Rapid response systems: a systematic review and meta-analysis.

INTRODUCTION: Although rapid response system teams have been widely adopted by many health systems, their effectiveness in reducing hospital mortality is uncertain. We conducted a meta-analysis to examine the impact of rapid response teams on hospital mortality and cardiopulmonary arrest. METHOD: We conducted a systematic review of studies published from January 1, 1990, through 31 December 2013, using PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and the Cochrane Library. We included studies that reported data on the primary outcomes of ICU and in-hospital mortality or cardiopulmonary arrests. RESULTS: Twenty-nine eligible studies were identified. The studies were analysed in groups based on adult and paediatric trials that were further sub-grouped on methodological design. There were 5 studies that were considered either cluster randomized control trial, controlled before after or interrupted time series. The remaining studies were before and after studies without a contemporaneous control. The implementation of RRS has been associated with an overall reduction in hospital mortality in both the adult (RR 0.87, 95 % CI 0.81-0.95, p<0.001) and paediatric (RR=0.82 95 % CI 0.76-0.89) in-patient population. There was substantial heterogeneity in both populations. The rapid response system team was also associated with a reduction in cardiopulmonary arrests in adults (RR 0.65, 95 % CI 0.61-0.70, p<0.001) and paediatric (RR=0.64 95 % CI 0.55-0.74) patients. CONCLUSION: Rapid response systems were associated with a reduction in hospital mortality and cardiopulmonary arrest. Meta-regression did not identify the presence of a physician in the rapid response system to be significantly associated with a mortality reduction.

Effect of Blood Pressure Lowering in Early Ischemic Stroke: Meta-Analysis.

BACKGROUND AND PURPOSE: Elevated blood pressure is common in acute stage of ischemic stroke and the strategy to manage this situation is not well established. We therefore conducted a meta-analysis of randomized controlled trials comparing active blood pressure lowering and control groups in early ischemic stroke. METHODS: Pubmed, EMBASE, and Clinicaltrials.gov from January 1966 to March 2015 were searched to identify relevant studies. We included randomized controlled trials with blood pressure lowering started versus control within 3 days of ischemic stroke onset. The primary outcome was unfavorable outcome at 3 months or at trial end point, defined as dependency or death, and the key secondary outcome was recurrent vascular events. Pooled relative risks and 95% confidence intervals were calculated using random-effects model. RESULTS: The systematic search identified 13 randomized controlled trials with 12 703 participants comparing early blood pressure lowering and control. Pooling the results with the random-effects model showed that blood pressure lowering in early ischemic stroke did not affect the risk of death or dependency at 3 months or at trial end point (relative risk, 1.04; 95% confidence interval, 0.96-1.13; P=0.35). Also, blood pressure lowering also had neutral effect on recurrent vascular events, as well as on disability or death, all-cause mortality, recurrent stroke, and serious adverse events. CONCLUSIONS: This meta-analysis suggested blood pressure lowering in early ischemic stroke had a neutral effect on the prevention of death or dependency.

Efficacy of drug-eluting stent for chronic total coronary occlusions at different follow-up duration: a systematic review and meta-analysis.

OBJECTIVE: DESs have been proved to be beneficial for patients with chronic total coronary occlusions (CTO) in terms of cardiac function and other prognosis. We aim to compare the efficacy and safety of drug-eluting stent (DES) and bare-metal stent (BMS) in CTO recanalization at different follow-up duration. METHODS: Articles comparing outcomes between DES and BMS implantation in patients with CTO was searched. A fixed-effect (inverse-variance weighted) and random-effect (DerSimonian and Laird) model were used to analyze the pooling results. RESULTS: A total of 29 comparative studies including 24 cohort studies and 5 randomized controlled studies were identified with a total of 9140 patients (5008 received BMS and 4132 received DES). The risk of all cause death for DES was higher at 6 months and lower at 12 months than BMS, and no significant difference was shown at 24, 36 and 60 months. DES group had lower risk of MI after 12 months implantation, and no difference was shown at 6, 24, 36 and 60 months. Major adverse cardiovascular event (MACE)-free survival was clinically and significantly improved by 73%, 68%, 49%, 40% and 37% respectively in DES group at 6,12, 24, 36, and 60 months. CONCLUSIONS: DES is superior to BMS in binary restenosis, reocclusion and MACE-free survival during long-term follow up. The occurrences of all-cause death and MI show that the risk rate of BMS is higher than that of DES at 12 months. The frequency of all-cause death of DES is higher than BMS at 6 months. DES has higher risk of in-stent thrombosis than BMS at 36 months of implantation.

Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect.

OBJECTIVES: We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians' opinion and usual practice for the selected interventions. DATA SOURCES: MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. STUDY SELECTION: We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. DATA EXTRACTION: For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. DATA SYNTHESIS: We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. CONCLUSIONS: We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

High-frequency ventilation does not provide mortality benefit in comparison with conventional lung-protective ventilation in acute respiratory distress syndrome: a meta-analysis of the randomized controlled trials.

BACKGROUND: Despite implementation of lung-protective ventilation strategy, acute respiratory distress syndrome is associated with significant mortality, which necessitates the evaluation of ventilatory modes other than conventional lung-protective strategy. This meta-analysis of the randomized controlled trials has been undertaken to know whether high-frequency oscillatory ventilation (HFOV) provides any mortality benefit over conventional ventilation in adult patients with acute respiratory distress syndrome. METHODS: Published randomized controlled trials comparing HFOV with conventional lung-protective ventilation in adult patients with acute respiratory distress syndrome were included in this meta-analysis. RESULTS: A total 1,759 patient data from seven randomized controlled trials have been analyzed here. Primary outcome of the review is in-hospital/30-day mortality and secondary outcomes are duration of intensive care unit stay, duration of mechanical ventilation, requirement of additional treatment, and complications associated with the interventions. HFOV does not offer any in-hospital/30-day mortality benefit (386 of 886 in HFOV vs. 368 of 873 in conventional ventilation; risk ratio, 0.96; 95% CI, 0.77 to 1.19; P = 0.70) over conventional ventilation. It may also prolong the duration of mechanical ventilation (mean difference, 1.18 days; 95% CI, 0.00 to 2.35 days; P = 0.05). Duration of intensive care unit stay (mean difference, 1.24 days; 95% CI, -0.08 to 2.56 days; P = 0.06) and requirement of neuromuscular blocker is similar between two treatment arm. Incidence of refractory hypoxemia is significantly less (risk ratio, 0.60; 95% CI, 0.39 to 0.93; P = 0.02) with the use of HFOV. HFOV is not associated with increased incidence of barotrauma and refractory hypotension. CONCLUSION: HFOV should not be used routinely in all adult patients with acute respiratory distress syndrome as primary ventilation strategy in place of conventional lung-protective ventilation.

Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials.

INTRODUCTION: The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis. METHODS: We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software. RESULTS: A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I(2) = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09). CONCLUSIONS: In this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.

Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients presenting acute cardiac and/or pulmonary dysfunctions, who are at high risk of developing acute kidney injury and fluid overload. Continuous renal replacement therapy (CRRT) is commonly used in intensive care units (ICU) to provide renal replacement and fluid management. We conducted a review to assess the feasibility, efficacy and safety of the combination of ECMO and CRRT and to illustrate the indications and methodology of providing renal replacement therapy during the ECMO procedure. METHOD: We searched for all published reports of a randomized controlled trial (RCT), quasi-RCT, or other comparative study design, conducted in patients undergoing ECMO plus CRRT. Two reviewers independently selected potential studies and extracted data. We used the modified Jadad scale and the Newcastle-Ottawa for quality assessment of RCTs and non-RCTs, respectively. Statistical analyses were performed using RevMan 5.2. RESULTS: We identified 19 studies meeting the eligibility criteria (seven cohort, six case control, one historically controlled trial and five studies of technical aspects). There are three major methods for performing CRRT during ECMO: 'independent CRRT access', 'introduction of a hemofiltration filter into the ECMO circuit (in-line hemofilter)' and 'introduction of a CRRT device into the ECMO circuit'. We conducted a review with limited data synthesis rather than a formal meta-analysis because there could be greater heterogeneity in a systematic review of non-randomized studies than that of randomized trials. For ECMO survivors receiving CRRT, overall fluid balance was less than that in non-CRRT survivors. There was a higher mortality and a longer ECMO duration when CRRT was added, which may reflect a relatively higher severity of illness in patients who received ECMO plus CRRT. CONCLUSIONS: The combination of ECMO and CRRT in a variety of methods appears to be a safe and effective technique that improves fluid balance and electrolyte disturbances. Prospective studies would be beneficial in determining the potential of this technique to improve the outcome in critically ill patients.

The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis.

INTRODUCTION: Sepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model. RESULTS: Of 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n = 128) and the mean age of children ranged from 0.9 to 18 years (n = 66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I(2) 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I(2) 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I(2) 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma. CONCLUSIONS: Insufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient-centered outcomes are required to evaluate the impact of plasma exchange in this condition.

Heparin-based treatment to prevent symptomatic deep venous thrombosis, pulmonary embolism or death in general medical inpatients is not supported by best evidence.

Prevention of venous thromboembolism (VTE) in medical patients is controversial. In contrast to surgical patients, the evidence supporting the use of heparin-based treatment for prevention of VTE (HVTEp) may not justify current guidelines. This study aims to determine whether current clinical guidelines for HVTEp are appropriate for medical patients. We searched medical databases for original randomised placebo-controlled studies of HVTEp in medical patients, excluding those with stroke and in intensive care. From 401 potentially relevant studies, we selected eight, which included over 16 000 patients. HVTEp decreased the incidence of all deep venous thromboses (DVT): 4.3% in the placebo group versus 2.3% in the treatment group, P = 0.002, number needed to treat, 50. However, this treatment effect was not seen for symptomatic DVT: 1.2% versus 0.9%, P = 0.18, odds ratio (OR) 0.72 (0.45-1.16). Similarly, HVTEp did not decrease the incidence of pulmonary embolism (PE): 0.54% versus 0.27%, P = 0.3, OR 0.57 (0.21-1.53), or fatal PE: 0.1% versus 0.0%, P = 0.3, OR 0.2 (0.01-4.11). Furthermore, HVTEp did not decrease total mortality: 5.63% versus 5.39%, P = 0.92, OR 0.96 (0.78-1.18). The use of HVTEp in hospitalised general medical patients does not result in a significant reduction in symptomatic DVT, PE, fatal PE or total mortality. The best evidence does not support the recommendations of the current clinical guidelines.

Analyzing overall survival in randomized controlled trials with crossover and implications for economic evaluation.

BACKGROUND: Offering patients in oncology trials the opportunity to cross over to active treatment at disease progression is a common strategy to address ethical issues associated with placebo controls but may lead to statistical challenges in the analysis of overall survival and cost-effectiveness because crossover leads to information loss and dilution of comparative clinical efficacy. OBJECTIVES: We provide an overview of how to address crossover, implications for risk-effect estimates of survival (hazard ratios) and cost-effectiveness, and how this influences decisions of reimbursement agencies. Two case studies using data from two phase III sunitinib oncology trials are used as illustration. METHODS: We reviewed the literature on statistical methods for adjusting for crossover and recent health technology assessment decisions in oncology. RESULTS: We show that for a trial with a high proportion of crossover from the control arm to the investigational arm, the choice of the statistical method greatly affects treatment-effect estimates and cost-effectiveness because the range of relative mortality risk for active treatment versus control is broad. With relatively frequent crossover, one should consider either the inverse probability of censoring weighting or the rank-preserving structural failure time model to minimize potential bias, with choice dependent on crossover characteristics, trial size, and available data. A large proportion of crossover favors the rank-preserving structural failure time model, while large sample size and abundant information about confounding factors favors the inverse probability of censoring weighting model. When crossover is very infrequent, methods yield similar results. CONCLUSIONS: Failure to correct for crossover may lead to suboptimal decisions by pricing and reimbursement authorities, thereby limiting an effective drug's potential.

Efficacy and adverse events of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome: a meta-analysis.

INTRODUCTION: Theoretically, high-frequency oscillatory ventilation (HFOV) achieves all goals of a lung-protective ventilatory mode and seems ideal for the treatment of adult patients with acute respiratory distress syndrome (ARDS). However, its effects on mortality and adverse clinical outcomes remain uncertain given the paucity of high-quality studies in this area. This meta-analysis was performed to evaluate the efficacy and adverse events of HFOV in adults with ARDS. METHODS: We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through February 2014 to retrieve randomized controlled trials of HFOV in adult ARDS patients. Two independent reviewers extracted data on study methods, clinical and physiological outcomes and adverse events. The primary outcome was 30-day or hospital mortality. Risk of bias was evaluated with the Cochrane Collaboration's tool. Mortality, oxygenation and adverse effects of HFOV were compared to those of conventional mechanical ventilation. A random-effects model was applied for meta-analysis. RESULTS: A total of five trials randomly assigning 1,580 patients met inclusion criteria. Pooled data showed that HFOV significantly improved oxygenation on day one of therapy (four studies; 24% higher; 95% confidence interval (CI) 11 to 40%; P <0.01). However, HFOV did not reduce mortality risk (five studies; risk ratio (RR) 1.04; 95% CI 0.83 to 1.31; P = 0.71) and two early terminated studies suggested a harmful effect of HFOV in ARDS (two studies; RR 1.33; 95% CI 1.09 to 1.62; P <0.01). Safety profiles showed that HFOV was associated with a trend toward increased risk of barotrauma (five studies; RR 1.19; 95% CI 0.83 to 1.72; P = 0.34) and unfavorable hemodynamics (five studies; RR 1.16; 95% CI 0.97 to 1.39; P = 0.12). CONCLUSIONS: HFOV improved oxygenation in adult patients with ARDS; however, it did not confer a survival benefit and might cause harm in the era of lung-protective ventilation strategy. The evidence suggests that HFOV should not be a routine practice in ARDS and further studies specifically selecting patients for this ventilator mode should be pursued.

Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials.

INTRODUCTION: Comprehensively evaluating the efficacy and safety of high-frequency oscillatory ventilation (HFOV) is important to allow clinicians who are using or considering this intervention to make appropriate decisions. METHODS: To find randomized controlled trials (RCTs) comparing HFOV with conventional mechanical ventilation (CMV) as an initial treatment for adult ARDS patients, we searched electronic databases (including PubMed, MedLine, Springer Link, Elsevier Science Direct, ISI web of knowledge, and EMBASE) with the following terms: "acute respiratory distress syndrome", "acute lung injury", and "high frequency oscillation ventilation". Additional sources included reference lists from the identified primary studies and relevant meta-analyses. Two investigators independently screened articles and extracted data. Meta-analysis was conducted using random-effects models. RESULTS: We included 6 RCTs with a total of 1,608 patients in this meta-analysis. Compared with CMV, HFOV did not significantly reduce the mortality at 30 or 28 days. The pooled relative risk (RR) was 1.051 (95% confidence interval (CI) 0.813 to 1.358). ICU mortality was also not significantly reduced in HFOV group, with a pooled RR of 1.218 (95% CI 0.925 to 1.604). The pooled effect sizes of HFOV for oxygenation failure, ventilation failure and duration of mechanical ventilation were 0.557 (95% CI 0.351 to 0.884), 0.892 (95% CI 0.435 to 1.829) and 0.079 (95% CI -0.045 to 0.203), respectively. The risk of barotrauma and hypotension were similar between the CMV group and HFOV group, with a RR of 1.205 (95% CI 0.834 to 1.742) and a RR of 1.326 (95% CI 0.271 to 6.476), respectively. CONCLUSIONS: Although HFOV seems not to increase the risk of barotrauma or hypotension, and reduces the risk of oxygenation failure, it does not improve survival in adult acute respiratory distress syndrome patients.

Impact of hypertension on clinical outcome in STEMI patients undergoing primary angioplasty with BMS or DES: insights from the DESERT cooperation.

BACKGROUND: Hypertension is a well known risk factor for atherosclerosis. However, data on the prognostic impact of hypertension in patients with ST elevation myocardial infarction (STEMI) are inconsistent and mainly related to studies performed in the thrombolytic era, with very few data in patients undergoing primary angioplasty. Therefore, the aim of the current study was to evaluate the impact hypertension on clinical outcome in STEMI patients undergoing primary PCI with BMS or DES. METHODS: Our population is represented by 6298 STEMI patients undergoing primary angioplasty included in the DESERT database from 11 randomized trials comparing DES vs BMS for STEMI. RESULTS: Hypertension was observed in 2764 patients (43.9%), and associated with ageing (p<0.0001), female gender (p<0.001), diabetes (p<0.0001), hypercholesterolemia (p<0.0001), previous MI (p=0.002), previous revascularization (p=0.002), longer time-to-treatment (p<0.001), preprocedural TIMI 3 flow, and with a lower prevalence of smoking (41% vs 53.9%, p<0.001) and anterior MI (42% vs 45.9%, p=0.002). Hypertension was associated with impaired postprocedural TIMI 0-2 flow (Adjusted OR [95% CI]=1.22 [1.01-1.47], p=0.034). At a follow-up of 1,201 ± 440 days, hypertension was associated with higher mortality (adjusted HR [95% CI]=1.24 [1.01-1.54], p=0.048), reinfarction (adjusted HR [95% CI]=1.31 [1.03-1.66], p=0.027), stent thrombosis (adjusted HR [95% CI]=1.29 [0.98-1.71], p=0.068) and TVR (adjusted HR [95% CI]=1.22 [1.04-1.44], p=0.013). CONCLUSIONS: This study showed that among STEMI patients undergoing primary angioplasty with DES or BMS, hypertension is independently associated with impaired epicardial reperfusion, mortality, reinfarction and TVR, and a trend in higher ST.