Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Risks of serious adverse events with non-steroidal anti-inflammatory drugs in gastrointestinal surgery: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly recommended for perioperative opioid-sparing multimodal analgesic treatments. Concerns regarding the potential for serious adverse events (SAEs) associated with perioperative NSAID treatment are especially relevant following gastrointestinal surgery. We assessed the risks of SAEs with perioperative NSAID treatment in patients undergoing gastrointestinal surgery. METHODS: We conducted a systematic review of randomised clinical trials assessing the harmful effects of NSAIDs versus placebo, usual care or no intervention in patients undergoing gastrointestinal surgery. The primary outcome was an incidence of SAEs. We systematically searched for eligible trials in five major databases up to January 2024. We performed risk of bias assessments to account for systematic errors, trial sequential analysis (TSA) to account for the risks of random errors, performed meta-analyses using R and used the Grading of Recommendations Assessment, Development and Evaluation framework to describe the certainty of evidence. RESULTS: We included 22 trials enrolling 1622 patients for our primary analyses. Most trials were at high risk of bias. Meta-analyses (risk ratio 0.78; 95% confidence interval [CI] 0.51-1.19; I2 = 4%; p = .24; very low certainty of evidence) and TSA indicated a lack of information on the effects of NSAIDs compared to placebo on the risks of SAEs. Post-hoc beta-binomial regression sensitivity analyses including trials with zero events showed a reduction in SAEs with NSAIDs versus placebo (odds ratio 0.73; CI 0.54-0.99; p = .042). CONCLUSION: In adult patients undergoing gastrointestinal surgery, there was insufficient information to draw firm conclusions on the effects of NSAIDs on SAEs. The certainty of the evidence was very low.

Associations of dexamethasone's effect on morphine consumption after total knee arthroplasty-Subgroup analyses.

The DEXamethasone twice for pain treatment after Total Knee Arthroplasty (DEX-2-TKA) trial showed that adding one and two doses of 24 mg intravenous dexamethasone to paracetamol, ibuprofen and local infiltration analgesia, reduced morphine consumption (primary outcome) within 48 h after TKA. We aimed to explore the differences in the effect of dexamethasone on morphine consumption in different subgroups. Quantile regression adjusted for site was used to test for significant interaction between the predefined dichotomised subgroups and treatment group. The subgroups were defined based on baseline data: sex (male/female), age (≤65 years/>65 years), American Society of Anaesthesiologists (ASA)-score (ASA I + II/III), visual analogue score of preoperative pain at rest (≤30 mm/>30 mm), pain during mobilisation (≤30 mm/>30 mm), type of anaesthesia (spinal anaesthesia/general anaesthesia and spinal converted to general anaesthesia), and prior daily use of analgesics (either paracetamol and/or NSAID/neither). These analyses were supplemented with post hoc multivariate linear regression analyses. Test of interaction comparing sex in the pairwise comparison between DX2 (dexamethasone [24 mg] + dexamethasone [24 mg]) versus placebo (p = .02), showed a larger effect of dexamethasone on morphine consumption in male patients compared to females. Test of interaction comparing age in the pairwise comparison between DX1 (dexamethasone [24 mg] + placebo) versus placebo (p = .04), showed a larger effect of dexamethasone on morphine consumption in younger patients (≤65 years) compared to older. All remaining subgroup analyses showed no evidence of a difference. The supplemental multivariate analyses did not support any significant interaction for sex (p = .256) or age (p = .730) but supported a significant interaction with the type of anaesthesia (p < .001). Our results from the quantile regression analyses indicate that the male sex and younger age (≤65 years) may be associated with a larger analgesic effect of dexamethasone than the effects in other types of patients. However, this is not supported by post-hoc multivariate linear regression analyses. The two types of analyses both supported a possible interaction with the type of anaesthesia.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Pain treatment after total hip arthroplasty: Detailed statistical analysis plan for the RECIPE randomised clinical trial.

BACKGROUND: The RECIPE trial systematically investigates the effects of different combinations of paracetamol, ibuprofen and dexamethasone for pain treatment after total hip arthroplasty. To preserve transparency, minimise risk of bias and to prevent data-driven analysis, we present this detailed statistical analysis plan. METHODS: The RECIPE trial is a randomised, blinded, parallel four-group multicenter clinical trial for patients undergoing planned primary total hip arthroplasty. Interventions are initiated preoperatively and continued for 24 h postoperatively. Primary outcome is total opioid consumption 0-24 h after end of surgery. Primary analysis will be performed in the modified intention to treat population of all patients undergoing total hip arthroplasty, and all analyses will be stratified for site. We will perform pairwise comparisons between each of the four groups. The primary outcome will be analysed using the van Elteren test and we will present Hodges-Lehmann median differences and confidence intervals. Binary outcomes will be analysed using logistic regression. To preserve a family-wise error rate of <0.05, we will use a Bonferroni-adjusted alfa of 0.05/6 = 0.0083 for all six pairwise comparisons between groups when analysing the primary outcome. We will systematically assess the underlying statistical assumptions for each analysis. Data will be analysed by two blinded independent statisticians, and we will write abstracts covering all possible combinations of conclusions, before breaking the blind. DISCUSSION: The RECIPE trial will provide important information on benefit and harm of combinations of the most frequently used non-opioid analgesics for pain after primary hip arthroplasty.

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial.

BACKGROUND: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA. METHODS: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups. RESULTS: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis. CONCLUSIONS: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016.

Risks of serious adverse events associated with non-steroidal anti-inflammatory drugs in gastrointestinal surgery. A protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Post-operative pain is frequent following gastrointestinal surgery and may result in prolonged hospitalisation, delayed recovery, and lower quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and recommended by Enhanced Recovery After Surgery guidelines as part of opioid-sparing multimodal treatment. However, perioperative NSAID treatment may be associated with increased risk of harm. We will investigate the risks of serious adverse events associated with perioperative NSAID treatment in patients undergoing gastrointestinal surgery. METHODS: This protocol uses the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. We wish to assess the effects of NSAIDs versus placebo, usual care, or no intervention on the incidence of serious adverse in patients undergoing gastrointestinal surgery. We will include all randomised trials. To identify trials, we will search the medical literature analysis and retrieval system online, excerpta medica database, cochrane central register of controlled trials, web of science core collection, and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess the risks of systematic errors. We will perform meta-analyses using R. We will use Trial Sequential Analysis to account for the risks of random errors. We will create a "Summary of Findings"-table in which we will present our primary and secondary outcome results. We will assess the certainty of the evidence using grading of recommendations assessment, development and evaluation. DISCUSSION: This systematic review can potentially elucidate the risks of perioperative NSAID treatment in gastrointestinal surgery and inform the already established non-opioid multimodal pain treatment regimen recommended by enhanced recovery after surgery guidelines.

Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest.

BACKGROUND: Hypotension is common after cardiac arrest (CA), and current guidelines recommend using vasopressors to target mean arterial blood pressure (MAP) higher than 65 mmHg. Pilot trials have compared higher and lower MAP targets. We will review the evidence on whether higher MAP improves outcome after cardiac arrest. METHODS: This systematic review and meta-analysis will be conducted based on a systematic search of relevant major medical databases from their inception onwards, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as clinical trial registries. We will identify randomised controlled trials published in the English language that compare targeting a MAP higher than 65-70 mmHg in CA patients using vasopressors, inotropes and intravenous fluids. The data extraction will be performed separately by two authors (a third author will be involved in case of disagreement), followed by a bias assessment with the Cochrane Risk of Bias tool using an eight-step procedure for assessing if thresholds for clinical significance are crossed. The outcomes will be all-cause mortality, functional long-term outcomes and serious adverse events. We will contact the authors of the identified trials to request individual anonymised patient data to enable individual patient data meta-analysis, aggregate data meta-analyses, trial sequential analyses and multivariable regression, controlling for baseline characteristics. The certainty of the evidence will be assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. We will register this systematic review with Prospero and aim to redo it when larger trials are published in the near future. CONCLUSIONS: This protocol defines the performance of a systematic review on whether a higher MAP after cardiac arrest improves patient outcome. Repeating this systematic review including more data likely will allow for more certainty regarding the effect of the intervention and possible sub-groups differences.

Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized clinical feasibility trial.

Current guidelines advocate to limit red blood cell (RBC) transfusion during surgery, but the feasibility and safety of such a strategy remain unclear, as the majority of evidence is based on postoperatively stable patients. We assessed the effects of a protocol aiming to restrict RBC transfusion throughout hospitalization for vascular surgery. Fifty-eight patients scheduled for lower limb bypass or open abdominal aortic aneurysm repair were randomly assigned, on hemoglobin drop below 9.7 g/dL, to either a low-trigger (hemoglobin < 8.0 g/dL) or a high-trigger (hemoglobin < 9.7 g/dL) group for RBC transfusion. Near-infrared spectroscopy assessed intraoperative oxygen desaturation in brain and muscle. Explorative outcomes included nationwide registry data on death and major vascular complications. The primary outcome, mean hemoglobin within 15 days of surgery, was significantly lower in the low-trigger group, at 9.46 vs 10.33 g/dL in the high-trigger group (mean difference, -0.87 g/dL; P = .022), as were units of RBCs transfused (median [interquartile range (IQR)], 1 [0-2] vs 3 [2-6]; P = .0015). Although the duration and magnitude of cerebral oxygen desaturation increased in the low-trigger group (median [IQR], 421 [42-888] vs 127 [11-331] minutes × %; P = .0036), muscle oxygenation was unaffected. The low-trigger group associated to a higher rate of death or major vascular complications (19/29 vs 8/29; hazard ratio, 3.20; P = .006) and fewer days alive outside the hospital within 90 days (median [IQR], 76 [67-82] vs 82 [76-84] days; P = .049). In conclusion, a perioperative protocol restricting RBC transfusion successfully separated hemoglobin levels and RBC units transfused. Exploratory outcomes suggested potential harm with the low-trigger group and warrant further trials before such a strategy is universally adopted. This trial was registered at www.clinicaltrials.gov as #NCT02465125.

Methodologies for systematic reviews with meta-analysis of randomised clinical trials in pain, anaesthesia, and perioperative medicine.

Systematic reviews and meta-analyses (SRMAs) are increasing in popularity, but should they be used to inform clinical decision-making in anaesthesia? We present evidence that the certainty of evidence from SRMAs in anaesthesia (and in general) may be unacceptably low because of risks of bias exaggerating treatment effects, unexplained heterogeneity reducing certainty in estimates, random errors, and widespread prevalence of publication bias. We also present the latest methodological advances to help improve the certainty of evidence from SRMAs. The target audience includes both review authors and practising clinicians to help with SRMA appraisal. Issues discussed include minimising risks of bias from included trials, trial sequential analysis to reduce random error, updated methods for presenting effect estimates, and novel publication bias tests for commonly used outcome measures. These methods can help to reduce spurious conclusions on clinical significance, explain statistical heterogeneity, and reduce false positives when evaluating small-study effects. By reducing concerns in these domains of Grading of Recommendations, Assessment, Development and Evaluation, it should help improve the certainty of evidence from SRMAs used for decision-making in anaesthesia, pain, and perioperative medicine.

Interventions for altering blood pressure in people with acute subarachnoid haemorrhage.

BACKGROUND: Subarachnoid haemorrhage has an incidence of up to nine per 100,000 person-years. It carries a mortality of 30% to 45% and leaves 20% dependent in activities of daily living. The major causes of death or disability after the haemorrhage are delayed cerebral ischaemia and rebleeding. Interventions aimed at lowering blood pressure may reduce the risk of rebleeding, while the induction of hypertension may reduce the risk of delayed cerebral ischaemia. Despite the fact that medical alteration of blood pressure has been clinical practice for more than three decades, no previous systematic reviews have assessed the beneficial and harmful effects of altering blood pressure (induced hypertension or lowered blood pressure) in people with acute subarachnoid haemorrhage. OBJECTIVES: To assess the beneficial and harmful effects of altering arterial blood pressure (induced hypertension or lowered blood pressure) in people with acute subarachnoid haemorrhage. SEARCH METHODS: We searched the following from inception to 8 September 2020 (Chinese databases to 27 January 2019): Cochrane Stroke Group Trials register; CENTRAL; MEDLINE; Embase; five other databases, and five trial registries. We screened reference lists of review articles and relevant randomised clinical trials. SELECTION CRITERIA: Randomised clinical trials assessing the effects of inducing hypertension or lowering blood pressure in people with acute subarachnoid haemorrhage. We included trials irrespective of publication type, status, date, and language. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We assessed the risk of bias of all included trials to control for the risk of systematic errors. We performed trial sequential analysis to control for the risks of random errors. We also applied GRADE. Our primary outcomes were death from all causes and death or dependency. Our secondary outcomes were serious adverse events, quality of life, rebleeding, delayed cerebral ischaemia, and hydrocephalus. We assessed all outcomes closest to three months' follow-up (primary point of interest) and maximum follow-up. MAIN RESULTS: We included three trials: two trials randomising 61 participants to induced hypertension versus no intervention, and one trial randomising 224 participants to lowered blood pressure versus placebo. All trials were at high risk of bias. The certainty of the evidence was very low for all outcomes. Induced hypertension versus control Two trials randomised participants to induced hypertension versus no intervention. Meta-analysis showed no evidence of a difference between induced hypertension versus no intervention on death from all causes (risk ratio (RR) 1.60, 95% confidence interval (CI) 0.57 to 4.42; P = 0.38; I2 = 0%; 2 trials, 61 participants; very low-certainty evidence). Trial sequential analyses showed that we had insufficient information to confirm or reject our predefined relative risk reduction of 20% or more. Meta-analysis showed no evidence of a difference between induced hypertension versus no intervention on death or dependency (RR 1.29, 95% CI 0.78 to 2.13; P = 0.33; I2 = 0%; 2 trials, 61 participants; very low-certainty evidence). Trial sequential analyses showed that we had insufficient information to confirm or reject our predefined relative risk reduction of 20% or more. Meta-analysis showed no evidence of a difference between induced hypertension and control on serious adverse events (RR 2.24, 95% CI 1.01 to 4.99; P = 0.05; I2 = 0%; 2 trials, 61 participants; very low-certainty evidence). Trial sequential analysis showed that we had insufficient information to confirm or reject our predefined relative risk reduction of 20% or more. One trial (41 participants) reported quality of life using the Stroke Specific Quality of Life Scale. The induced hypertension group had a median of 47 points (interquartile range 35 to 55) and the no-intervention group had a median of 49 points (interquartile range 35 to 55). The certainty of evidence was very low. One trial (41 participants) reported rebleeding. Fisher's exact test (P = 1.0) showed no evidence of a difference between induced hypertension and no intervention on rebleeding. The certainty of evidence was very low. Trial sequential analysis showed that we had insufficient information to confirm or reject our predefined relative risk reduction of 20% or more. One trial (20 participants) reported delayed cerebral ischaemia. Fisher's exact test (P = 1.0) showed no evidence of a difference between induced hypertension and no intervention on delayed cerebral ischaemia. The certainty of the evidence was very low. Trial sequential analysis showed that we had insufficient information to confirm or reject our predefined relative risk reduction of 20% or more. None of the trials randomising participants to induced hypertension versus no intervention reported on hydrocephalus. No subgroup analyses could be conducted for trials randomising participants to induced hypertension versus no intervention. Lowered blood pressure versus control One trial randomised 224 participants to lowered blood pressure versus placebo. The trial only reported on death from all causes. Fisher's exact test (P = 0.058) showed no evidence of a difference between lowered blood pressure versus placebo on death from all causes. The certainty of evidence was very low. AUTHORS' CONCLUSIONS: Based on the current evidence, there is a lack of information needed to confirm or reject minimally important intervention effects on patient-important outcomes for both induced hypertension and lowered blood pressure. There is an urgent need for trials assessing the effects of altering blood pressure in people with acute subarachnoid haemorrhage. Such trials should use the SPIRIT statement for their design and the CONSORT statement for their reporting. Moreover, such trials should use methods allowing for blinded altering of blood pressure and report on patient-important outcomes such as mortality, rebleeding, delayed cerebral ischaemia, quality of life, hydrocephalus, and serious adverse events.

Antibiotics for hospital-acquired pneumonia in neonates and children.

BACKGROUND: Hospital-acquired pneumonia is one of the most common hospital-acquired infections in children worldwide. Most of our understanding of hospital-acquired pneumonia in children is derived from adult studies. To our knowledge, no systematic review with meta-analysis has assessed the benefits and harms of different antibiotic regimens in neonates and children with hospital-acquired pneumonia. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for hospital-acquired pneumonia in neonates and children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases, and two trial registers to February 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised clinical trials comparing one antibiotic regimen with any other antibiotic regimen for hospital-acquired pneumonia in neonates and children. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were all-cause mortality and serious adverse events; our secondary outcomes were health-related quality of life, pneumonia-related mortality, non-serious adverse events, and treatment failure. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included four randomised clinical trials (84 participants). We assessed all trials as having high risk of bias. We did not conduct any meta-analyses, as the included trials did not compare similar antibiotic regimens. Each of the four trials assessed a different comparison, as follows: cefepime versus ceftazidime; linezolid versus vancomycin; meropenem versus cefotaxime; and ceftobiprole versus cephalosporin. Only one trial reported our primary outcomes of all-cause mortality and serious adverse events. Three trials reported our secondary outcome of treatment failure. Two trials primarily included community-acquired pneumonia and hospitalised children with bacterial infections, hence the children with hospital-acquired pneumonia constituted subgroups of the total sample sizes. Where outcomes were reported, the certainty of the evidence was very low for each of the comparisons. We are unable to draw meaningful conclusions from the numerical results. None of the included trials assessed health-related quality of life, pneumonia-related mortality, or non-serious adverse events. AUTHORS' CONCLUSIONS: The relative beneficial and harmful effects of different antibiotic regimens remain unclear due to the very low certainty of the available evidence. The current evidence is insufficient to support any antibiotic regimen being superior to another. Randomised clinical trials assessing different antibiotic regimens for hospital-acquired pneumonia in children and neonates are warranted.

Antibiotic regimens for early-onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Possibly due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units. The last Cochrane Review was updated in 2004. Given the clinical importance, an updated systematic review assessing the effects of different antibiotic regimens for early-onset neonatal sepsis is needed. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for early-onset neonatal sepsis. SEARCH METHODS: We searched the following electronic databases: CENTRAL (2020, Issue 8); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs comparing different antibiotic regimens for early-onset neonatal sepsis. We included participants from birth to 72 hours of life at randomisation. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included five RCTs (865 participants). All trials were at high risk of bias. The certainty of the evidence according to GRADE was very low. The included trials assessed five different comparisons of antibiotics. We did not conduct any meta-analyses due to lack of relevant data. Of the five included trials one trial compared ampicillin plus gentamicin with benzylpenicillin plus gentamicin; one trial compared piperacillin plus tazobactam with amikacin; one trial compared ticarcillin plus clavulanic acid with piperacillin plus gentamicin; one trial compared piperacillin with ampicillin plus amikacin; and one trial compared ceftazidime with benzylpenicillin plus gentamicin. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support any antibiotic regimen being superior to another. Large RCTs assessing different antibiotic regimens in early-onset neonatal sepsis with low risk of bias are warranted.

Antibiotic regimens for late-onset neonatal sepsis.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality. It is the third leading cause of neonatal mortality globally constituting 13% of overall neonatal mortality. Despite the high burden of neonatal sepsis, high-quality evidence in diagnosis and treatment is scarce. Due to the diagnostic challenges of sepsis and the relative immunosuppression of the newborn, many neonates receive antibiotics for suspected sepsis. Antibiotics have become the most used therapeutics in neonatal intensive care units, and observational studies in high-income countries suggest that 83% to 94% of newborns treated with antibiotics for suspected sepsis have negative blood cultures. The last Cochrane Review was updated in 2005. There is a need for an updated systematic review assessing the effects of different antibiotic regimens for late-onset neonatal sepsis. OBJECTIVES: To assess the beneficial and harmful effects of different antibiotic regimens for late-onset neonatal sepsis. SEARCH METHODS: We searched the following electronic databases: CENTRAL (2021, Issue 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED and Conference Proceedings Citation Index - Science on 12 March 2021. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: We included RCTs comparing different antibiotic regimens for late-onset neonatal sepsis. We included participants older than 72 hours of life at randomisation, suspected or diagnosed with neonatal sepsis, meningitis, osteomyelitis, endocarditis, or necrotising enterocolitis. We excluded trials that assessed treatment of fungal infections. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. Our primary outcome was all-cause mortality, and our secondary outcomes were: serious adverse events, respiratory support, circulatory support, nephrotoxicity, neurological developmental impairment, necrotising enterocolitis, and ototoxicity. Our primary time point of interest was at maximum follow-up. MAIN RESULTS: We included five RCTs (580 participants). All trials were at high risk of bias, and had very low-certainty evidence. The five included trials assessed five different comparisons of antibiotics. We did not conduct a meta-analysis due to lack of relevant data. Of the five included trials one trial compared cefazolin plus amikacin with vancomycin plus amikacin; one trial compared ticarcillin plus clavulanic acid with flucloxacillin plus gentamicin; one trial compared cloxacillin plus amikacin with cefotaxime plus gentamicin; one trial compared meropenem with standard care (ampicillin plus gentamicin or cefotaxime plus gentamicin); and one trial compared vancomycin plus gentamicin with vancomycin plus aztreonam. None of the five comparisons found any evidence of a difference when assessing all-cause mortality, serious adverse events, circulatory support, nephrotoxicity, neurological developmental impairment, or necrotising enterocolitis; however, none of the trials were near an information size that could contribute significantly to the evidence of the comparative benefits and risks of any particular antibiotic regimen. None of the trials assessed respiratory support or ototoxicity. The benefits and harms of different antibiotic regimens remain unclear due to the lack of well-powered trials and the high risk of systematic errors. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support any antibiotic regimen being superior to another. RCTs assessing different antibiotic regimens in late-onset neonatal sepsis with low risks of bias are warranted.

ANTECEDENTES: La sepsis neonatal es una causa importante de morbilidad y mortalidad. Es la tercera causa de mortalidad neonatal a nivel mundial y constituye el 13% de la mortalidad neonatal total. A pesar de la elevada carga de la sepsis neonatal, la evidencia de alta calidad en el diagnóstico y el tratamiento es escasa. Debido a las dificultades de diagnóstico de la sepsis y a la relativa inmunosupresión del neonato, muchos reciben antibióticos por sospecha de sepsis. Los antibióticos se han convertido en el tratamiento más utilizado en las unidades de cuidados intensivos neonatales, y los estudios observacionales realizados en países de ingresos altos indican que entre el 83% y el 94% de los neonatos tratados con antibióticos por sospecha de sepsis tienen hemocultivos negativos. La última revisión Cochrane se actualizó en 2005. Se necesita una revisión sistemática actualizada que evalúe los efectos de los diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de diferentes regímenes antibióticos para la sepsis neonatal de inicio tardío. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en las siguientes bases de datos electrónicas: CENTRAL (2021, número 3); Ovid MEDLINE; Embase Ovid; CINAHL; LILACS; Science Citation Index EXPANDED y Conference Proceedings Citation Index ­ Science el 12 de marzo de 2021. También se buscaron ensayos controlados aleatorizados (ECA) y cuasialeatorizados en las bases de datos de ensayos clínicos y en las listas de referencias de artículos identificados. CRITERIOS DE SELECCIÓN: Se incluyeron ECA que compararon diferentes regímenes de antibióticos para la sepsis neonatal de inicio tardío. Se incluyeron participantes mayores de 72 horas de vida en el momento de la asignación al azar, con sospecha o diagnóstico de sepsis neonatal, meningitis, osteomielitis, endocarditis o enterocolitis necrosante. Se excluyeron los ensayos que evaluaron el tratamiento de las infecciones micóticas. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los estudios para inclusión, extrajeron los datos y evaluaron el riesgo de sesgo. Se utilizó el método GRADE para evaluar la certeza de la evidencia. El desenlace principal fue la mortalidad por todas las causas, y los desenlaces secundarios fueron: eventos adversos graves, asistencia respiratoria, apoyo circulatorio, nefrotoxicidad, deterioro del desarrollo neurológico, enterocolitis necrosante y ototoxicidad. El punto temporal principal de interés fue el seguimiento máximo. RESULTADOS PRINCIPALES: Se incluyeron cinco ECA (580 participantes). Todos los ensayos tuvieron alto riesgo de sesgo y evidencia de certeza muy baja. Los cinco ensayos incluidos evaluaron cinco comparaciones diferentes de antibióticos. No se realizó un metanálisis debido a la falta de datos relevantes. De los cinco ensayos incluidos, un ensayo comparó cefazolina más amikacina con vancomicina más amikacina; un ensayo comparó ticarcilina más ácido clavulánico con flucloxacilina más gentamicina; un ensayo comparó cloxacilina más amikacina con cefotaxima más gentamicina; un ensayo comparó meropenem con atención estándar (ampicilina más gentamicina o cefotaxima más gentamicina); y un ensayo comparó vancomicina más gentamicina con vancomicina más aztreonam. Ninguna de las cinco comparaciones encontró evidencia de una diferencia al evaluar la mortalidad por todas las causas, los eventos adversos graves, el apoyo circulatorio, la nefrotoxicidad, el deterioro del desarrollo neurológico o la enterocolitis necrosante; sin embargo, ninguno de los ensayos se acercó a un tamaño de información que pudiera contribuir significativamente a la evidencia de los beneficios y los riesgos comparativos de cualquier régimen antibiótico en particular. Ninguno de los ensayos evaluó la asistencia respiratoria o la ototoxicidad. Los efectos beneficiosos y perjudiciales de los diferentes regímenes de antibióticos aún no están claros debido a la falta de ensayos con un poder estadístico adecuado y al alto riesgo de errores sistemáticos. CONCLUSIONES DE LOS AUTORES: La evidencia actual no es suficiente para apoyar que un régimen de antibióticos sea superior a otro. Se justifica la realización de ECA con bajo riesgo de sesgo que evalúen diferentes regímenes antibióticos en la sepsis neonatal de inicio tardío.

Beta-blockers in patients without heart failure after myocardial infarction.

BACKGROUND: Cardiovascular disease is the number one cause of death globally. According to the World Health Organization (WHO), 7.4 million people died from ischaemic heart disease in 2012, constituting 15% of all deaths. Beta-blockers are recommended and are often used in patients with heart failure after acute myocardial infarction. However, it is currently unclear whether beta-blockers should be used in patients without heart failure after acute myocardial infarction. Previous meta-analyses on the topic have shown conflicting results. No previous systematic review using Cochrane methods has assessed the effects of beta-blockers in patients without heart failure after acute myocardial infarction. OBJECTIVES: To assess the benefits and harms of beta-blockers compared with placebo or no treatment in patients without heart failure and with left ventricular ejection fraction (LVEF) greater than 40% in the non-acute phase after myocardial infarction. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index - Expanded, BIOSIS Citation Index, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, European Medicines Agency, Food and Drug Administration, Turning Research Into Practice, Google Scholar, and SciSearch from their inception to February 2021. SELECTION CRITERIA: We included all randomised clinical trials assessing effects of beta-blockers versus control (placebo or no treatment) in patients without heart failure after myocardial infarction, irrespective of publication type and status, date, and language. We excluded trials randomising participants with diagnosed heart failure at the time of randomisation. DATA COLLECTION AND ANALYSIS: We followed our published protocol, with a few changes made, and methodological recommendations provided by Cochrane and Jakobsen and colleagues. Two review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse events, and major cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial reinfarction). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow-up. We assessed all outcomes at maximum follow-up. We systematically assessed risks of bias using seven bias domains and we assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 25 trials randomising a total of 22,423 participants (mean age 56.9 years). All trials and outcomes were at high risk of bias. In all, 24 of 25 trials included a mixed group of participants with ST-elevation myocardial infarction and non-ST myocardial infarction, and no trials provided separate results for each type of infarction. One trial included participants with only ST-elevation myocardial infarction. All trials except one included participants younger than 75 years of age. Methods used to exclude heart failure were various and were likely insufficient. A total of 21 trials used placebo, and four trials used no intervention, as the comparator. All patients received usual care; 24 of 25 trials were from the pre-reperfusion era (published from 1974 to 1999), and only one trial was from the reperfusion era (published in 2018). The certainty of evidence was moderate to low for all outcomes. Our meta-analyses show that beta-blockers compared with placebo or no intervention probably reduce the risks of all-cause mortality (risk ratio (RR) 0.81, 97.5% confidence interval (CI) 0.73 to 0.90; I² = 15%; 22,085 participants, 21 trials; moderate-certainty evidence) and myocardial reinfarction (RR 0.76, 98% CI 0.69 to 0.88; I² = 0%; 19,606 participants, 19 trials; moderate-certainty evidence). Our meta-analyses show that beta-blockers compared with placebo or no intervention may reduce the risks of major cardiovascular events (RR 0.72, 97.5% CI 0.69 to 0.84; 14,994 participants, 15 trials; low-certainty evidence) and cardiovascular mortality (RR 0.73, 98% CI 0.68 to 0.85; I² = 47%; 21,763 participants, 19 trials; low-certainty evidence). Hence, evidence seems to suggest that beta-blockers versus placebo or no treatment may result in a minimum reduction of 10% in RR for risks of all-cause mortality, major cardiovascular events, cardiovascular mortality, and myocardial infarction. However, beta-blockers compared with placebo or no intervention may not affect the risk of angina (RR 1.04, 98% CI 0.93 to 1.13; I² = 0%; 7115 participants, 5 trials; low-certainty evidence). No trials provided data on serious adverse events according to good clinical practice from the International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP), nor on quality of life. AUTHORS' CONCLUSIONS: Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction in patients younger than 75 years of age without heart failure following acute myocardial infarction. Beta-blockers may further reduce the risks of major cardiovascular events and cardiovascular mortality compared with placebo or no intervention in patients younger than 75 years of age without heart failure following acute myocardial infarction. These effects could, however, be driven by patients with unrecognised heart failure. The effects of beta-blockers on serious adverse events, angina, and quality of life are unclear due to sparse data or no data at all. All trials and outcomes were at high risk of bias, and incomplete outcome data bias alone could account for the effect seen when major cardiovascular events, angina, and myocardial infarction are assessed. The evidence in this review is of moderate to low certainty, and the true result may depart substantially from the results presented here. Future trials should particularly focus on patients 75 years of age and older, and on assessment of serious adverse events according to ICH-GCP and quality of life. Newer randomised clinical trials at low risk of bias and at low risk of random errors are needed if the benefits and harms of beta-blockers in contemporary patients without heart failure following acute myocardial infarction are to be assessed properly. Such trials ought to be designed according to the SPIRIT statement and reported according to the CONSORT statement.

Antibiotics for secondary prevention of coronary heart disease.

BACKGROUND: Coronary heart disease is the leading cause of mortality worldwide with approximately 7.4 million deaths each year. People with established coronary heart disease have a high risk of subsequent cardiovascular events including myocardial infarction, stroke, and cardiovascular death. Antibiotics might prevent such outcomes due to their antibacterial, antiinflammatory, and antioxidative effects. However, a randomised clinical trial and several observational studies have suggested that antibiotics may increase the risk of cardiovascular events and mortality. Furthermore, several non-Cochrane Reviews, that are now outdated, have assessed the effects of antibiotics for coronary heart disease and have shown conflicting results. No previous systematic review using Cochrane methodology has assessed the effects of antibiotics for coronary heart disease. OBJECTIVES: We assessed the benefits and harms of antibiotics compared with placebo or no intervention for the secondary prevention of coronary heart disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS in December 2019 in order to identify relevant trials. Additionally, we searched TRIP, Google Scholar, and nine trial registries in December 2019. We also contacted 11 pharmaceutical companies and searched the reference lists of included trials, previous systematic reviews, and other types of reviews. SELECTION CRITERIA: Randomised clinical trials assessing the effects of antibiotics versus placebo or no intervention for secondary prevention of coronary heart disease in adult participants (≥18 years). Trials were included irrespective of setting, blinding, publication status, publication year, language, and reporting of our outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse event according to the International Conference on Harmonization - Good Clinical Practice (ICH-GCP), and quality of life. Our secondary outcomes were cardiovascular mortality, myocardial infarction, stroke, and sudden cardiac death. Our primary time point of interest was at maximum follow-up. Additionally, we extracted outcome data at 24±6 months follow-up. We assessed the risks of systematic errors using Cochrane 'Rosk of bias' tool. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes. We calculated absolute risk reduction (ARR) or increase (ARI) and number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH) if the outcome result showed a beneficial or harmful effect, respectively. The certainty of the body of evidence was assessed by GRADE. MAIN RESULTS: We included 38 trials randomising a total of 26,638 participants (mean age 61.6 years), with 23/38 trials reporting data on 26,078 participants that could be meta-analysed. Three trials were at low risk of bias and the 35 remaining trials were at high risk of bias. Trials assessing the effects of macrolides (28 trials; 22,059 participants) and quinolones (two trials; 4162 participants) contributed with the vast majority of the data. Meta-analyses at maximum follow-up showed that antibiotics versus placebo or no intervention seemed to increase the risk of all-cause mortality (RR 1.06; 95% CI 0.99 to 1.13; P = 0.07; I2 = 0%; ARI 0.48%; NNTH 208; 25,774 participants; 20 trials; high certainty of evidence), stroke (RR 1.14; 95% CI 1.00 to 1.29; P = 0.04; I2 = 0%; ARI 0.73%; NNTH 138; 14,774 participants; 9 trials; high certainty of evidence), and probably also cardiovascular mortality (RR 1.11; 95% CI 0.98 to 1.25; P = 0.11; I2= 0%; 4674 participants; 2 trials; moderate certainty of evidence). Little to no difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.88 to 1.03; P = 0.23; I2 = 0%; 25,523 participants; 17 trials; high certainty of evidence). No evidence of a difference was observed when assessing sudden cardiac death (RR 1.08; 95% CI 0.90 to 1.31; P = 0.41; I2 = 0%; 4520 participants; 2 trials; moderate certainty of evidence). Meta-analyses at 24±6 months follow-up showed that antibiotics versus placebo or no intervention increased the risk of all-cause mortality (RR 1.25; 95% CI 1.06 to 1.48; P = 0.007; I2 = 0%; ARI 1.26%; NNTH 79 (95% CI 335 to 42); 9517 participants; 6 trials; high certainty of evidence), cardiovascular mortality (RR 1.50; 95% CI 1.17 to 1.91; P = 0.001; I2 = 0%; ARI 1.12%; NNTH 89 (95% CI 261 to 49); 9044 participants; 5 trials; high certainty of evidence), and probably also sudden cardiac death (RR 1.77; 95% CI 1.28 to 2.44; P = 0.0005; I2 = 0%; ARI 1.9%; NNTH 53 (95% CI 145 to 28); 4520 participants; 2 trials; moderate certainty of evidence). No evidence of a difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.82 to 1.11; P = 0.53; I2 = 43%; 9457 participants; 5 trials; moderate certainty of evidence) and stroke (RR 1.17; 95% CI 0.90 to 1.52; P = 0.24; I2 = 0%; 9457 participants; 5 trials; high certainty of evidence). Meta-analyses of trials at low risk of bias differed from the overall analyses when assessing cardiovascular mortality at maximum follow-up. For all other outcomes, meta-analyses of trials at low risk of bias did not differ from the overall analyses. None of the trials specifically assessed serious adverse event according to ICH-GCP. No data were found on quality of life. AUTHORS' CONCLUSIONS: Our present review indicates that antibiotics (macrolides or quinolones) for secondary prevention of coronary heart disease seem harmful when assessing the risk of all-cause mortality, cardiovascular mortality, and stroke at maximum follow-up and all-cause mortality, cardiovascular mortality, and sudden cardiac death at 24±6 months follow-up. Current evidence does, therefore, not support the clinical use of macrolides and quinolones for the secondary prevention of coronary heart disease. Future trials on the safety of macrolides or quinolones for the secondary prevention in patients with coronary heart disease do not seem ethical. In general, randomised clinical trials assessing the effects of antibiotics, especially macrolides and quinolones, need longer follow-up so that late-occurring adverse events can also be assessed.

The effects of adding quinolones to beta-lactam antibiotics for sepsis.

BACKGROUND: Sepsis is common, deadly, and a major challenge to treat. Quinolones added to beta-lactam antibiotics are currently recommended as a second-line empiric regimen in sepsis, but the evidence regarding their benefits and harms is unclear. OBJECTIVE: To assess the benefits and harms of adding quinolones to standard care for sepsis. DATA SOURCES: We conducted a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis. We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, and BIOSIS. STUDY SELECTION: Randomized clinical trials assessing the effects of adding any quinolone to standard care for children and adults with sepsis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened studies and extracted data. The certainty of the evidence was assessed by GRADE. RESULTS: We included three trials randomizing 995 adults. All trials were at overall "high risk of bias." All trials compared a quinolone (moxifloxacin, levofloxacin, or ciprofloxacin) and a beta-lactam antibiotic versus the same beta-lactam antibiotic. We found no evidence of an effect of adding quinolones to beta-lactam antibiotics when assessing all-cause mortality (RR 1.07, 95% CI 0.86 to 1.33; 2 trials; 915 participants; very low certainty of evidence) and serious adverse events (RR 1.00, 95% CI 0.67 to 1.50; 977 participants; two trials; very low certainty of evidence). No trials reported on quality of life. CONCLUSIONS: The effects of adding quinolones to beta-lactam antibiotics for the treatment of sepsis were unclear for all outcomes. Additional trial data are warranted to support the recommendation of empirical use of quinolones for sepsis.

Letter to Editor: Response to AASLD Editorial/Message from the President.

A commentary [1] criticized our systematic review regarding the use of direct-acting agents (DAAs) in chronic hepatitis C [2]. The following represents our major disagreements. Sustained virological response (SVR) is a non-validated surrogate outcome. The principles of evidence-based medicine require that it be validated in randomized clinical trials (RCTs) by showing parallel benefits in clinical outcomes [3]. This article is protected by copyright. All rights reserved.

Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Acutely ill patients are at risk of stress-related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients. METHODS: We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). The primary outcomes were all-cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials. RESULTS: We included 65 comparisons from 62 trials (n = 9713); 43 comparisons were from intensive care units. Only three trials (n = 3596) had overall low risk of bias. We did not find an effect on all-cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA-adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA-adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health-related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses. CONCLUSIONS: We did not observe a difference in all-cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive. STUDY REGISTRATION: PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.

Haloperidol for the treatment of delirium in critically ill patients: A systematic review with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium. METHODS: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomized clinical trials (RCTs) assessing the effects of haloperidol vs any intervention on all-cause mortality, serious adverse reactions/events, days alive without delirium, health-related quality of life (HRQoL), cognitive function and delirium severity in critically ill patients with delirium. We also report on QTc prolongation, delirium resolution and extrapyramidal symptoms. RESULTS: We included 8 RCTs with 11 comparisons (n = 951). We adjudicated one trial as having overall low risk of bias. Three trials used rescue haloperidol; excluding these, we did not find an effect of haloperidol vs control on all-cause mortality (RR 1.01; 95% CI 0.33-3.06; I2  = 0%; 112 participants; 3 trials; 4 comparisons; very low certainty) or delirium severity (SMD -0.15; 95% CI -0.61-0.30; I2  = 27%; 134 participants; 3 trials; 4 comparisons; very low certainty). No trials reported adequately on serious adverse reactions/events. Only one trial reported on days alive without delirium, cognitive function and QTc prolongation, and no trials reported on HRQoL. Sensitivity analyses, including trials using rescue haloperidol, did not change the results. CONCLUSIONS: The evidence for the use of haloperidol to treat critically ill patients with delirium is sparse, of low quality and inconclusive. We therefore have no certainty regarding any beneficial, harmful or neutral effects of haloperidol in these patients.