, mobile or prosthetic mechanical valve vegetation, and lower with Streptococcus spp. infection. Most findings were unchanged in sensitivity analyses that removed studies with pulmonary EEs from the outcome. CONCLUSIONS: Given the serious consequences of embolism, surgical evaluation may be considered in patients with these risk factors.

Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Comparison of pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a protocol for a systematic review incorporating network meta-analyses.

BACKGROUND: Delirium is characterized by acute changes in mental status including inattention, disorganized thinking, and altered level of consciousness, and is highly prevalent in critically ill adults. Delirium has adverse consequences for both patients and the healthcare system; however, at this time, no effective treatment exists. The identification of effective prevention strategies is therefore a clinical and research imperative. An important limitation of previous reviews of delirium prevention is that interventions were considered in isolation and only direct evidence was used. Our systematic review will synthesize all existing data using network meta-analysis, a powerful statistical approach that enables synthesis of both direct and indirect evidence. METHODS: We will search Ovid MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science from 1980 to March 2016. We will search the PROSPERO registry for protocols and the Cochrane Library for published systematic reviews. We will examine reference lists of pertinent reviews and search grey literature and the International Clinical Trials Registry Platform for unpublished studies and ongoing trials. We will include randomized and quasi-randomized trials of critically ill adults evaluating any pharmacological, non-pharmacological, or multi-component intervention for delirium prevention, administered in or prior to (i.e., peri-operatively) transfer to the ICU. Two authors will independently screen search results and extract data from eligible studies. Risk of bias assessments will be completed on all included studies. To inform our network meta-analysis, we will first conduct conventional pair-wise meta-analyses for primary and secondary outcomes using random-effects models. We will generate our network meta-analysis using a Bayesian framework, assuming a common heterogeneity parameter across all comparisons, and accounting for correlations in multi-arm studies. We will perform analyses using WinBUGS software. DISCUSSION: This systematic review will address the existing knowledge gap regarding best practices for delirium prevention in critically ill adults by synthesizing evidence from trials of pharmacological, non-pharmacological, and multi-component interventions administered in or prior to transfer to the ICU. Use of network meta-analysis will clarify which delirium prevention strategies are most effective in improving clinical outcomes while causing least harm. The network meta-analysis is a novel approach and will provide knowledge users and decision makers with comparisons of multiple interventions of delirium prevention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036313.

Pharmacological treatments for acute respiratory distress syndrome: systematic review.

BACKGROUND: Our objective was to systematically review the effect of pharmacological therapies on mortality in patients with acute respiratory distress syndrome (ARDS), focusing on randomized controlled trials (RCTs) published since a previous review in 2004. METHODS: We updated previous searches and searched OVID versions of MEDLINE, EMBASE and CENTRAL (to January 2013) and proceedings from conferences and bibliographies of included studies. We included RCTs of pharmacologic therapies compared with placebo or no therapy for adult patients with ARDS, using authors' definitions, which reported on mortality (≤ 3 months after randomization). We excluded subgroups of patients with ARDS reported in RCTs enrolling other populations and RCTs of therapies to prevent ARDS, nutritional or fluid interventions, inhaled nitric oxide, therapies coupled to a mechanical ventilation strategy, or oxygen. Two reviewers independently screened citations, selected articles for inclusion, and abstracted clinical and methodological data from included studies with disagreements resolved by a third reviewer. Mortality data were pooled using random-effects models. RESULTS: From 13461 citations, 58 trials (6635 patients) of 21 classes of medications met selection criteria; 26 trials (3880 patients) were published after 2003. Meta-analyses showed reduced 28-day mortality with a 48-hour infusion of cis-atracurium in early ARDS (relative risk 0.66, 95% confidence interval 0.50 to 0.87; 431 patients, 138 deaths). There was no effect on mortality with granulocyte-macrophage colony stimulating factor, late low-dose methylprednisolone, neutrophil elastase inhibitors, intravenous salbutamol, surfactant, or N-acetylcysteine; each meta-analysis included ≥ 1 trial published after 2003. Seven single trials of other treatments published after 2003 showed no effect. Meta-analysis of older trials of prostaglandin E1 also showed no effect. CONCLUSION: Effective pharmacotherapy for ARDS remains extremely limited. Cis-atracurium is a promising treatment for early moderate-severe ARDS (using Berlin definition nomenclature) and merits further investigation in a large RCT.

Physicians declining patient enrollment in a critical care trial: a case study in thromboprophylaxis.

PURPOSE: To analyze the frequency, rationale and determinants of attending physicians requesting that their eligible patients not be approached for participation in a thromboprophylaxis trial. METHODS: Research personnel in 67 centers prospectively documented eligible non-randomized patients due to physicians declining to allow their patients to be approached. RESULTS: In 67 centers, 3,764 patients were enrolled, but 1,460 eligible patients had no consent encounter. For 218 (14.9 %) of these, attending physicians requested that their patients not be approached. The most common reasons included a high risk of bleeding (31.2 %) related to fear of heparin bioaccumulation in renal failure, the presence of an epidural catheter, peri-operative status or other factors; specific preferences for thromboprophylaxis (12.4 %); morbid obesity (9.6 %); uncertain prognosis (6.4 %); general discomfort with research (3.7 %) and unclear reasons (17.0 %). Physicians were more likely to decline when approached by less experienced research personnel; considering those with[10 years of experience as the reference category, the odds ratios (OR) for physician refusals to personnel without trial experience was 10.47 [95 % confidence interval (CI) 2.19-50.02] and those with less than 10 years experience was 1.72 (95 % CI 0.61-4.84). Physicians in open rather than closed units were more likely to decline (OR 4.26; 95 % CI 1.27-14.34). Refusals decreased each year of enrollment compared to the pilot phase. CONCLUSIONS: Tracking, analyzing, interpreting and reporting the rates and reasons for physicians declining to allow their patients to be approached for enrollment provides insights into clinicians' concerns and attitudes to trials. This information can encourage physician communication and education, and potentially enhance efficient recruitment.

Real-time clinical alerting: effect of an automated paging system on response time to critical laboratory values--a randomised controlled trial.

BACKGROUND: Timely and reliable communication of critical laboratory values is a Joint Commission National Patient Safety Goal. The objective was to evaluate the effect of an automated system for paging critical values directly to the responsible physician. METHODS: A randomised controlled trial on the general medicine clinical teaching units at an urban academic hospital was conducted from February to May 2006; the unit of randomisation was the critical laboratory value. The intervention was an automated paging system that sent the critical value directly to the responsible physician's pager. The control arm was usual care, which was a telephone call to the patient's ward by the laboratory technician. The primary outcome was response time, defined as the interval between acceptance of the critical value into the laboratory information system to the writing of an order on the patient's chart in response to the critical value. If the time of order was not documented, the time of administration of treatment was used to calculate response time. RESULTS: For primary analysis, 165 critical values were evaluated on 108 patients with full response time data. The median response time was 16 min (IQR 2-141) for the automated paging group and 39.5 min (IQR 7-104.5) for the usual care group (p=0.33). CONCLUSIONS: The automated paging system reduced the length of time physicians took to respond to critical laboratory values, but this difference was not statistically significant. Future reseach should evaluate the effects of alerts for conditions that currently do not generate a phone call and the addition of real-time decision support to the critical value alerts.

Utility of Gram stain in the clinical management of suspected ventilator-associated pneumonia. Secondary analysis of a multicenter randomized trial.

PURPOSE: Gram stains of endotracheal aspirates (EA) and bronchoalveolar lavages (BAL) may guide empiric antibiotic therapy in critically ill patients with suspected ventilator-associated pneumonia (VAP). Previous studies differ regarding the ability of the Gram stain to predict final culture results. The aim of the present study was to evaluate the relationship between EA or BAL Gram stains and final culture results in intensive care unit patients with a suspected VAP. MATERIAL AND METHODS: We retrospectively analyzed data from the Canadian multicenter VAP study to correlate EA or BAL Gram stain and final culture results. We categorized Gram stains as Gram positive (GP) and Gram negative (GN) if any GP or GN organisms respectively were seen on staining. Cultures were considered "positive" if they yielded pathogenic organisms on final results. RESULTS: Seven hundred forty patients were enrolled in the study; 35 did not have a Gram stain done leaving 350 BALs and 355 EAs from 705 patients. Pooling BAL and EA results, we found the overall agreement between Gram stain class and pathogenic bacteria culture results to be poor (kappa = 0.36; 95% CI, 0.31-0.40). Among specimens with Gram stains showing no organisms, 99 (30%) of 331 grew pathogenic organisms. Among specimens with Gram stains showing no GN organisms, 113 (25%) of 452 grew pathogenic GN organisms. Among specimens with Gram stains showing no GP organisms, 45 (11%) of 428 grew pathogenic GP organisms. CONCLUSIONS: Gram stains performed for clinically suspected VAP poorly predict the final culture result and thus have a limited role in guiding initial empiric antibiotic therapy in such patients.

Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase.

Current guidelines support the use of corticosteroids and azathioprine as one possible treatment strategy for idiopathic pulmonary fibrosis (IPF). However, some patients with genetic polymorphisms of thiopurine methyltransferase (TPMT) are at risk of severe azathioprine myelotoxicity. The current authors present the case of an 85-yr-old Caucasian male with IPF who developed diffuse alveolar haemorrhage as a complication of azathioprine-induced myelosuppression. Leukocyte genetic TPMT testing revealed that the patient had homozygous polymorphisms associated with the absence of TPMT activity and severe azathioprine-induced myelotoxicity. Thiopurine methyltransferase deficiency should be considered in patients who develop leukopenia early in treatment with azathiopurine, or who present with severe marrow suppression at usual doses. For centres with equipped laboratories, a dosing suggestion is provided based on thiopurine methyltransferase testing. Even with screening strategies, frequent monitoring of complete blood count and liver biochemistry should remain the mainstay of surveillance for azathioprine toxicity.

Noninvasive positive pressure ventilation as a weaning strategy for intubated adults with respiratory failure.

BACKGROUND: Noninvasive positive pressure ventilation (NPPV) provides ventilatory support without the need for an invasive airway. Interest has emerged in using NPPV to facilitate earlier removal of the endotracheal tube and decrease complications associated with prolonged intubation. OBJECTIVES: To summarize the evidence comparing NPPV and invasive positive pressure ventilation (IPPV) weaning on clinical outcomes in intubated adults with respiratory failure. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 2, 2003), MEDLINE (January 1966 to July 2003) and EMBASE (January 1980 to July 2003) for randomized controlled trials comparing NPPV and IPPV weaning. Additional data sources included personal files, conference proceedings and author contact. SELECTION CRITERIA: Randomized and quasi-randomized studies comparing early extubation with immediate application of NPPV to IPPV weaning in intubated adults with respiratory failure. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and abstracted data according to prespecified criteria. Sensitivity and subgroup analyses were planned to assess the impact of (i) excluding quasi-randomized trials and (ii) the etiology of respiratory failure on outcomes. MAIN RESULTS: We identified eleven trials, of which five were included, involving 171 participants with predominantly chronic obstructive pulmonary disease. Overall, the included studies were of moderate to good quality. Compared to the IPPV strategy, the NPPV strategy decreased mortality (RR 0.41, 95% CI 0.22 to 0.76), the incidence of ventilator associated pneumonia (RR 0.28, 95% CI 0.09 to 0.85), intensive care unit length of stay (WMD -6.88 days, 95% CI -12.60 to -1.15), hospital length of stay (WMD -7.33 days, 95%CI -14.05 to -0.61), total duration of mechanical support (WMD -7.33 days, 95% CI -11.45 to -3.22) and the duration of endotracheal mechanical ventilation (WMD -6.79 days, 95% CI -11.70 to -1.87). There was no effect of NPPV on weaning failures or the duration of mechanical support related to weaning and insufficient data to pool adverse events or quality of life. Excluding a single quasi-randomized trial maintained the significant reduction in mortality and ventilator associated pneumonia. Subgroup analyses suggested that the mortality benefit of the NPPV approach is greater in patients with chronic obstructive pulmonary disease. REVIEWER'S CONCLUSIONS: Summary estimates from five studies of moderate to good quality demonstrated a consistent positive effect on overall mortality. At present, use of NPPV to facilitate weaning in mechanically ventilated patients, with predominantly chronic obstructive lung disease, is associated with promising, although insufficient, evidence of net clinical benefit.