Effectiveness of Continuous Cuff Pressure Control in Preventing Ventilator-Associated Pneumonia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Microaspiration of subglottic secretions is the main pathogenic mechanism for ventilator-associated pneumonia (VAP). Adequate inflation of the endotracheal cuff is pivotal to providing an optimal seal of the extraluminal airway. However, cuff pressure substantially fluctuates due to patient or tube movements, which can induce microaspiration. Therefore, devices for continuous cuff pressure control (CCPC) have been developed in recent years. The purpose of this systematic review and meta-analysis is to assess the effectiveness of CCPC in VAP prevention. DATA SOURCES: A systematic search of Embase, the Cochrane Central Register of Controlled Trials, and the International Clinical Trials Registry Platform was conducted up to February 2022. STUDY SELECTION: Eligible studies were randomized controlled trials (RCTs) and quasi-RCTs comparing the impact of CCPC versus intermittent cuff pressure control on the occurrence of VAP. DATA EXTRACTION: Random-effects meta-analysis was used to calculate odds ratio (OR) and 95% CI for VAP incidence between groups. Secondary outcome measures included mortality and duration of mechanical ventilation (MV) and ICU stay. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: Eleven RCTs with 2,092 adult intubated patients were included. The use of CCPC was associated with a reduced risk of VAP (OR, 0.51). Meta-analyses of secondary endpoints showed no significant difference in mortality but significant differences in durations of MV (mean difference, -1.07 d) and ICU stay (mean difference, -3.41 d) in favor of CCPC. However, the risk of both reporting and individual study bias was considered important. The main issues were the lack of blinding, potential commercial conflicts of interest of study authors and high heterogeneity due to methodological differences between studies, differences in devices used for CCPC and in applied baseline preventive measures. Certainty of the evidence was considered "very low." CONCLUSIONS: The use of CCPC was associated with a reduction in VAP incidence; however, this was based on very low certainty of evidence due to concerns related to risk of bias and inconsistency.

Cumulative Evidence of Randomized Controlled and Observational Studies on Catheter-Related Infection Risk of Central Venous Catheter Insertion Site in ICU Patients: A Pairwise and Network Meta-Analysis.

BACKGROUND: Selection of central venous catheter insertion site in ICU patients could help reduce catheter-related infections. Although subclavian was considered the most appropriate site, its preferential use in ICU patients is not generalized and questioned by contradicted meta-analysis results. In addition, conflicting data exist on alternative site selection whenever subclavian is contraindicated. OBJECTIVE: To compare catheter-related bloodstream infection and colonization risk between the three sites (subclavian, internal jugular, and femoral) in adult ICU patients. DATA SOURCE: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled trials, CINAHL, and ClinicalTrials.gov. STUDY SELECTION: Eligible studies were randomized controlled trials and observational ones. DATA EXTRACTION: Extracted data were analyzed by pairwise and network meta-analysis. DATA SYNTHESIS: Twenty studies were included; 11 were observational, seven were randomized controlled trials for other outcomes, and two were randomized controlled trials for sites. We evaluated 18,554 central venous catheters: 9,331 from observational studies, 5,482 from randomized controlled trials for other outcomes, and 3,741 from randomized controlled trials for sites. Colonization risk was higher for internal jugular (relative risk, 2.25 [95% CI, 1.84-2.75]; I = 0%) and femoral (relative risk, 2.92 [95% CI, 2.11-4.04]; I = 24%), compared with subclavian. Catheter-related bloodstream infection risk was comparable for internal jugular and subclavian, higher for femoral than subclavian (relative risk, 2.44 [95% CI, 1.25-4.75]; I = 61%), and lower for internal jugular than femoral (relative risk, 0.55 [95% CI, 0.34-0.89]; I = 61%). When observational studies that did not control for baseline characteristics were excluded, catheter-related bloodstream infection risk was comparable between the sites. CONCLUSIONS: In ICU patients, internal jugular and subclavian may, similarly, decrease catheter-related bloodstream infection risk, when compared with femoral. Subclavian could be suggested as the most appropriate site, whenever colonization risk is considered and not, otherwise, contraindicated. Current evidence on catheter-related bloodstream infection femoral risk, compared with the other sites, is inconclusive.

Homocysteine-lowering interventions for preventing cardiovascular events.

BACKGROUND: Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015. OBJECTIVES: To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I2 statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate. MAIN RESULTS: In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence).We found no evidence of publication bias. AUTHORS' CONCLUSIONS: In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.

Homocysteine-lowering interventions for preventing cardiovascular events.

BACKGROUND: Cardiovascular disease, which includes coronary artery disease, stroke and congestive heart failure, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor is an elevated circulating total homocysteine level, which is associated with cardiovascular events. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events. This is an update of a review previously published in 2009 and 2013. OBJECTIVES: To determine whether homocysteine-lowering interventions, provided in patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as all-cause mortality and evaluate their safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), MEDLINE (1950 to January week 5 2014), EMBASE (1980 to 2014 week 6) and LILACS (1986 to February 2014). We also searched Web of Science (1970 to 7 February 2014). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS: In this second updated Cochrane Review, we identified no new randomised controlled trials. Therefore, this new version includes 12 randomised controlled trials involving 47,429 participants. In general terms, 75% (9/12) trials had a low risk of bias. Homocysteine-lowering interventions compared with placebo did not significantly affect non-fatal or fatal myocardial infarction (1743/23,590 (7.38%) versus 1247/20,190 (6.17%); RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I(2) = 0%, high quality evidence), stroke (968/22,348 (4.33%) versus 974/18,957 (5.13%); RR 0.91, 95% CI 0.82 to 1.0, I(2) = 11%, high quality evidence) or death from any cause (2784/22,648 (12.29%) versus 2502/19,250 (10.64%); RR 1.01, 95% CI 0.96 to 1.07, I(2) = 6%, high quality evidence). Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer) (1558/18,130 (8.59%) versus 1334/14,739 (9.05%); RR 1.06, 95% CI 0.98 to 1.13; I(2) = 0%, high quality evidence). AUTHORS' CONCLUSIONS: This second update of this Cochrane Review found no evidence to suggest that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination should be used for preventing cardiovascular events. Furthermore, there is no evidence to suggest that homocysteine-lowering interventions are associated with an increased risk of cancer.

Homocysteine-lowering interventions for preventing cardiovascular events.

BACKGROUND: Cardiovascular disease (including coronary artery disease, stroke and congestive heart failure), is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor is elevated circulating total homocysteine levels, which are associated with cardiovascular events. This is an update of a review previously published in 2009. OBJECTIVES: To assess the clinical effectiveness of homocysteine-lowering interventions in people with or without pre-existing cardiovascular disease. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2012, Issue 2), MEDLINE (1950 to Feb week 2 2012), EMBASE (1980 to 2012 week 07), and LILACS (1986 to February 2012). We also searched ISI Web of Science (1970 to February 2012). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using I(2). We used a random-effects model. MAIN RESULTS: In this updated systematic review, we identified four new randomised trials, resulting in a total of 12 randomised controlled trials involving 47,429 participants. In general terms, the trials had a low risk of bias. Homocysteine-lowering interventions compared with placebo did not significantly affect non-fatal or fatal myocardial infarction (pooled RR 1.02, 95% CI 0.95 to 1.10, I(2) = 0%), stroke (pooled RR 0.91, 95% CI 0.82 to 1.0, I(2) = 11%) or death by any cause (pooled RR 1.01 (95% CI 0.96 to 1.07, I(2): 6%)). Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer) (1 RR 1.06, 95% CI 0.98 to 1.13; I(2) = 0%). AUTHORS' CONCLUSIONS: This updated Cochrane review found no evidence to suggest that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination should be used for preventing cardiovascular events. Furthermore, there is no evidence suggesting that homocysteine-lowering interventions are associated with an increased risk of cancer.

COVID-19-Associated Pulmonary Aspergillosis (CAPA) in Northern Greece during 2020-2022: A Comparative Study According to the Main Consensus Criteria and Definitions.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as an important complication among patients with acute respiratory failure due to SARS-CoV-2 infection. Almost 2.5 years since the start of the COVID-19 pandemic, it continues to raise concerns as an extra factor that contributes to increased mortality, which is mostly because its diagnosis and management remain challenging. The present study utilises the cases of forty-three patients hospitalised between August 2020 and February 2022 whose information was gathered from ten ICUs and special care units based in northern Greece. The main aim was to describe the gained experience in diagnosing CAPA, according to the implementation of the main existing diagnostic consensus criteria and definitions, and present the different classification of the clinical cases due to the alternative algorithms.

Comparison of Oligon catheters and chlorhexidine-impregnated sponges with standard multilumen central venous catheters for prevention of associated colonization and infections in intensive care unit patients: a multicenter, randomized, controlled study.

OBJECTIVE: To evaluate silver-impregnated (Oligon) central venous catheters and chlorhexidine-gluconate-impregnated sponges for reducing catheter-related colonization and infection, nonbacteremic or bacteremic. DESIGN: Multicenter, prospective, randomized, controlled study. SETTING: Five general intensive care units in Greece. PATIENTS: Intensive care unit patients requiring a multilumen central venous catheter between June 2006 and May 2008. INTERVENTIONS: Patients were randomly assigned to receive a standard catheter (standard group), a standard catheter plus chlorhexidine-gluconate-impregnated sponge (chlorhexidine-gluconate-impregnated sponge group), or an Oligon catheter (Oligon group). Catheter colonization was defined as a positive quantitative tip culture (≥10 colony-forming units/mL), catheter-related infection was defined by the previous criterion plus clinical evidence of sepsis, and bacteremia catheter-related infection as catheter-related infection plus a positive peripheral blood culture with the same micro-organism as in the catheter tip. MEASUREMENTS AND MAIN RESULTS: Data were obtained from 465 patients, 156 in the standard-group, 150 in the chlorhexidine-gluconate-impregnated sponge group, and 159 in the Oligon-group. Colonization occurred in 24 (15.4%) standard catheters, 21 (14%) in the chlorhexidine-gluconate-impregnated sponge group, and 25 (15.7%) in the Oligon catheters (p = .35) (20.9, 19.9, 21.8/1000 catheter-days, respectively). Catheter-related infections were recorded in nine (5.8%) standard catheters, six (4%) in the chlorhexidine-gluconate-impregnated sponge group, and seven (4.4%) in the Oligon catheters (p = .58) (7.8/1,000, 5.7/1,000, 6.1/1,000 catheter-days, respectively). No difference was observed between the chlorhexidine- gluconate-impregnated sponge group and the standard group regarding catheter colonization (hazard ratio 1.21; 95% confidence interval 0.56-2.61; p = .64) and catheter-related infections (hazard ratio 0.65; 95% confidence interval 0.23-1.85; p = .42). The Oligon catheter did not reduce colonization or catheter-related infections when compared with the standard catheter (colonization: hazard ratio 1.0; 95% confidence interval 0.46-2.21; p = .98; catheter-related infection: hazard ratio 0.72; 95% confidence interval 0.27-1.95; p = .52). Seven patients (1.5%, 2.09/1,000 catheter-days) presented bacteremic catheter-related infections. Central venous catheters inserted either in the internal jugular or the femoral vein had greater risk to be colonized than catheters inserted in the subclavian vein (internal jugular vs. subclavian: hazard ratio 3.29; 95% confidence interval 1.26-8.61; p = .01; femoral vs. subclavian: hazard ratio 3.36; 95% confidence interval 1.17-9.65; p = .02). Acinetobacter baumannii was the predominant pathogen (37.1% episodes of colonization, 36.4% catheter-related infections, 57.1% bacteremic catheter-related infections). CONCLUSION: For short-term (median duration 7 days) central venous catheters in intensive care units with high prevalence of multiresistant Gram-negative bacteria, chlorhexidine-impregnated sponges and Oligon catheters as single preventive measures did not reduce catheter colonization or catheter-related infections. As a result of the limited amount of events, no conclusion could be reached regarding bacteremic catheter-related infections. The femoral site was the most frequently colonized insertion site in all types of catheters.

The importance of colonization pressure in multiresistant Acinetobacter baumannii acquisition in a Greek intensive care unit.

INTRODUCTION: We investigated the role of colonization pressure on multiresistant Acinetobacter baumannii acquisition and defined patient-related predictors for carriage at admission and acquisition during hospitalization in intensive care unit (ICU) patients. METHODS: This was a 12-month, prospective, cohort study of all patients admitted to a single ICU of a tertiary hospital. Screening samples were collected at ICU admission to identify imported carriers, and weekly during hospitalization to identify acquisition. Colonization pressure (carriers' patient-days × 100/all patients' patient-days) and the absolute number of carriers were calculated weekly, and the statistical correlation between these parameters and acquisition was explored. Multivariable analysis was performed to identify predictors for A. baumannii carriage at admission and acquisition during hospitalization. A. baumannii isolates were genotyped by repetitive-extragenic-palindromic polymerase chain reaction (PCR; rep-PCR). RESULTS: At ICU admission, 284 patients were screened for carriage. A. baumannii was imported in 16 patients (5.6%), and acquisition occurred in 32 patients (15.7%). Acquisition was significantly correlated to weekly colonization pressure (correlation coefficient, 0.379; P = 0.004) and to the number of carriers per week (correlation coefficient, 0.499; P <0.001). More than one carrier per week significantly increased acquisition risk (two to three carriers, odds ratio (OR), 12.66; P = 0.028; more than four carriers, OR, 25.33; P = 0.004). Predictors of carriage at admission were infection at admission (OR, 11.03; confidence interval (CI), 3.56 to 34.18; P < 0.01) and hospitalization days before ICU (OR, 1.09; CI, 1.01 to 1.16; P = 0.02). Predictors of acquisition were a medical reason for ICU admission (OR, 5.11; CI, 1.31 to 19.93; P = 0.02), duration of antibiotic administration in the unit (OR, 1.24; CI, 1.12 to 1.38; P < 0.001), and duration of mechanical ventilation (OR, 1.08; CI, 1.04 to 1.13; P = 0.001). All strains were multiresistant. Rep-PCR analysis showed one dominant cluster. CONCLUSIONS: Acquisition of multiresistant A. baumannii in ICU patients is strongly correlated to colonization pressure. High levels of colonization pressure and more than two carriers per week independently increase acquisition risk. Patient-related factors, such as infection at admission and long hospitalization before the ICU, can identify imported A. baumannii carriers. Medical patients with extended administration of antibiotics and long duration of mechanical ventilation in the ICU were the most vulnerable to acquisition.

Human recombinant activated protein C for severe sepsis.

BACKGROUND: Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been used to reduce the high rate of death by severe sepsis or septic shock. This is an update of a Cochrane review (originally published in 2007 and updated in 2008). OBJECTIVES: We assessed the clinical effectiveness and safety of APC for the treatment of patients with severe sepsis or septic shock. SEARCH METHODS: For this updated review we searched CENTRAL (The Cochrane Library 2010, Issue 6); MEDLINE (1966 to June 2010); EMBASE (1980 to July 1, 2010); BIOSIS (1965 to July 1, 2010); CINAHL (1982 to 16 June 2010) and LILACS (1982 to 16 June 2010). There was no language restriction. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28, at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS: We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS: We identified one new RCT in this update. We included a total of five RCTs involving 5101 participants. For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.97, 95% confidence interval (CI) 0.78 to 1.22; P = 0.82, I(2) = 68%). APC use was associated with an increased risk of bleeding (RR 1.47, 95% CI 1.09 to 2.00; P = 0.01, I(2) = 0%). In paediatric patients, APC did not reduce the risk of death (RR 0.98, 95% CI 0.66 to 1.46; P = 0.93). Although the included trials had no major limitations most of them modified their original completion or recruitment protocols. AUTHORS' CONCLUSIONS: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC is associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.Warning: On October 25th 2011, the European Medicines Agency issued a press release on the worldwide withdrawal of Xigris (activated protein C / drotrecogin alfa) from the market by Eli Lilly due to lack of beneficial effect on 28-day mortality in the PROWESS-SHOCK study. Furthermore, Eli Lily has announced the discontinuation of all other ongoing clinical trials. The final results of the PROWESS-SHOCK study are expected to be published in 2012. This systematic review will be updated when results of the PROWESS-SHOCK or other trials are published.

Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.

BACKGROUND: Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007. OBJECTIVES: We assessed the benefits and harms of APC for patients with severe sepsis or septic shock. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction. SELECTION CRITERIA: We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS: We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS: We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes. AUTHORS' CONCLUSIONS: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.

Human recombinant activated protein C for severe sepsis.

BACKGROUND: Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been used to reduce the high rate of death by severe sepsis or septic shock. This is an update of a Cochrane review (originally published in 2007 and updated in 2008). OBJECTIVES: We assessed the clinical effectiveness and safety of APC for the treatment of patients with severe sepsis or septic shock. SEARCH STRATEGY: For this updated review we searched CENTRAL (The Cochrane Library 2010, Issue 6); MEDLINE (1966 to June 2010); EMBASE (1980 to July 1, 2010); BIOSIS (1965 to July 1, 2010); CINAHL (1982 to 16 June 2010) and LILACS (1982 to 16 June 2010). There was no language restriction. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28, at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS: We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS: We identified one new RCT in this update. We included a total of five RCTs involving 5101 participants. For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.97, 95% confidence interval (CI) 0.78 to 1.22; P = 0.82, I(2) = 68%). APC use was associated with an increased risk of bleeding (RR 1.47, 95% CI 1.09 to 2.00; P = 0.01, I(2) = 0%). In paediatric patients, APC did not reduce the risk of death (RR 0.98, 95% CI 0.66 to 1.46; P = 0.93). Although the included trials had no major limitations most of them modified their original completion or recruitment protocols. AUTHORS' CONCLUSIONS: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC is associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

Outcomes of ICU patients with and without perceptions of excessive care: a comparison between cancer and non-cancer patients.

BACKGROUND: Whether Intensive Care Unit (ICU) clinicians display unconscious bias towards cancer patients is unknown. The aim of this study was to compare the outcomes of critically ill patients with and without perceptions of excessive care (PECs) by ICU clinicians in patients with and without cancer. METHODS: This study is a sub-analysis of the large multicentre DISPROPRICUS study. Clinicians of 56 ICUs in Europe and the United States completed a daily questionnaire about the appropriateness of care during a 28-day period. We compared the cumulative incidence of patients with concordant PECs, treatment limitation decisions (TLDs) and death between patients with uncontrolled and controlled cancer, and patients without cancer. RESULTS: Of the 1641 patients, 117 (7.1%) had uncontrolled cancer and 270 (16.4%) had controlled cancer. The cumulative incidence of concordant PECs in patients with uncontrolled and controlled cancer versus patients without cancer was 20.5%, 8.1%, and 9.1% (p < 0.001 and p = 0.62, respectively). In patients with concordant PECs, we found no evidence for a difference in time from admission until death (HR 1.02, 95% CI 0.60-1.72 and HR 0.87, 95% CI 0.49-1.54) and TLDs (HR 0.81, 95% CI 0.33-1.99 and HR 0.70, 95% CI 0.27-1.81) across subgroups. In patients without concordant PECs, we found differences between the time from admission until death (HR 2.23, 95% CI 1.58-3.15 and 1.66, 95% CI 1.28-2.15), without a corresponding increase in time until TLDs (NA, p = 0.3 and 0.7) across subgroups. CONCLUSIONS: The absence of a difference in time from admission until TLDs and death in patients with concordant PECs makes bias by ICU clinicians towards cancer patients unlikely. However, the differences between the time from admission until death, without a corresponding increase in time until TLDs, suggest prognostic unawareness, uncertainty or optimism in ICU clinicians who did not provide PECs, more specifically in patients with uncontrolled cancer. This study highlights the need to improve intra- and interdisciplinary ethical reflection and subsequent decision-making at the ICU.

Homocysteine lowering interventions for preventing cardiovascular events.

BACKGROUND: Cardiovascular disease such as coronary artery disease, stroke and congestive heart failure, is a leading cause of death worldwide. A postulated risk factor is elevated circulating total homocysteine (tHcy) levels which is influenced mainly by blood levels of cyanocobalamin (vitamin B12), folic acid (vitamin B9) and pyridoxine (vitamin B6). There is uncertainty regarding the strength of association between tHcy and the risk of cardiovascular disease. OBJECTIVES: To assess the clinical effectiveness of homocysteine-lowering interventions (HLI) in people with or without pre-existing cardiovascular disease. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (issue 3 2008), MEDLINE (1950 to August 2008), EMBASE (1988 to August 2008), and LILACS (1982 to September 2, 2008). We also searched in Allied and Complementary Medicine (AMED; 1985 to August 2008), ISI Web of Science (1993 to August 2008), and the Cochrane Stroke Group Specialised Register (April 2007). We hand searched pertinent journals and the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised clinical trials (RCTs) assessing the effects of HLI for preventing cardiovascular events with a follow-up period of 1 year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I(2). We used a random-effects model to synthesise the findings. MAIN RESULTS: We included eight RCTs involving 24,210 participants with a low risk of bias in general terms. HLI did not reduce the risk of non-fatal or fatal myocardial infarction, stroke, or death by any cause (pooled RR 1.03, 95% CI 0.94 to 1.13, I(2) = 0%; pooled RR 0.89, 95% CI 0.73 to 1.08, I(2) = 15%); and pooled RR 1.00 (95% CI 0.92 to 1.09, I(2): 0%), respectively. AUTHORS' CONCLUSIONS: Results from available published trials suggest that there is no evidence to support the use of HLI to prevent cardiovascular events.

Infections Due to Multidrug-Resistant Bacteria in Oncological Patients: Insights from a Five-Year Epidemiological and Clinical Analysis.

Bacterial infections are frequent complications in cancer patients. Among them, those caused by multidrug-resistant (MDR) bacteria increase morbidity and mortality mainly because of limited therapeutic options. Current knowledge regarding MDR infections in patients with solid tumors is limited. We assessed the epidemiology and risk factors of increased mortality in these patients. In this retrospective five-year single cohort observational study, we included all oncological patients with MDR infections. Cancer-related parameters, comorbidities, prior use of antibiotics, previous surgical interventions and hospitalization, as well as the use of invasive procedures were investigated as potential risk factors causing adverse outcomes. Seventy-three patients with MDR infection were included: 37% with carbapenem-resistant Klebsiella pneumoniae, 24% with oxacillin-resistant Staphylococcus aureus (MRSA) and 21% with carbapenem-resistant Acinetobacter baumanni. Previous colonization with MDR bacteria was detected in 14% patients, while 20% of the patients presented MDR colonization or infection at ward admission. Mortality during the infection episode was 32%. Duration of hospitalization and CRP were statistically significant risk factors of mortality, whereas administration of guided antibiotics was a protective factor. Knowledge of local epidemiology of MDR bacteria can help physicians promptly identify cancer patients at risk of MDR infections and initiate timely effective empirical antibiotic treatment that can eventually improve the overall therapeutic management.

Evidence from crossover trials: empirical evaluation and comparison against parallel arm trials.

BACKGROUND: We aimed to evaluate empirically how crossover trial results are analysed in meta-analyses of randomized evidence and whether their results agree with parallel arm studies on the same questions. METHODS: We used a systematic sample of Cochrane meta-analyses including crossover trials. We evaluated the methods of analysis for crossover results and compared the concordance of the estimated effect sizes in crossover vs parallel arm trials. RESULTS: Of 334 screened reviews, 62 had crossover trials. Of those, 33 meta-analyses performed quantitative syntheses involving two-arm two-period crossover trials. There was large variability on how these trials were analysed; only one of the 33 meta-analyses stated that they used the data from both the first and second period with an appropriate paired approach. Nine meta-analyses used the first period data only and 14 gave no information at all on what they had done. Twenty-eight meta-analyses had both crossover (n = 137, sample size n = 7,162) and parallel arm (n = 132, sample size n = 11,398) trials. Effect sizes correlated well with the two types of designs (rho = 0.72). Differences on whether the summary effect had a P < 0.05 or not were common due to limited sample sizes. The summary relative odds ratio for parallel arm vs crossover designs for favourable outcomes was 0.87 (95% CI, 0.74-1.02). CONCLUSIONS: Crossover designs may contribute evidence in a fifth of systematic reviews, but few meta-analyses make use of their full data. The results of crossover trials tend to agree with those of parallel arm trials, although there was a trend for more conservative treatment effect estimates in parallel arm trials.

Safety and efficacy of chloral hydrate for procedural sedation in paediatric ophthalmology: a systematic review and meta-analysis.

PURPOSE: Although chloral hydrate (CH) has been used as a sedative for decades, it is not widely accepted as a valid choice for ophthalmic examinations in uncooperative children. This study aimed to systematically review the literature on the drug's safety and efficacy. METHODS: We searched PubMed, EMBASE, ISI Web of Science, Scopus, CENTRAL, Google Scholar and Trip database to 1 October 2015, using the keywords 'chloral hydrate', 'paediatric' and 'procedural sedation OR diagnostic sedation'. A meta-analysis of randomised controlled trials (RCTs) was performed. RESULTS: A total of 6961 articles were screened and 104 were included in the review. Thirteen of these concerned paediatric ophthalmic examination, while 13 others were RCTs and were meta-analysed. CH was reported to have been administered in a total of 24 265 sedation episodes in children aged from <1 month to 18 years. The meta-analysis showed CH had a higher OR (2.95, 95% CI 1.09 to 7.99) for successful sedation compared to other sedatives, but significant limitations apply. The commonest reported adverse events (AE) were not serious (eg, paradoxical reaction or transient vomiting) and required no intervention. Severe AE, including two deaths, were related to comorbidity, overdose or aspiration. CONCLUSIONS: Despite the paucity of high quality evidence, the existing literature suggests that the use of CH for procedural sedation in children appears to be an effective alternative to general anaesthesia, and it can be safe when administered in the hospital setting with appropriate monitoring and vigilance for intervention.

Safety of medical interventions in children versus adults.

OBJECTIVE: Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs). METHODS: We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults. RESULTS: We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses. CONCLUSIONS: Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.