Systematic literature review to inform the EULAR recommendations for the use of imaging in crystal-induced arthropathies in clinical practice.

OBJECTIVE: To summarise current data regarding the use of imaging in crystal-induced arthropathies (CiAs) informing a European Alliance of Associations for Rheumatology task force. METHODS: We performed four systematic searches in Embase, Medline and Central on imaging for diagnosis, monitoring, prediction of disease severity/treatment response, guiding procedures and patient education in gout, calcium pyrophosphate dihydrate deposition (CPPD) and basic calcium phosphate deposition (BCPD). Records were screened, manuscripts reviewed and data of the included studies extracted. The risk of bias was assessed by validated instruments. RESULTS: For gout, 88 studies were included. Diagnostic studies reported good to excellent sensitivity and specificity of dual-energy CT (DECT) and ultrasound (US), high specificity and lower sensitivity for conventional radiographs (CR) and CT. Longitudinal studies demonstrated sensitivity to change with regard to crystal deposition by US and DECT and inflammation by US and structural progression by CR and CT. For CPPD, 50 studies were included. Diagnostic studies on CR and US showed high specificity and variable sensitivity. There was a single study on monitoring, while nine assessed the prediction in CPPD. For BCPD, 56 studies were included. There were two diagnostic studies, while monitoring by CR and US was assessed in 43 studies, showing a reduction in crystal deposition. A total of 12 studies with inconsistent results assessed the prediction of treatment response. The search on patient education retrieved two studies, suggesting a potential role of DECT. CONCLUSION: This SLR confirmed a relevant and increasing role of imaging in the field of CiAs.

Effects of extracorporeal CO2 removal on gas exchange and ventilator settings: a systematic review and meta-analysis.

PURPOSE: A systematic review and meta-analysis to evaluate the impact of extracorporeal carbon dioxide removal (ECCO2R) on gas exchange and respiratory settings in critically ill adults with respiratory failure. METHODS: We conducted a comprehensive database search, including observational studies and randomized controlled trials (RCTs) from January 2000 to March 2022, targeting adult ICU patients undergoing ECCO2R. Primary outcomes were changes in gas exchange and ventilator settings 24 h after ECCO2R initiation, estimated as mean of differences, or proportions for adverse events (AEs); with subgroup analyses for disease indication and technology. Across RCTs, we assessed mortality, length of stay, ventilation days, and AEs as mean differences or odds ratios. RESULTS: A total of 49 studies encompassing 1672 patients were included. ECCO2R was associated with a significant decrease in PaCO2, plateau pressure, and tidal volume and an increase in pH across all patient groups, at an overall 19% adverse event rate. In ARDS and lung transplant patients, the PaO2/FiO2 ratio increased significantly while ventilator settings were variable. "Higher extraction" systems reduced PaCO2 and respiratory rate more efficiently. The three available RCTs did not demonstrate an effect on mortality, but a significantly longer ICU and hospital stay associated with ECCO2R. CONCLUSIONS: ECCO2R effectively reduces PaCO2 and acidosis allowing for less invasive ventilation. "Higher extraction" systems may be more efficient to achieve this goal. However, as RCTs have not shown a mortality benefit but increase AEs, ECCO2R's effects on clinical outcome remain unclear. Future studies should target patient groups that may benefit from ECCO2R. PROSPERO Registration No: CRD 42020154110 (on January 24, 2021).

Impact of neonatal pain and opiate administration in animal models: A meta-analysis concerning pain threshold.

BACKGROUND AND AIM: Neonatal intensive care treatment, including frequently performed painful procedures and administration of analgesic drugs, can have different effects on the neurodevelopment. This systematic review and meta-analysis aimed to investigate the influence of pain, opiate administration, and pre-emptive opiate administration on pain threshold in animal studies in rodents, which had a brain development corresponding to preterm and term infants. METHODS: A systematic literature search of electronic data bases including CENTRAL (OVID), CINAHL (EBSCO), Embase.com, Medline (OVID), Web of Science, and PsycInfo (OVID) was conducted. A total of 42 studies examining the effect of pain (n = 38), opiate administration (n = 9), and opiate administration prior to a painful event (n = 5) in rodents were included in this analysis. RESULTS: The results revealed that pain (g = 0.42, 95%CI 0.16-0.67, p = 0.001) increased pain threshold leading to hypoalgesia. Pre-emptive opiate administration had the opposite effect, lowering pain threshold, when compared to pain without prior treatment (g = -1.79, 95%CI -2.71-0.86, p = 0.0001). Differences were found in the meta regression for type of stimulus (thermal: g = 0.66, 95%CI 0.26-1.07, p = 0.001; vs. mechanical: g = 0.13, 95%CI -0.98-1.25, p = 0.81) and gestational age (b = -1.85, SE = 0.82, p = 0.027). In addition, meta regression indicated an association between higher pain thresholds and the amount of cumulative pain events (b = 0.06, SE = 0.03, p = 0.05) as well as severity of pain events (b = 0.94, SE = 0.28, p = 0.001). CONCLUSION: Neonatal exposure to pain results in higher pain thresholds. However, caution is warranted in extrapolating these findings directly to premature infants. Further research is warranted to validate similar effects in clinical contexts and inform evidence-based practices in neonatal care.

The effect of prenatal maternal distress on offspring brain development: A systematic review.

BACKGROUND: Prenatal maternal distress can negatively affect pregnancy outcomes, yet its impact on the offspring's brain structure and function remains unclear. This systematic review summarizes the available literature on the relationship between prenatal maternal distress and brain development in fetuses and infants up to 12 months of age. METHODS: We searched Central, Embase, MEDLINE, PsycINFO, and PSYNDEXplus for studies published between database inception and December 2023. Studies were included if prenatal maternal anxiety, stress, and/or depression was assessed, neuroimaging was used to examine the offspring, and the offspring's brain was imaged within the first year of life. The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-II. RESULTS: Out of the 1516 studies retrieved, 71 met our inclusion criteria. Although the studies varied greatly in their methodology, the results generally pointed to structural and functional aberrations in the limbic system, prefrontal cortex, and insula in fetuses and infants prenatally exposed to maternal distress. CONCLUSIONS: The hippocampus, amygdala, and prefrontal cortex have a high density of glucocorticoid receptors, which play a key role in adapting to stressors and maintaining stress-related homeostasis. We thus conclude that in utero exposure to maternal distress prompts these brain regions to adapt by undergoing structural and functional changes, with the consequence that these alterations increase the risk for developing a neuropsychiatric illness later on. Future research should investigate the effect of providing psychological support for pregnant women on the offspring's early brain development.

2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice.

OBJECTIVE: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). METHODS: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. RESULTS: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). CONCLUSIONS: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.

Treatment of myopic choroidal neovascularization: a network meta-analysis and review.

PURPOSE: This is, to our knowledge, the first network meta-analysis aiming to compare all treatment modalities for myopic choroidal neovascularization (CNV). METHODS: After the electronic databases were searched, two independent reviewers screened titles, abstracts, full-texts, and extracted information. Primary endpoints were change in visual outcome and central retinal thickness. We used a network meta-analysis to compare treatment outcomes in the early (≤ 6 months) and late (> 6 months) phase. RESULTS: We included 34 studies (2,098 eyes) in our network meta-analysis. In the early phase, the use of anti-VEGF led to a gain of 14.1 letters (95% CI, 10.8-17.4) compared to untreated patients (p < 0.0001), 12.1 letters (95% CI, 8.3-15.8) to photodynamic therapy (PDT) (p < 0.0001), 7.5 (95% CI, 1.2-13.8) letters to intravitreal triamcinolone acetonide (TCA) (p = 0.019), and - 2.9 letters (95% CI, - 6.0-0.2) to the combination of anti-VEGF and PDT (p = 0.065). In the later phase, these results were largely maintained. There were no significant differences in visual outcomes between patients treated with 1 + PRN and 3 + PRN. However, the 1 + PRN group received 1.8 (SD 1.3), while the 3 + PRN group received 3.2 (SD 0.9) injections within 12 months (p < 0.0001). CONCLUSION: This network meta-analysis confirms that anti-VEGF is the most effective treatment for myopic CNV using the 1 + PRN treatment strategy.

Pharmacokinetic-guided versus standard prophylaxis in hemophilia: a systematic review and meta-analysis.

BACKGROUND: With population pharmacokinetic (PK) modeling more readily available and PK-guided prophylaxis endorsed by current hemophilia guidelines, we conducted a systematic review to summarize current evidence in the literature. OBJECTIVES: To assess the efficacy of PK-guided compared with non-PK-guided prophylaxis. METHODS: We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full-text screening conducted independently by 2 review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCTs) quantitatively by fitting random-effects models. RESULTS: Search of databases on February 3, 2023, yielded 25 studies fitting our inclusion criteria. Of those, only 2 RCTs and 17 nonrandomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, nonrandomized studies were only presented qualitatively. A random-effects meta-analysis of the 2 identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means, 1.15; 95% CI, 0.85-1.56) and factor consumption (ratio of means, 0.82; 95% CI, 0.58-1.18). CONCLUSION: Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in nonrandomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias.

The consequences of neonatal pain, stress and opiate administration in animal models: An extensive meta-analysis concerning neuronal cell death, motor and behavioral outcomes.

This systematic review and meta-analysis aimed to investigate the association of neonatal exposure to pain, stress, opiate administration alone, as well as opiate administration prior to a painful procedure on neuronal cell death, motor, and behavioral outcomes in rodents. In total, 36 studies investigating the effect of pain (n = 18), stress (n = 15), opiate administration (n = 13), as well as opiate administration prior to a painful event (n = 7) in rodents were included in our meta-analysis. The results showed a large effect of pain (g = 1.37, 95% CI 1.00-1.74, p < .001) on neuronal cell death. Moreover, higher number of neonatal pain events were significantly associated with increased neuronal cell death, increased anxiety (b = -1.18, SE = 0.43, p = .006), and depressant-like behavior (b = 1.74, SE = 0.51, p = .027) in rodents. Both opiates and pain had no impact on motor function (g = 0.26, 95% CI 0.18-0.70, p = .248).

Cholesterol and glaucoma: a systematic review and meta-analysis.

PURPOSE: Intraocular pressure is the main risk factor for glaucoma; however, additional risk factors may also matter. This systematic review and meta-analysis were conducted to summarize the evidence regarding the association of cholesterol parameters (total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels) and glaucoma. METHODS: Four electronic databases were searched for all publications containing 'glaucoma' and one of various forms of 'cholesterol' or 'lipoprotein'. Two independent reviewers screened abstracts and potentially full texts of identified articles for eligibility. Risk of bias was assessed with the Newcastle-Ottawa Scale. A random-effects meta-analysis was used to investigate the differences in total cholesterol, LDL and HDL levels between patients with and without glaucoma. RESULTS: Overall, 29 observational studies were included in the systematic review and 26 reported quantitative information to investigate differences in cholesterol parameters between patients with glaucoma (N = 7196) and patients without glaucoma (N = 350 441). Patients with glaucoma had significantly higher total cholesterol levels than patients without glaucoma (Mean Difference (MD) 7.9 mg/dl, 95% CI 3.3 to 12.5, p = 0.001) and lower mean HDL levels (MD -2.0 mg/dl, 95% CI: -3.1 to -0.9, p = 0.001). Patients with glaucoma had higher mean LDL levels than patients without glaucoma, albeit not statistically significant (MD 6.1 mg/dl, 95% CI: -4.3 to 16.4, p = 0.251). CONCLUSION: This systematic review and meta-analysis of observational studies found an association of glaucoma and high total cholesterol and low HDL levels, respectively. Although this supports the hypothesis that lipid levels pose an additional risk for glaucoma development, heterogeneity was substantial and causality cannot be presumed from identified observational studies.

Pain and Sedation Scales for Neonatal and Pediatric Patients in a Preverbal Stage of Development: A Systematic Review.

Importance: Because children in a preverbal stage of development are unable to voice their feelings, they completely depend on their caregiving team for the interpretation and management of their pain and discomfort. Thus, accurately validated scales to assess pain and sedation levels are crucial. Objective: To provide clinicians a complete overview on the validity and reliability of the existing pain and sedation scales for different target populations (preterm infants, term infants, and toddlers) and in different clinical contexts. Evidence Review: BIOSIS Previews, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycCRITIQUES, PsycINFO, PSYNDEXplus Literature and Audiovisual Media, and PSYNDEXplus Tests were the databases screened from their inception to August 2018. All studies examining the validity or reliability of a given pain or sedation scale for patients in a preverbal stage of development were included in this systematic review. Those scales that were tested for at least construct validity, internal consistency, and interrater reliability were subsequently scored using the consensus-based standards for the selection of health measurement instruments (COSMIN) checklist. Findings: In total, 89 validation articles comprising 65 scales were included. Fifty-seven scales (88%) were useful for assessing pain, 13 scales (20%) for assessing sedation, and 4 scales (6%) for assessing both conditions. Forty-two (65%) were behavioral scales, and 23 (35%) were multidimensional scales. Eleven scales (17%) were validated for infants on mechanical ventilation. Thirty-seven scales (57%) were validated for preterm infants, 24 scales (37%) for term and preterm infants, 7 scales (11%) for term-born children, 7 scales (11%) for preterm infants, term infants, and toddlers, and 17 scales (26%) for term infants and toddlers. Twenty-eight scales (43%) considered construct validity, internal consistency, and interrater reliability. Conclusions and Relevance: Clinicians should consider using scales that are validated for at least construct validity, internal consistency, and interrater reliability, combining this information with the population of interest and the construct the scale is intended to measure.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery.

BACKGROUND: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update and assesses the evidence in cardiac surgery only. OBJECTIVES: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles. SELECTION CRITERIA: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing cardiac surgery. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain.Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence).We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency. AUTHORS' CONCLUSIONS: We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.

BACKGROUND: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only. OBJECTIVES: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles. SELECTION CRITERIA: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants. AUTHORS' CONCLUSIONS: The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.

Comparison of transcatheter aortic valve implantation with other approaches to treat aortic valve stenosis: a systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVI) is an alternative treatment for patients with symptomatic severe aortic stenosis ineligible for surgical aortic valve replacement (SAVR) or at increased perioperative risk. Due to continually emerging evidence, we performed a systematic review and meta-analysis comparing benefits and harms of TAVI, SAVR, medical therapy, and balloon aortic valvuloplasty. METHODS: We searched MEDLINE, Embase, and Cochrane CENTRAL from 2002 to June 6, 2017. We dually screened abstracts and full-text articles for randomized controlled trials (RCTs) and propensity score-matched observational studies. Two investigators independently rated the risk of bias of included studies and determined the certainty of evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). If data permitted, we performed meta-analyses using random- and fixed-effects models. RESULTS: Out of 7755 citations, we included six RCTs (5862 patients) and 13 observational studies (6376 patients). In meta-analyses, patients treated with SAVR or TAVI had similar risks for mortality at 30 days (relative risk [RR] 1.05; 95% confidence interval [CI] 0.82 to 1.33) and 1 year (RR 1.02; 95% CI 0.93 to 1.13). TAVI had significantly lower risks for major bleeding but increased risks for major vascular complications, moderate or severe paravalvular aortic regurgitation, and new pacemaker implantation compared to SAVR. Comparing TAVI to medical therapy, mortality did not differ at 30 days but was significantly reduced at 1 year (RR 0.51; 95% CI 0.34 to 0.77). CONCLUSIONS: Given similar mortality risks but different patterns of adverse events, the choice between TAVI and SAVR remains an individual one.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. SEARCH METHODS: We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. SELECTION CRITERIA: We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. MAIN RESULTS: We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery.CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.• All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.• Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB five, 6420 participants, high quality evidence.• On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality evidence).NON-CARDIAC SURGERY (35 trials)Beta-blockers significantly increased the occurrence of the following adverse events.• All-cause mortality: RR 1.25, 95% CI 1.00 to 1.57, 11,413 participants, low quality of evidence, number needed to treat for an additional harmful outcome (NNTH) 167.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 16, 10,947 participants, high quality evidence.• Bradycardia: RR 2.23, 95% CI 1.48 to 3.36, NNTH 21, 11,033 participants, moderate quality evidence.We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 265, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 76, 10,958 participants, high quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.34 to 0.77, NNTB nine, 978 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.73, 95% CI 0.57 to 0.94, NNTB 112, 8744 participants, high quality evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.68, 95% CI 0.31 to 1.49, 476 participants, moderate quality evidence.• Congestive heart failure: RR 1.18, 95% CI 0.94 to 1.48, 9173 participants, moderate quality evidence.• Length of hospital stay: mean difference -0.45 days, 95% CI -1.75 to 0.84, 551 participants, low quality evidence. AUTHORS' CONCLUSIONS: According to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery, as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.In non-cardiac surgery, evidence shows an association of beta-blockers with increased all-cause mortality. Data from low risk of bias trials further suggests an increase in stroke rate with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. SEARCH METHODS: We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. SELECTION CRITERIA: We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. MAIN RESULTS: We included 89 randomized controlled trials with 19,211 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery. CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.• All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality of evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality of evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality of evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality of evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality of evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality of evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality of evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.• Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality of evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB six, 6420 participants, high quality of evidence.• On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality of evidence). NON-CARDIAC SURGERY (36 trials)We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• All-cause mortality: RR 1.24, 95% CI 0.99 to 1.54, 11,463 participants, low quality of evidence.Whereas no clear evidence of an effect was noted when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in all-cause mortality with the use of beta-blockers: RR 1.27, 95% CI 1.01 to 1.59, number needed to treat for an additional harmful outcome (NNTH) 189, 10,845 participants.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality of evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 255, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 72, 10,958 participants, high quality of evidence.• Myocardial ischaemia: RR 0.43, 95% CI 0.27 to 0.70, NNTB seven, 1028 participants, moderate quality of evidence.• Supraventricular arrhythmias: RR 0.72, 95% CI 0.56 to 0.92, NNTB 111, 8794 participants, high quality of evidence.Beta-blockers significantly increased the occurrence of the following adverse events.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 15, 10,947 participants, high quality of evidence.• Bradycardia: RR 2.24, 95% CI 1.49 to 3.35, NNTH 18, 11,083 participants, moderate quality of evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.64, 95% CI 0.30 to 1.33, 526 participants, moderate quality of evidence.• Congestive heart failure: RR 1.17, 95% CI 0.93 to 1.47, 9223 participants, moderate quality of evidence.• Length of hospital stay: mean difference -0.27 days, 95% CI -1.29 to 0.75, 601 participants, low quality of evidence. AUTHORS' CONCLUSIONS: According to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery , as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.In non-cardiac surgery, evidence from low risk of bias trials shows an increase in all-cause mortality and stroke with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

Antipsychotics for acute and chronic pain in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 4, 2008. The role of antipsychotics as adjuvant analgesics is a subject of longstanding controversy. Neuroleptanalgesia (that is a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic), an established term for the management of acute pain, was shown to negatively influence disease course and total mortality in unstable angina patients. Nevertheless, antipsychotics are used to treat chronic pain (for example chronic headache, fibromyalgia and diabetic neuropathia). With atypical antipsychotics, a new class of antipsychotics, both fewer extrapyramidal side effects and additional benefits may be available. OBJECTIVES: To assess the analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE in October 2011 and January 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults prescribed any dose of an oral antipsychotic for acute or chronic pain, where subjective pain assessment was described as either the primary or a secondary outcome, were included in this review. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent review authors, and results were compared for differences. Discrepancies were resolved by discussion. All trials were quality scored according to the methods set out in section six of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: A total of 770 participants were involved in the 11 included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound, weighted mean difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data; and relative risk (RR) 0.43 (95% CI 0.25 to 0.73), number needed to treat to benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for both the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). Obviously this makes the calculated NNT less reliable and caution is warranted when interpreting these results.The most frequently reported adverse effects were extrapyramidal (that is involuntary movements, parkinsonism and akathisia) and sedating effects. AUTHORS' CONCLUSIONS: The recent search found five new studies which were all excluded, so the review remains the same as previously.Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions.Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo-controlled studies that include standardised pain assessment and documentation are warranted.

Antipsychotics for acute and chronic pain in adults.

CONTEXT: The role of antipsychotics as adjuvant analgesics is a subject of long-standing controversy. Antipsychotics have been used to treat chronic pain (e.g., chronic headache, fibromyalgia, and painful diabetic neuropathy). With atypical antipsychotics, a new class of antipsychotics, with fewer extrapyramidal side effects and additional benefits, may be available. OBJECTIVES: This review aimed to assess analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain. METHODS: Randomized controlled trials of adults prescribed any dose of oral antipsychotics for acute or chronic pain, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review. RESULTS: We included 11 studies involving a total number of 770 participants. Data from five randomized, double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Because of the clinical heterogeneity of painful conditions studied and significant statistical heterogeneity, the intended meta-analysis was omitted. The most frequently reported adverse effects were extrapyramidal (i.e., involuntary movements, parkinsonism, and akathisia) and sedating effects. CONCLUSION: Because of limitations in the available evidence, further research is needed to understand whether antipsychotics are effective for acute or chronic pain or specific pain conditions.

Antipsychotics for acute and chronic pain in adults.

BACKGROUND: The role of antipsychotics as adjuvant analgesics is a subject of longstanding controversy. Neuroleptanalgesia (i.e. a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic), an established term for the management of acute pain, was shown to negatively influence disease course and total mortality in unstable angina patients. Nevertheless, antipsychotics are used to treat chronic pain (e.g. chronic headache, fibromyalgia and diabetic neuropathia). With atypical antipsychotics, a new class of antipsychotics, fewer extrapyramidal side effects and additional benefits may be available. OBJECTIVES: Assess analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain. SEARCH STRATEGY: Cochrane Pain, Palliative & Supportive Care Register, CENTRAL, MEDLINE, PsycINFO, and EMBASE searched in October 2007. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults prescribed any dose of oral antipsychotics for acute or chronic pain, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review. DATA COLLECTION AND ANALYSIS: Data was extracted by two independent review authors, and results were compared for differences. Discrepancies were resolved by discussion. All trials were quality scored according to the methods set out in section six of the Cochrane Handbook. MAIN RESULTS: A total of 770 participants were involved in the eleven included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound: Weighted Mean Difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data and Relative Risk (RR) 0.43 (95% CI 0.25 to 0.73), number-needed-to-treat-to-benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). The most frequently reported adverse effects were extrapyramidal (i.e. involuntary movements, parkinsonism and akathisia) and sedating effects. AUTHORS' CONCLUSIONS: Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions.Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo-controlled studies including standardised pain assessment/documentation are warranted.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity: a systematic review and meta-analysis.

BACKGROUND: Perioperative beta-blockers are suggested to reduce cardiovascular mortality, myocardial-ischemia/infarction, and supraventricular arrhythmias after surgery. We reviewed the evidence regarding the effectiveness of perioperative beta-blockers for improving patient outcomes after cardiac and noncardiac surgery. METHODS: Eleven large databases were searched from the time of their inception until October 2005. Various online-resources were consulted for the identification of unpublished trials and conference abstracts. We included randomized, controlled trials comparing perioperative beta-blockers with either placebo or the standard-of-care. Of the 3680 retrieved titles, 69 met inclusion criteria for analysis. Odds ratios (OR) assuming random effects were computed in the absence of significant clinical heterogeneity. RESULTS: Beta-blockers reduced the frequency of ventricular tachyarrhythmias [OR (cardiac surgery): 0.28, 95% CI 0.13-0.57; OR (noncardiac surgery): 0.56, 95% CI 0.21-1.45], atrial fibrillation/flutter [OR (cardiac surgery): 0.37, 95% CI 0.28-0.48], other supraventricular arrhythmias [OR (cardiac surgery): 0.25, 95% CI 0.18-0.35; OR (noncardiac surgery): 0.43, 95% CI 0.14-1.37], and myocardial ischemia [OR (cardiac surgery): 0.49, 95% CI 0.17-1.4; OR (noncardiac surgery): 0.38, 95% CI 0.21-0.69]. Length of hospitalization was not reduced [weighted mean difference (cardiac surgery): -0.35 days, 95% CI -0.77-0.07; weighted mean difference (noncardiac surgery): -5.59 days, 95% CI -12.22-1.04] and, in contrast to previous reports, beta-blockers did not reduce mortality [OR (cardiac surgery): 0.55, 95% CI 0.17-1.83; OR (noncardiac surgery): 0.78, 95% CI 0.33-1.87], and they had no influence on the occurrence of perioperative myocardial infarction [OR (cardiac surgery): 0.89, 95% CI 0.53-1.5; OR (noncardiac surgery): 0.59; 0.25-1.39]. CONCLUSIONS: Beta-blockers reduced perioperative arrhythmias and myocardial ischemia, but they had no effect on myocardial infarction, mortality, or length of hospitalization.