The relationship between study findings and publication outcome in anesthesia research following implementation of mandatory trial registration: A systematic review of publication bias.

Previously, we reviewed 1052 randomized-controlled trial abstracts presented at the American Society of Anesthesiologists annual meetings from 2001-2004. We found significant positive publication bias in the period examined, with the odds ratio for abstracts with positive results proceeding to journal publication over those with null results being 2.01 [95% confidence interval: 1.52, 2.66; P < 0.001]. Mandatory trial registration was introduced in 2005 as a required standard for publication. We sought to examine whether mandatory trial registration has decreased publication bias in the anesthesia and perioperative medicine literature. We reviewed all abstracts from the 2010-2016 American Society of Anesthesiologists meetings that reported on randomized-controlled trials in humans. We scored the result of each abstract as positive or null according to a priori definitions. We systematically searched for any subsequent publication of the studies and calculated the odds ratio for journal publication, comparing positive vs null studies. We compared the odds ratio from the 2010-2016 abstracts (post-mandatory trial registration) with the odds ratio from the 2001-2004 abstracts (pre-mandatory trial registration) as a ratio of odds ratios. We defined a 33% decrease in the odds ratio as significant, corresponding to a new odds ratio of 1.33. We reviewed 9789 abstracts; 1049 met inclusion criteria as randomized-controlled trials, with 542 (51.7%) of the abstracts going on to publication. The odds ratio for abstracts with positive results proceeding to journal publication was 1.28 [95% CI: 0.97, 1.67; P = 0.076]. With adjustment for sample size and abstract quality, the difference in publication rate between positive and null abstracts was statistically significant (odds ratio 1.34; 95% CI: 1.02, 1.76; P = 0.037). The ratio of odds ratios, comparing the odds ratio from the 2010-2016 abstracts (post-mandatory trial registration) to the odds ratio from the 2001-2004 abstracts (pre-mandatory trial registration), was 0.63 (95% CI: 0.43, 0.93); P = 0.021). We present the first study in the anesthesia and perioperative medicine literature that examines and compares publication bias over two discrete periods of time, prior to and after the implementation of mandatory trial registration. Our results suggest that the amount of publication bias has decreased markedly following implementation of mandatory trial registration. However, some positive publication bias in the anesthesia and perioperative medicine literature remains.

Trial registration of abstracts from the American Society of Anesthesiologists Meetings 2010-2016: A review of prospective trial registration and selective outcome reporting.

Mandatory prospective trial registration was introduced in 2005 to reduce publication bias and selective outcome reporting. In this study, we measured the proportion of prospective trial registration in randomized controlled trials in the anesthesia literature after this introduction, discrepancies between these trial protocols and subsequent publications, the association between being prospectively registered and reporting positive or negative results, and between being prospectively registered and achieving publication. We reviewed all abstracts from the American Society of Anesthesiologists annual meetings between 2010-2016 and included randomized controlled trials in humans. The abstract conclusions were scored as positive or negative according to predetermined definitions. We conducted a systematic search for trial registration and subsequent publication. Of the 9789 abstracts reviewed, 1070 abstracts were included. 222 (21%) of these abstracts had undergone prospective trial registration. 168/222 (76%) had a corresponding journal publication. 81(48%) had a major discrepancy between registration and publication. 149 (67%) of the abstracts with registration had positive outcomes compared with 616 (73%) of those without (Odds Ratio 0.77; 95% CI: 0.56 to 1.06; P = 0.105). Abstracts that had been registered were more likely to proceed to publication than those that had not (Odds Ratio 3.82; 95% CI 2.73 to 5.35; P < 0.001). The proportion of randomized controlled trials being prospectively registered in anesthesia remains low. Discrepancies between registry entries and corresponding journal publications are common. There was no association between prospective trial registration and subsequent positive outcomes. There was a strong association between prospective trial registration and the likelihood of progression to journal publication.

Effects of rotational thromboelastometry-guided transfusion management in patients undergoing surgical intervention for postpartum hemorrhage: An observational study.

BACKGROUND: Postpartum hemorrhage (PPH) can be associated with coagulopathy, which may be difficult to rapidly assess and may exacerbate blood loss. Rotational thromboelastometry (ROTEM) at the point of care can guide clinician choice of blood products and has been shown in some settings to reduce transfusions and improve outcomes. This hospital-based observational study aims to measure effects of a ROTEM-guided transfusion protocol on transfusion practice and clinical outcomes in patients with PPH managed in the operating theater. STUDY DESIGN AND METHODS: We compared a retrospective cohort of 450 consecutive patients with PPH treated in the operating theater before the introduction of a ROTEM-guided transfusion algorithm in June 2016, with 450 patients treated after its introduction. Multivariate regression was used to evaluate the effect of ROTEM introduction on the primary outcome, patients requiring a packed red blood cell (PRBC) transfusion and adjusting for demographic and obstetric confounders. Secondary outcomes included other blood product transfusions, hysterectomy, and intensive care unit admission. RESULTS: A total of 90 (20%) of patients treated prior to ROTEM introduction received a PRBC transfusion, compared with 102 (22.7%) of those treated after ROTEM introduction (95% confidence interval [CI] 1.0-2.0, p = .04). There was no difference in PRBC transfusion in patients undergoing caesarean section (95% CI 0.5-1.8, p = .99). There was a trend toward increased use of cryoprecipitate and reduced use of platelets and fresh frozen plasma after ROTEM introduction. CONCLUSION: In our institution, the introduction of ROTEM-guided transfusion did not reduce PRBC transfusion in patients with PPH treated in the operating theater.

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

OBJECTIVE: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions. STUDY DESIGN AND SETTING: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups. RESULTS: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters. CONCLUSION: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.

Intravenous iron therapy for non-anaemic, iron-deficient adults.

BACKGROUND: Iron deficiency is one of the most common nutritional deficiencies, and has a number of physiological manifestations. Early, or non-anaemic iron deficiency can result in fatigue and diminished exercise capacity. Oral iron preparations have a high incidence of intolerable side effects, and are ineffective in certain forms of iron deficiency. Consequently, intravenous iron preparations are increasingly used in the treatment of non-anaemic iron deficiency. The newer, more stable iron preparations in particular purport to have a lower incidence of side effects, and are now used across a range of different patient populations. OBJECTIVES: To assess the effects of intravenous iron therapy in the treatment of adults with non-anaemic iron deficiency. SEARCH METHODS: On 18 October 2019 we electronically searched CENTRAL, MEDLINE, Embase, two further databases and two trials registries 2019. We handsearched the references of full-text extracted studies, and contacted relevant study authors for additional data. SELECTION CRITERIA: We included randomised controlled trials that compared any intravenous iron preparation to placebo in adults. We excluded other forms of comparison such as oral iron versus placebo, intramuscular iron versus placebo, or intravenous iron studies where other iron preparations were used as the comparator. We also excluded studies involving erythropoietin therapy or obstetric populations. DATA COLLECTION AND ANALYSIS: Two review authors screened references for eligibility, extracted data and assessed risk of bias. We resolved differences in opinion through discussion and consensus, and where necessary, involved a third review author to adjudicate disputes. We contacted study authors to request additional data where appropriate. The primary outcome measures were haemoglobin concentration at the end of follow-up, and quality-of-life scores at end of follow-up. Secondary outcome measures were serum ferritin, peak oxygen consumption (as measured by cardiopulmonary exercise testing), adverse effects (graded as mild to moderate and severe) and bacterial infection. We pooled data for continuous outcomes, which we then reported as mean differences (MDs) with 95% confidence intervals (CIs). We reported quality-of-life metrics as standardised mean difference (SMD), and then converted them back into a more familiar measure, the Piper Fatigue Scale. We analysed dichotomous outcomes as risk ratios (RRs). Given an expected degree of heterogeneity, we used a random-effects model for all outcomes. We performed the analysis with the software package Review Manager 5. MAIN RESULTS: This review includes 11 studies with 1074 participants. Outcome metrics for which data were available (haemoglobin concentration, quality-of-life scores, serum ferritin, peak oxygen consumption and mild to moderate adverse effects) were similar across the included studies. The incidence of severe adverse events across all studies was zero. None of the studies measured bacterial infection as a specific outcome metric. Substantial heterogeneity influenced the results of the meta-analysis, arising from differing patient populations, definitions of iron deficiency, iron preparations and dosing regimens, and time to end of follow-up. Consequently, many outcomes are reported with small group sizes and wide confidence intervals, with a subsequent downgrading in the quality of evidence. The level of bias in many included studies was high, further reducing confidence in the robustness of the results. We found that intravenous iron therapy may lead to a small increase in haemoglobin concentration of limited clinical significance compared to placebo (MD 3.04 g/L, 95% CI 0.65 to 5.42; I2 = 42%; 8 studies, 548 participants; low-quality evidence). Quality-of-life scores (Piper Fatigue Scale MD 0.73, 95% CI 0.29 to 1.18; I2 = 0%; studies = 3) and peak oxygen consumption (MD 2.77 mL/kg/min, 95% CI -0.89 to 6.43; I2 = 36%; 2 studies, 32 participants) were associated with very low-quality evidence, and we remain uncertain about the role of intravenous iron for these metrics. We were unable to present pooled estimates for the outcomes of serum ferritin at the end of follow-up or mild to moderate adverse effects due to extreme statistical heterogeneity. Ultimately, despite the results of the meta-analysis, the low- or very low-quality evidence for all outcomes precludes any meaningful interpretation of results beyond suggesting that further research is needed. We performed a Trial Sequential Analysis for all major outcomes, none of which could be said to have reached a necessary effect size. AUTHORS' CONCLUSIONS: Current evidence is insufficient to show benefit of intravenous iron preparations for the treatment of non-anaemic iron deficiency across a variety of patient populations, beyond stating that it may result in a small, clinically insignificant increase in haemoglobin concentration. However, the certainty for even this outcome remains limited. Robust data for the effectiveness of intravenous iron for non-anaemic iron deficiency is still lacking, and larger studies are required to assess the effect of this therapy on laboratory, patient-centric, and adverse-effect outcomes.

Prolonged Unexplained Hypoxemia as Initial Presentation of Cirrhosis: A Case Report.

BACKGROUND Hepatopulmonary syndrome (HPS) is a pulmonary complication of advanced liver disease with dyspnea as the predominant presenting symptom. The diagnosis of HPS can often be missed due to its nonspecific presentation and the presence of other comorbidities. CASE REPORT We present an interesting case of an obese 43-year-old man who presented with progressive, unexplained hypoxemia and shortness of breath in the absence of any symptoms or signs of chronic liver disease. After extensive cardiopulmonary investigations, he was diagnosed with severe HPS as a result of non-alcoholic steatohepatitis (NASH) leading to cirrhosis. He subsequently underwent successful hepatic transplantation and continues to improve at 12-month follow-up. CONCLUSIONS HPS needs to be considered in the differential diagnosis of unexplained hypoxemia. Given its poor prognosis, early diagnosis is warranted and treatment with liver transplantation is the preferred choice.

Erythropoiesis-stimulating Agents in Critically Ill Trauma Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a meta-analysis of all relevant randomized controlled trials assessing the effect of erythropoiesis-stimulating agents (ESAs) in critically ill trauma patients. BACKGROUND: ESAs have effects beyond erythropoiesis. The administration of the ESA epoetin alfa to critically ill trauma patients has been associated with a reduction in mortality. METHODS: We performed a systematic review and meta-analysis with trial sequential analysis. We searched Medline, Medline in Process, and other nonindexed citations, EMBASE, and the Cochrane Database from inception until September 9, 2015, for randomized controlled trials comparing ESAs to placebo (or no ESA). RESULTS: We identified 9 eligible studies that randomly assigned 2607 critically ill patients after trauma to an ESA or placebo (or no ESA). Compared with placebo (or no ESA), ESA therapy was associated with a substantial reduction in mortality [risk ratio (RR) 0.63, 95% confidence interval (CI) 0.49-0.79, P = 0.0001, I = 0%). In patients with traumatic brain injury, ESA therapy did not increase the number of patients surviving with moderate disability or good recovery (RR 1.00, 95% CI 0.88-1.15, P = 0.95, I = 0%). With the dosing regimens employed in the included studies, ESA therapy did not increase the risk of lower limb proximal deep venous thrombosis (RR 0.97, 95% CI 0.72-1.29, P = 0.78, I = 0%). CONCLUSIONS: The administration of ESAs to critically ill trauma patients is associated with a significant improvement in mortality without an increase in the rate of lower limb proximal deep venous thrombosis. Given the worldwide public health significance of these findings research to validate or refute them is required.

Viscoelastic testing for hepatic surgery: a systematic review with meta-analysis-a protocol.

BACKGROUND: Viscoelastic tests, including thromboelastography (TEG) and rotational thromboelastometry (ROTEM), provide a global assessment of haemostatic function at the point of care. The use of a TEG or ROTEM system to guide blood product administration has been shown in some surgical settings to reduce transfusion requirements. The aim of this review is to evaluate all published evidence regarding viscoelastic testing in the setting of hepatic surgery. METHODS: We will search MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials databases to identify randomised controlled trials examining the use of viscoelastic testing for hepatic surgery. Two reviewers will independently screen titles and abstracts of studies identified and will independently extract data. Any disagreements will be resolved by discussion with a third reviewer. A meta-analysis will be conducted if feasible. DISCUSSION: Viscoelastic devices such as TEG and ROTEM are increasingly available to clinicians as a bedside test. Patients undergoing hepatic surgery have a significant risk of blood loss and coagulopathy requiring transfusion. Theoretical benefits of use of a TEG or ROTEM system in the hepatic surgical setting include a rationalisation of blood products, a reduction in transfusion-related side effects, an improvement in patient outcomes including mortality, and a reduction in cost. This systematic review will summarise the current evidence regarding the use of viscoelastic testing for hepatic surgery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036732.

False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: an empirical review.

OBJECTIVE: Many published meta-analyses are underpowered. We explored the role of trial sequential analysis (TSA) in assessing the reliability of conclusions in underpowered meta-analyses. METHODS: We screened The Cochrane Database of Systematic Reviews and selected 100 meta-analyses with a binary outcome, a negative result and sufficient power. We defined a negative result as one where the 95% CI for the effect included 1.00, a positive result as one where the 95% CI did not include 1.00, and sufficient power as the required information size for 80% power, 5% type 1 error, relative risk reduction of 10% or number needed to treat of 100, and control event proportion and heterogeneity taken from the included studies. We re-conducted the meta-analyses, using conventional cumulative techniques, to measure how many false positives would have occurred if these meta-analyses had been updated after each new trial. For each false positive, we performed TSA, using three different approaches. RESULTS: We screened 4736 systematic reviews to find 100 meta-analyses that fulfilled our inclusion criteria. Using conventional cumulative meta-analysis, false positives were present in seven of the meta-analyses (7%, 95% CI 3% to 14%), occurring more than once in three. The total number of false positives was 14 and TSA prevented 13 of these (93%, 95% CI 68% to 98%). In a post hoc analysis, we found that Cochrane meta-analyses that are negative are 1.67 times more likely to be updated (95% CI 0.92 to 2.68) than those that are positive. CONCLUSIONS: We found false positives in 7% (95% CI 3% to 14%) of the included meta-analyses. Owing to limitations of external validity and to the decreased likelihood of updating positive meta-analyses, the true proportion of false positives in meta-analysis is probably higher. TSA prevented 93% of the false positives (95% CI 68% to 98%).

Systematic Reviews of Anesthesiologic Interventions Reported as Statistically Significant: Problems with Power, Precision, and Type 1 Error Protection.

BACKGROUND: The GRADE Working Group assessment of the quality of evidence is being used increasingly to inform clinical decisions and guidelines. The assessment involves explicit consideration of all sources of uncertainty. One of these sources is imprecision or random error. Many published meta-analyses are underpowered and likely to be updated in the future. When data are sparse and there are repeated updates, the risk of random error is increased. Trial Sequential Analysis (TSA) is one of several methodologies that estimates this increased risk (and decreased precision) in meta-analyses. With nominally statistically significant meta-analyses of anesthesiologic interventions, we used TSA to estimate power and imprecision in the context of sparse data and repeated updates. METHODS: We conducted a search to identify all systematic reviews with meta-analyses that investigated an intervention that may be implemented by an anesthesiologist during the perioperative period. We randomly selected 50 meta-analyses that reported a statistically significant dichotomous outcome in their abstract. We applied TSA to these meta-analyses by using 2 main TSA approaches: relative risk reduction 20% and relative risk reduction consistent with the conventional 95% confidence limit closest to null. We calculated the power achieved by each included meta-analysis, by using each TSA approach, and we calculated the proportion that maintained statistical significance when allowing for sparse data and repeated updates. RESULTS: From 11,870 titles, we found 682 systematic reviews that investigated anesthesiologic interventions. In the 50 sampled meta-analyses, the median number of trials included was 8 (interquartile range [IQR], 5-14), the median number of participants was 964 (IQR, 523-1736), and the median number of participants with the outcome was 202 (IQR, 96-443). By using both of our main TSA approaches, only 12% (95% CI, 5%-25%) of the meta-analyses had power ≥ 80%, and only 32% (95% CI, 20%-47%) of the meta-analyses preserved the risk of type 1 error <5%. CONCLUSIONS: Most nominally statistically significant meta-analyses of anesthesiologic interventions are underpowered, and many do not maintain their risk of type 1 error <5% if TSA monitoring boundaries are applied. Consideration of the effect of sparse data and repeated updates is needed when assessing the imprecision of meta-analyses of anesthesiologic interventions.

Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology.

The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient's tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

Evolution of heterogeneity (I2) estimates and their 95% confidence intervals in large meta-analyses.

BACKGROUND: Assessment of heterogeneity is essential in systematic reviews and meta-analyses of clinical trials. The most commonly used heterogeneity measure, I(2), provides an estimate of the proportion of variability in a meta-analysis that is explained by differences between the included trials rather than by sampling error. Recent studies have raised concerns about the reliability of I(2) estimates, due to their dependence on the precision of included trials and time-dependent biases. Authors have also advocated use of 95% confidence intervals (CIs) to express the uncertainty associated with I(2) estimates. However, no previous studies have explored how many trials and events are required to ensure stable and reliable I(2) estimates, or how 95% CIs perform as evidence accumulates. METHODOLOGY/PRINCIPAL FINDINGS: To assess the stability and reliability of I(2) estimates and their 95% CIs, in relation to the cumulative number of trials and events in meta-analysis, we looked at 16 large Cochrane meta-analyses--each including a sufficient number of trials and events to reliably estimate I(2)--and monitored the I(2) estimates and their 95% CIs for each year of publication. In 10 of the 16 meta-analyses, the I(2) estimates fluctuated more than 40% over time. The median number of events and trials required before the cumulative I(2) estimates stayed within +/-20% of the final I(2) estimate was 467 and 11. No major fluctuations were observed after 500 events and 14 trials. The 95% confidence intervals provided good coverage over time. CONCLUSIONS/SIGNIFICANCE: I(2) estimates need to be interpreted with caution when the meta-analysis only includes a limited number of events or trials. Confidence intervals for I(2) estimates provide good coverage as evidence accumulates, and are thus valuable for reflecting the uncertainty associated with estimating I(2).

Statistical multiplicity in systematic reviews of anaesthesia interventions: a quantification and comparison between Cochrane and non-Cochrane reviews.

BACKGROUND: Systematic reviews with meta-analyses often contain many statistical tests. This multiplicity may increase the risk of type I error. Few attempts have been made to address the problem of statistical multiplicity in systematic reviews. Before the implications are properly considered, the size of the issue deserves clarification. Because of the emphasis on bias evaluation and because of the editorial processes involved, Cochrane reviews may contain more multiplicity than their non-Cochrane counterparts. This study measured the quantity of statistical multiplicity present in a population of systematic reviews and aimed to assess whether this quantity is different in Cochrane and non-Cochrane reviews. METHODS/PRINCIPAL FINDINGS: We selected all the systematic reviews published by the Cochrane Anaesthesia Review Group containing a meta-analysis and matched them with comparable non-Cochrane reviews. We counted the number of statistical tests done in each systematic review. The median number of tests overall was 10 (interquartile range (IQR) 6 to 18). The median was 12 in Cochrane and 8 in non-Cochrane reviews (difference in medians 4 (95% confidence interval (CI) 2.0-19.0). The proportion that used an assessment of risk of bias as a reason for doing extra analyses was 42% in Cochrane and 28% in non-Cochrane reviews (difference in proportions 14% (95% CI -8 to 36). The issue of multiplicity was addressed in 6% of all the reviews. CONCLUSION/SIGNIFICANCE: Statistical multiplicity in systematic reviews requires attention. We found more multiplicity in Cochrane reviews than in non-Cochrane reviews. Many of the reasons for the increase in multiplicity may well represent improved methodological approaches and greater transparency, but multiplicity may also cause an increased risk of spurious conclusions. Few systematic reviews, whether Cochrane or non-Cochrane, address the issue of multiplicity.

The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis--a simulation study.

BACKGROUND: Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated. METHODS: We simulated a comprehensive array of meta-analysis scenarios where no intervention effect existed (i.e., relative risk reduction (RRR) = 0%) or where a small but possibly unimportant effect existed (RRR = 10%). We constructed different scenarios by varying the control group risk, the degree of heterogeneity, and the distribution of trial sample sizes. For each scenario, we calculated the probability of observing overestimates of RRR>20% and RRR>30% for each cumulative 500 patients and 50 events. We calculated the cumulative number of patients and events required to reduce the probability of overestimation of intervention effect to 10%, 5%, and 1%. We calculated the optimal information size for each of the simulated scenarios and explored whether meta-analyses that surpassed their optimal information size had sufficient protection against overestimation of intervention effects due to random error. RESULTS: The risk of overestimation of intervention effects was usually high when the number of patients and events was small and this risk decreased exponentially over time as the number of patients and events increased. The number of patients and events required to limit the risk of overestimation depended considerably on the underlying simulation settings. Surpassing the optimal information size generally provided sufficient protection against overestimation. CONCLUSIONS: Random errors are a frequent cause of overestimation of intervention effects in meta-analyses. Surpassing the optimal information size will provide sufficient protection against overestimation.