Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis.

BACKGROUND: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial. MATERIAL AND METHODS: This report is the second update of our systematic review with meta-analysis on randomized controlled trials (RCTs) comparing standard thromboprophylaxis, intermediate or therapeutic dose anticoagulation or no anticoagulation in COVID-19 in- and outpatients. We searched eligible studies up to 5 October 2023. Certainty of evidence was assessed using GRADE. RESULTS: For this update we included fourteen new RCTs and a total of 27 RCTs with 16,789 patients. Certainty of evidence ranged from very low to high depending on outcome and comparison. Standard thromboprophylaxis with low dose anticoagulation may have little or no effect for COVID-19 outpatients compared to no anticoagulation. In inpatients with moderate or severe COVID-19, intermediate dose anticoagulation may decrease any thrombotic events or death, but may increase major bleeding compared to standard thromboprophylaxis. Therapeutic dose anticoagulation decreases thrombotic events or deaths in inpatients with moderate COVID-19, but probably has little or no effect in patients with severe COVID-19 compared to standard thromboprophylaxis with low or intermediate dose anticoagulation. With therapeutic dose anticoagulation, the risk of major bleeding probably increases regardless of COVID-19 severity. We are uncertain on the effect of thromboprophylaxis with low dose anticoagulation compared to no anticoagulation in the post-discharge setting. CONCLUSIONS: Hospitalized, moderately-ill COVID-19 patients may benefit from intermediate or therapeutic dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

Perioperative pain management with regional analgesia techniques for visceral cancer surgery: A systematic review and meta-analysis.

STUDY OBJECTIVE: Regional analgesia following visceral cancer surgery might provide an advantage but evidence for best treatment options related to risk-benefit is unclear. DESIGN: Systematic review of randomized controlled trials (RCT) with meta-analysis and GRADE assessment. SETTING: Postoperative pain treatment. PATIENTS: Adult patients undergoing visceral cancer surgery. INTERVENTIONS: Any kind of peripheral (PRA) or epidural analgesia (EA) with/without systemic analgesia (SA) was compared to SA with or without placebo treatment or any other regional anaesthetic techniques. MEASUREMENTS: Primary outcome measures were postoperative acute pain intensity at rest and during activity 24 h after surgery, the number of patients with block-related adverse events and postoperative paralytic ileus. MAIN RESULTS: 59 RCTs (4345 participants) were included. EA may reduce pain intensity at rest (mean difference (MD) -1.05; 95% confidence interval (CI): -1.35 to -0.75, low certainty evidence) and during activity 24 h after surgery (MD -1.83; 95% CI: -2.34 to -1.33, very low certainty evidence). PRA likely results in little difference in pain intensity at rest (MD -0.75; 95% CI: -1.20 to -0.31, moderate certainty evidence) and pain during activity (MD -0.93; 95% CI: -1.34 to -0.53, moderate certainty evidence) 24 h after surgery compared to SA. There may be no difference in block-related adverse events (very low certainty evidence) and development of paralytic ileus (very low certainty of evidence) between EA, respectively PRA and SA. CONCLUSIONS: Following visceral cancer surgery EA may reduce pain intensity. In contrast, PRA had only limited effects on pain intensity at rest and during activity. However, we are uncertain regarding the effect of both techniques on block-related adverse events and paralytic ileus. Further research is required focusing on regional analgesia techniques especially following laparoscopic visceral cancer surgery.

Regional anaesthesia for postoperative pain management following laparoscopic, visceral, non-oncological surgery a systematic review and meta-analysis.

BACKGROUND: Postoperative pain management following laparoscopic, non-oncological visceral surgery in adults is challenging. Regional anaesthesia could be a promising component in multimodal pain management. METHODS: We performed a systematic review and meta-analysis with GRADE assessment. Primary outcomes were postoperative acute pain intensity at rest/during movement after 24 h, the number of patients with block-related adverse events and the number of patients with postoperative paralytic ileus. RESULTS: 82 trials were included. Peripheral regional anaesthesia combined with general anaesthesia versus general anaesthesia may result in a slight reduction of pain intensity at rest at 24 h (mean difference (MD) - 0.72 points; 95% confidence interval (CI) - 0.91 to - 0.54; I2 = 97%; low-certainty evidence), which was not clinically relevant. The evidence is very uncertain regarding the effect on pain intensity during activity at 24 h (MD -0.8 points; 95%CI - 1.17 to - 0.42; I2 = 99%; very low-certainty evidence) and on the incidence of block-related adverse events. In contrast, neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) may reduce postoperative pain intensity at rest in a clinical relevant matter (MD - 1.19 points; 95%CI - 1.99 to - 0.39; I2 = 97%; low-certainty evidence), but the effect is uncertain during activity (MD - 1.13 points; 95%CI - 2.31 to 0.06; I2 = 95%; very low-certainty evidence). There is uncertain evidence, that neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) increases the risk for block-related adverse events (relative risk (RR) 5.11; 95%CI 1.13 to 23.03; I2 = 0%; very low-certainty evidence). CONCLUSION: This meta-analysis confirms that regional anaesthesia might be an important part of multimodal postoperative analgesia in laparoscopic visceral surgery, e.g. in patients at risk for severe postoperative pain, and with large differences between surgical procedures and settings. Further research is required to evaluate the use of adjuvants and the additional benefit of regional anaesthesia in ERAS programmes. PROTOCOL REGISTRATION: PROSPERO CRD42021258281.

Erector spinae plane block for postoperative pain.

BACKGROUND: Acute and chronic postoperative pain are important healthcare problems, which can be treated with a combination of opioids and regional anaesthesia. The erector spinae plane block (ESPB) is a new regional anaesthesia technique, which might be able to reduce opioid consumption and related side effects. OBJECTIVES: To compare the analgesic effects and side effect profile of ESPB against no block, placebo block or other regional anaesthetic techniques. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Web of Science on 4 January 2021 and updated the search on 3 January 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating adults undergoing surgery with general anaesthesia were included. We included ESPB in comparison with no block, placebo blocks or other regional anaesthesia techniques irrespective of language, publication year, publication status or technique of regional anaesthesia used (ultrasound, landmarks or peripheral nerve stimulator). Quasi-RCTs, cluster-RCTs, cross-over trials and studies investigating co-interventions in either arm were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials for inclusion and exclusion criteria, and risk of bias (RoB), and extracted data. We assessed risk of bias using the Cochrane RoB 2 tool, and we used GRADE to rate the certainty of evidence for the primary outcomes. The primary outcomes were postoperative pain at rest at 24 hours and block-related adverse events. Secondary outcomes were postoperative pain at rest (2, 48 hours) and during activity (2, 24 and 48 hours after surgery), chronic pain after three and six months, as well as cumulative oral morphine requirements at 2, 24 and 48 hours after surgery and rates of opioid-related side effects. MAIN RESULTS: We identified 69 RCTs in the first search and included these in the systematic review. We included 64 RCTs (3973 participants) in the meta-analysis. The outcome postoperative pain was reported in 38 out of 64 studies; block-related adverse events were reported in 40 out of 64 studies. We assessed RoB as low in 44 (56%), some concerns in 24 (31%) and high in 10 (13%) of the study results. Overall, 57 studies reported one or both primary outcomes. Only one study reported results on chronic pain after surgery. In the updated literature search on 3 January 2022 we found 37 new studies and categorised these as awaiting classification. ESPB compared to no block There is probably a slight but not clinically relevant reduction in pain intensity at rest 24 hours after surgery in patients treated with ESPB compared to no block (visual analogue scale (VAS), 0 to 10 points) (mean difference (MD) -0.77 points, 95% confidence interval (CI) -1.08 to -0.46; 17 trials, 958 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between the groups treated with ESPB and those receiving no block (no events in 18 trials reported, 1045 participants, low-certainty evidence). ESPB compared to placebo block ESPB probably has no effect on postoperative pain intensity at rest 24 hours after surgery compared to placebo block (MD -0.14 points, 95% CI -0.29 to 0.00; 8 trials, 499 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between ESPB and placebo blocks (no events in 10 trials reported; 592 participants; low-certainty evidence). ESPB compared to other regional anaesthetic techniques Paravertebral block (PVB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PVB (MD 0.23 points, 95% CI -0.06 to 0.52; 7 trials, 478 participants; low-certainty evidence). There is probably no difference in block-related adverse events (risk ratio (RR) 0.27, 95% CI 0.08 to 0.95; 7 trials, 522 participants; moderate-certainty evidence). Transversus abdominis plane block (TAPB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to TAPB (MD -0.16 points, 95% CI -0.46 to 0.14; 3 trials, 160 participants; low-certainty evidence). There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.21 to 4.83; 4 trials, 202 participants; low-certainty evidence). Serratus anterior plane block (SAPB) The effect on postoperative pain could not be assessed because no studies reported this outcome. There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.06 to 15.59; 2 trials, 110 participants; low-certainty evidence). Pectoralis plane block (PECSB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PECSB (MD 0.24 points, 95% CI -0.11 to 0.58; 2 trials, 98 participants; low-certainty evidence). The effect on block-related adverse events could not be assessed. Quadratus lumborum block (QLB) Only one study reported on each of the primary outcomes. Intercostal nerve block (ICNB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to ICNB, but this is uncertain (MD -0.33 points, 95% CI -3.02 to 2.35; 2 trials, 131 participants; very low-certainty evidence). There may be no difference in block-related adverse events, but this is uncertain (RR 0.09, 95% CI 0.04 to 2.28; 3 trials, 181 participants; very low-certainty evidence). Epidural analgesia (EA) We are uncertain whether ESPB has an effect on postoperative pain intensity at rest 24 hours after surgery compared to EA (MD 1.20 points, 95% CI -2.52 to 4.93; 2 trials, 81 participants; very low-certainty evidence). A risk ratio for block-related adverse events was not estimable because only one study reported this outcome. AUTHORS' CONCLUSIONS: ESPB in addition to standard care probably does not improve postoperative pain intensity 24 hours after surgery compared to no block. The number of block-related adverse events following ESPB was low. Further research is required to study the possibility of extending the duration of analgesia. We identified 37 new studies in the updated search and there are three ongoing studies, suggesting possible changes to the effect estimates and the certainty of the evidence in the future.

Reported outcomes in patients with iron deficiency or iron deficiency anemia undergoing major surgery: a systematic review of outcomes.

BACKGROUND: Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia. METHODS: We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted. RESULTS: Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the 'blood and lymphatic system' domain, followed by "adverse event" (77%) and "need for further resources" (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting. CONCLUSION: This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020214247.

Peripheral Regional Anesthetic Techniques in Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this systematic review was to investigate postoperative pain outcomes and adverse events after peripheral regional anesthesia (PRA) compared to no regional anesthesia (RA), placebo, or neuraxial anesthesia in children and adults undergoing cardiac surgery. DESIGN: A systematic review and meta-analysis with an assessment of the risk of bias (Cochrane RoB 1) and certainty of evidence (Grading of Recommendations, Assessment, Development, and Evaluation). SETTING: Randomized controlled trials (RCTs). PARTICIPANTS: Adults and children undergoing heart surgery. INTERVENTIONS: Any kind of PRA compared to no RA or placebo or neuraxial anesthesia. MEASUREMENTS AND MAIN RESULTS: In total, 33 RCTs (2,044 patients) were included-24 of these had a high risk of bias, and 28 were performed in adults. Compared to no RA, PRA may reduce pain intensity at rest 24 hours after surgery (mean difference [MD] -0.81 points, 95% CI -1.51 to -0.10; I2 = 92%; very low certainty evidence). Peripheral regional anesthesia, compared to placebo, may reduce pain intensity at rest (MD -1.36 points, 95% CI -1.59 to -1.13; I2 = 54%; very low certainty evidence) and during movement (MD -1.00 points, 95% CI -1.34 to -0.67; I² = 72%; very low certainty evidence) 24 hours after surgery. No data after pediatric cardiac surgery could be meta-analyzed due to the low number of included trials. CONCLUSIONS: Compared to no RA or placebo, PRA may reduce pain intensity at rest and during movement. However, these results should be interpreted cautiously because the certainty of evidence is only very low.

Efficacy and safety of perioperative ketamine for the prevention of chronic postsurgical pain: A meta-analysis.

STUDY OBJECTIVE: Assessment of the efficacy and safety of perioperative intravenous ketamine in reducing incidence and severity of chronic postsurgical pain. STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: The following data sources were systematically searched: MEDLINE, CENTRAL, and EMBASE (till 02/2021). PATIENTS: Adult patients undergoing any surgery. INTERVENTIONS: Perioperative use of intravenous ketamine as an additive analgesic drug compared to placebo, no active control treatment, and other additive drugs. MEASUREMENTS: Primary outcomes were number of patients with chronic postsurgical pain after 6 months and ketamine related adverse effects. Secondary outcomes were chronic postsurgical pain incidence after 3 and 12 months, chronic postsurgical neuropathic pain incidence, chronic postsurgical moderate to severe pain incidence, intensity of chronic postsurgical pain at rest, and during movement, oral morphine consumption after 3, 6, and 12 months and incidence of opioid-related adverse effects. MAIN RESULTS: Thirty-six RCTs were included with a total of 3572 patients. Ketamine compared to placebo may result in no difference in the number of patients with chronic postsurgical pain after 6 months (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.71-1.05; I2 = 34%; 16 studies; low-certainty evidence). Ketamine may reduce the incidence of chronic postsurgical neuropathic pain after 3 months in comparison to placebo (RR 0.78, 95% CI 0.62-0.99, I2 = 31%, seven trials, low-certainty evidence). Ketamine compared to placebo may increase the risk for postoperative nystagmus (RR 9.04, 95% CI 1.15-70.90, I2 30%, two trials, low-certainty evidence) and postoperative visual disturbances (RR 2.29, 95% CI 1.05-4.99, I2 10%, seven trials, low-certainty evidence). CONCLUSIONS: There is low-certainty evidence that perioperative ketamine has no effect on chronic postsurgical pain in adult patients. Low-certainty evidence suggests that ketamine compared to placebo may reduce incidence of chronic postsurgical neuropathic pain after 3 months. Questions like ideal dosing, treatment duration and more patient-related outcome measures remain unanswered, which warrants further studies. PROTOCOL REGISTRATION: Prospero CRD42021223625, 07.01.2021.

Methods and guidance on conducting, reporting, publishing, and appraising living systematic reviews: a scoping review.

BACKGROUND AND OBJECTIVE: The living systematic review (LSR) approach is based on ongoing surveillance of the literature and continual updating. Most currently available guidance documents address the conduct, reporting, publishing, and appraisal of systematic reviews (SRs), but are not suitable for LSRs per se and miss additional LSR-specific considerations. In this scoping review, we aim to systematically collate methodological guidance literature on how to conduct, report, publish, and appraise the quality of LSRs and identify current gaps in guidance. METHODS: A standard scoping review methodology was used. We searched MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library on August 28, 2021. As for searching gray literature, we looked for existing guidelines and handbooks on LSRs from organizations that conduct evidence syntheses. The screening was conducted by two authors independently in Rayyan, and data extraction was done in duplicate using a pilot-tested data extraction form in Excel. Data was extracted according to four pre-defined categories for (i) conducting, (ii) reporting, (iii) publishing, and (iv) appraising LSRs. We mapped the findings by visualizing overview tables created in Microsoft Word. RESULTS: Of the 21 included papers, methodological guidance was found in 17 papers for conducting, in six papers for reporting, in 15 papers for publishing, and in two papers for appraising LSRs. Some of the identified key items for (i) conducting LSRs were identifying the rationale, screening tools, or re-revaluating inclusion criteria. Identified items of (ii) the original PRISMA checklist included reporting the registration and protocol, title, or synthesis methods. For (iii) publishing, there was guidance available on publication type and frequency or update trigger, and for (iv) appraising, guidance on the appropriate use of bias assessment or reporting funding of included studies was found. Our search revealed major evidence gaps, particularly for guidance on certain PRISMA items such as reporting results, discussion, support and funding, and availability of data and material of a LSR. CONCLUSION: Important evidence gaps were identified for guidance on how to report in LSRs and appraise their quality. Our findings were applied to inform and prepare a PRISMA 2020 extension for LSR.

Nirmatrelvir combined with ritonavir for preventing and treating COVID-19.

BACKGROUND: Oral nirmatrelvir/ritonavir (Paxlovid) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. It remains to be evaluated for which indications and patient populations the drug is suitable. OBJECTIVES: To assess the efficacy and safety of nirmatrelvir/ritonavir plus standard of care (SoC) compared to SoC with or without placebo, or any other intervention for treating COVID-19 or preventing SARS-CoV-2 infection. To explore equity aspects in subgroup analyses. To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Scopus, and World Health Organization COVID-19 Research Database, identifying completed and ongoing studies without language restrictions and incorporating studies up to 15 May 2023. This is a LSR. We conduct update searches every two months and make them publicly available on the open science framework (OSF) platform. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing nirmatrelvir/ritonavir plus SoC to SoC with or without placebo, or any other intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. We screened all studies for research integrity. Studies were ineligible if they had been retracted, or if they were not prospectively registered including appropriate ethics approval. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology and used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the following outcomes: 1. to treat outpatients with mild COVID-19; 2. to treat inpatients with moderate to severe COVID-19: mortality, clinical worsening or improvement, quality of life, (serious) adverse events, and viral clearance; 3. to prevent SARS-CoV-2 infection in postexposure prophylaxis (PEP); and 4. pre-exposure prophylaxis (PrEP) scenarios: SARS-CoV-2 infection, development of COVID-19 symptoms, mortality, admission to hospital, quality of life, and (serious) adverse events. We explored inequity by subgroup analysis for elderly people, socially-disadvantaged people with comorbidities, populations from low-income countries and low- to middle-income countries, and people from different ethnic and racial backgrounds. MAIN RESULTS: As of 15 May 2023, we included two RCTs with 2510 participants with mild and mild to moderate symptomatic COVID-19 in outpatient and inpatient settings comparing nirmatrelvir/ritonavir plus SoC to SoC with or without placebo. All trial participants were without previous confirmed SARS-CoV-2 infection and at high risk for progression to severe disease. Randomization coincided with the Delta wave for outpatients and Omicron wave for inpatients. Outpatient trial participants and 73% of inpatients were unvaccinated. Symptom onset in outpatients was no more than five days before randomisation and prior or concomitant therapies including medications highly dependent on CYP3A4 were not allowed. We excluded two studies due to concerns with research integrity. We identified 13 ongoing studies. Three studies are currently awaiting classification. Nirmatrelvir/ritonavir for treating people with asymptomatic or mild COVID-19 in outpatient settings Nirmatrelvir/ritonavir plus SoC compared to SoC plus placebo may reduce all-cause mortality at 28 days (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.68; 1 study, 2224 participants; low-certainty evidence) and admission to hospital or death within 28 days (RR 0.13, 95% CI 0.07 to 0.27; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus SoC may reduce serious adverse events during the study period compared to SoC plus placebo (RR 0.24, 95% CI 0.15 to 0.41; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus SoC probably has little or no effect on treatment-emergent adverse events (RR 0.95, 95% CI 0.82 to 1.10; 1 study, 2224 participants; moderate-certainty evidence), and probably increases treatment-related adverse events such as dysgeusia and diarrhoea during the study period compared to SoC plus placebo (RR 2.06, 95% CI 1.44 to 2.95; 1 study, 2224 participants; moderate-certainty evidence). Nirmatrelvir/ritonavir plus SoC probably decreases discontinuation of study drug due to adverse events compared to SoC plus placebo (RR 0.49, 95% CI 0.30 to 0.80; 1 study, 2224 participants; moderate-certainty evidence). No studies reported improvement of clinical status, quality of life, or viral clearance. Nirmatrelvir/ritonavir for treating people with moderate to severe COVID-19 in inpatient settings We are uncertain whether nirmatrelvir/ritonavir plus SoC compared to SoC reduces all-cause mortality at 28 days (RR 0.63, 95% CI 0.21 to 1.86; 1 study, 264 participants; very low-certainty evidence), or increases viral clearance at seven days (RR 1.06, 95% CI 0.71 to 1.58; 1 study, 264 participants; very low-certainty evidence) and 14 days (RR 1.05, 95% CI 0.92 to 1.20; 1 study, 264 participants; very low-certainty evidence). No studies reported improvement or worsening of clinical status and quality of life. We did not include data for safety outcomes due to insufficient and inconsistent information. Subgroup analyses for equity For outpatients, the outcome 'admission to hospital or death' was investigated for equity regarding age (less than 65 years versus 65 years or greater) and ethnicity. There were no subgroup differences for age or ethnicity. For inpatients, the outcome 'all-cause mortality' was investigated for equity regarding age (65 years or less versus greater than 65 years). There was no difference between subgroups of age. No further equity-related subgroups were reported, and no subgroups were reported for other outcomes. Nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection (PrEP and PEP) No studies available. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests nirmatrelvir/ritonavir reduces the risk of all-cause mortality and hospital admission or death in high-risk, unvaccinated COVID-19 outpatients infected with the Delta variant of SARS-CoV-2. There is low- to moderate-certainty evidence of the safety of nirmatrelvir/ritonavir. Very low-certainty evidence exists regarding the effects of nirmatrelvir/ritonavir on all-cause mortality and viral clearance in mildly to moderately affected, mostly unvaccinated COVID-19 inpatients infected with the Omicron variant of SARS-CoV-2. Insufficient and inconsistent information prevents the assessment of safety outcomes. No reliable differences in effect size and direction were found regarding equity aspects. There is no available evidence supporting the use of nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection. We are continually updating our search and making search results available on the OSF platform.

Erector spinae plane block for postoperative pain.

BACKGROUND: Acute and chronic postoperative pain are important healthcare problems, which can be treated with a combination of opioids and regional anaesthesia. The erector spinae plane block (ESPB) is a new regional anaesthesia technique, which might be able to reduce opioid consumption and related side effects. OBJECTIVES: To compare the analgesic effects and side effect profile of ESPB against no block, placebo block or other regional anaesthetic techniques. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Web of Science on 4 January 2021 and updated the search on 3 January 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating adults undergoing surgery with general anaesthesia were included. We included ESPB in comparison with no block, placebo blocks or other regional anaesthesia techniques irrespective of language, publication year, publication status or technique of regional anaesthesia used (ultrasound, landmarks or peripheral nerve stimulator). Quasi-RCTs, cluster-RCTs, cross-over trials and studies investigating co-interventions in either arm were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials for inclusion and exclusion criteria, and risk of bias (RoB), and extracted data. We assessed risk of bias using the Cochrane RoB 2 tool, and we used GRADE to rate the certainty of evidence for the primary outcomes. The primary outcomes were postoperative pain at rest at 24 hours and block-related adverse events. Secondary outcomes were postoperative pain at rest (2, 48 hours) and during activity (2, 24 and 48 hours after surgery), chronic pain after three and six months, as well as cumulative oral morphine requirements at 2, 24 and 48 hours after surgery and rates of opioid-related side effects. MAIN RESULTS: We identified 69 RCTs in the first search and included these in the systematic review. We included 64 RCTs (3973 participants) in the meta-analysis. The outcome postoperative pain was reported in 38 out of 64 studies; block-related adverse events were reported in 40 out of 64 studies. We assessed RoB as low in 44 (56%), some concerns in 24 (31%) and high in 10 (13%) of the study results. Overall, 57 studies reported one or both primary outcomes. Only one study reported results on chronic pain after surgery. In the updated literature search on 3 January 2022 we found 37 new studies and categorised these as awaiting classification. ESPB compared to no block There is probably a slight but not clinically relevant reduction in pain intensity at rest 24 hours after surgery in patients treated with ESPB compared to no block (visual analogue scale (VAS), 0 to 10 points) (mean difference (MD) -0.77 points, 95% confidence interval (CI) -1.08 to -0.46; 17 trials, 958 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between the groups treated with ESPB and those receiving no block (no events in 18 trials reported, 1045 participants, low-certainty evidence). ESPB compared to placebo block ESPB probably has no effect on postoperative pain intensity at rest 24 hours after surgery compared to placebo block (MD -0.14 points, 95% CI -0.29 to 0.00; 8 trials, 499 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between ESPB and placebo blocks (no events in 10 trials reported; 592 participants; low-certainty evidence). ESPB compared to other regional anaesthetic techniques Paravertebral block (PVB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PVB (MD 0.23 points, 95% CI -0.06 to 0.52; 7 trials, 478 participants; low-certainty evidence). There is probably no difference in block-related adverse events (risk ratio (RR) 0.27, 95% CI 0.08 to 0.95; 7 trials, 522 participants; moderate-certainty evidence). Transversus abdominis plane block (TAPB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to TAPB (MD -0.16 points, 95% CI -0.46 to 0.14; 3 trials, 160 participants; low-certainty evidence). There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.21 to 4.83; 4 trials, 202 participants; low-certainty evidence). Serratus anterior plane block (SAPB) The effect on postoperative pain could not be assessed because no studies reported this outcome. There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.06 to 15.59; 2 trials, 110 participants; low-certainty evidence). Pectoralis plane block (PECSB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PECSB (MD 0.24 points, 95% CI -0.11 to 0.58; 2 trials, 98 participants; low-certainty evidence). The effect on block-related adverse events could not be assessed. Quadratus lumborum block (QLB) Only one study reported on each of the primary outcomes. Intercostal nerve block (ICNB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to ICNB, but this is uncertain (MD -0.33 points, 95% CI -3.02 to 2.35; 2 trials, 131 participants; very low-certainty evidence). There may be no difference in block-related adverse events, but this is uncertain (RR 0.09, 95% CI 0.04 to 2.28; 3 trials, 181 participants; very low-certainty evidence). Epidural analgesia (EA) We are uncertain whether ESPB has an effect on postoperative pain intensity at rest 24 hours after surgery compared to EA (MD 1.20 points, 95% CI -2.52 to 4.93; 2 trials, 81 participants; very low-certainty evidence). A risk ratio for block-related adverse events was not estimable because only one study reported this outcome. AUTHORS' CONCLUSIONS: ESPB in addition to standard care probably does not improve postoperative pain intensity 24 hours after surgery compared to no block. The number of block-related adverse events following ESPB was low. Further research is required to study the possibility of extending the duration of analgesia. We identified 37 new studies in the updated search and there are three ongoing studies, suggesting possible changes to the effect estimates and the certainty of the evidence in the future.

Antiplatelet agents for the treatment of adults with COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) can cause thrombotic events that lead to severe complications or death. Antiplatelet agents, such as acetylsalicylic acid, have been shown to effectively reduce thrombotic events in other diseases: they could influence the course of COVID-19 in general. OBJECTIVES: To assess the efficacy and safety of antiplatelets given with standard care compared to no treatment or standard care (with/without placebo) for adults with COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which comprises MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv, CENTRAL), Web of Science, WHO COVID-19 Global literature on coronavirus disease and the Epistemonikos COVID-19 L*OVE Platform to identify completed and ongoing studies without language restrictions to December 2022. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating antiplatelet agents for the treatment of COVID-19 in adults with COVID-19, irrespective of disease severity, gender or ethnicity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (RoB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the outcomes. MAIN RESULTS: Antiplatelets plus standard care versus standard care (with/without placebo) Adults with a confirmed diagnosis of moderate to severe COVID-19 We included four studies (17,541 participants) that recruited hospitalised people with a confirmed diagnosis of moderate to severe COVID-19. A total of 8964 participants were analysed in the antiplatelet arm (either with cyclooxygenase inhibitors or P2Y12 inhibitors) and 8577 participants in the control arm. Most people were older than 50 years and had comorbidities such as hypertension, lung disease or diabetes. The studies were conducted in high- to lower middle-income countries prior to wide-scale vaccination programmes. Antiplatelets compared to standard care: - probably result in little to no difference in 28-day mortality (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.05; 3 studies, 17,249 participants; moderate-certainty evidence). In absolute terms, this means that for every 177 deaths per 1000 people not receiving antiplatelets, there were 168 deaths per 1000 people who did receive the intervention (95% CI 151 to 186 per 1000 people); - probably result in little to no difference in worsening (new need for invasive mechanical ventilation or death up to day 28) (RR 0.95, 95% CI 0.90 to 1.01; 2 studies, 15,266 participants; moderate-certainty evidence); - probably result in little to no difference in improvement (participants discharged alive up to day 28) (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 15,454 participants; moderate-certainty evidence); - probably result in a slight reduction of thrombotic events at longest follow-up (RR 0.90, 95% CI 0.80 to 1.02; 4 studies, 17,518 participants; moderate-certainty evidence); - may result in a slight increase in serious adverse events at longest follow-up (Peto odds ratio (OR) 1.57, 95% CI 0.48 to 5.14; 1 study, 1815 participants; low-certainty evidence), but non-serious adverse events during study treatment were not reported; - probably increase the occurrence of major bleeding events at longest follow-up (Peto OR 1.68, 95% CI 1.29 to 2.19; 4 studies, 17,527 participants; moderate-certainty evidence). Adults with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included two RCTs allocating participants, of whom 4209 had confirmed mild COVID-19 and were not hospitalised. A total of 2109 participants were analysed in the antiplatelet arm (treated with acetylsalicylic acid) and 2100 participants in the control arm. No study included people with asymptomatic SARS-CoV-2 infection. Antiplatelets compared to standard care: - may result in little to no difference in all-cause mortality at day 45 (Peto OR 1.00, 95% CI 0.45 to 2.22; 2 studies, 4209 participants; low-certainty evidence); - may slightly decrease the incidence of new thrombotic events up to day 45 (Peto OR 0.37, 95% CI 0.09 to 1.46; 2 studies, 4209 participants; low-certainty evidence); - may make little or no difference to the incidence of serious adverse events up to day 45 (Peto OR 1.00, 95% CI 0.60 to 1.64; 1 study, 3881 participants; low-certainty evidence), but non-serious adverse events were not reported. The evidence is very uncertain about the effect of antiplatelets on the following outcomes (compared to standard care plus placebo): - admission to hospital or death up to day 45 (Peto OR 0.79, 95% CI 0.57 to 1.10; 2 studies, 4209 participants; very low-certainty evidence); - major bleeding events up to longest follow-up (no event occurred in 328 participants; very low-certainty evidence). Quality of life and adverse events during study treatment were not reported. AUTHORS' CONCLUSIONS: In people with confirmed or suspected COVID-19 and moderate to severe disease, we found moderate-certainty evidence that antiplatelets probably result in little to no difference in 28-day mortality, clinical worsening or improvement, but probably result in a slight reduction in thrombotic events. They probably increase the occurrence of major bleeding events. Low-certainty evidence suggests that antiplatelets may result in a slight increase in serious adverse events. In people with confirmed COVID-19 and mild symptoms, we found low-certainty evidence that antiplatelets may result in little to no difference in 45-day mortality and serious adverse events, and may slightly reduce thrombotic events. The effects on the combined outcome admission to hospital or death up to day 45 and major bleeding events are very uncertain. Quality of life was not reported. Included studies were conducted in high- to lower middle-income settings using antiplatelets prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, adverse events and people with asymptomatic infection. The 14 ongoing and three completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review.

Model selection for component network meta-analysis in connected and disconnected networks: a simulation study.

BACKGROUND: Network meta-analysis (NMA) allows estimating and ranking the effects of several interventions for a clinical condition. Component network meta-analysis (CNMA) is an extension of NMA which considers the individual components of multicomponent interventions. CNMA allows to "reconnect" a disconnected network with common components in subnetworks. An additive CNMA assumes that component effects are additive. This assumption can be relaxed by including interaction terms in the CNMA. METHODS: We evaluate a forward model selection strategy for component network meta-analysis to relax the additivity assumption that can be used in connected or disconnected networks. In addition, we describe a procedure to create disconnected networks in order to evaluate the properties of the model selection in connected and disconnected networks. We apply the methods to simulated data and a Cochrane review on interventions for postoperative nausea and vomiting in adults after general anaesthesia. Model performance is compared using average mean squared errors and coverage probabilities. RESULTS: CNMA models provide good performance for connected networks and can be an alternative to standard NMA if additivity holds. For disconnected networks, we recommend to use additive CNMA only if strong clinical arguments for additivity exist. CONCLUSIONS: CNMA methods are feasible for connected networks but questionable for disconnected networks.

Efficacy and safety of molnupiravir for the treatment of SARS-CoV-2 infection: a systematic review and meta-analysis.

BACKGROUND: The role of molnupiravir for coronavirus disease 2019 (COVID-19) treatment is unclear. METHODS: We conducted a systematic review until 1 November 2022 searching for randomized controlled trials (RCTs) involving COVID-19 patients comparing molnupiravir [±standard of care (SoC)] versus SoC and/or placebo. Data were pooled in random-effects meta-analyses. Certainty of evidence was assessed according to the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: Nine RCTs were identified, eight investigated outpatients (29 254 participants) and one inpatients (304 participants). Compared with placebo/SoC, molnupiravir does not reduce mortality [risk ratio (RR) 0.27, 95% CI 0.07-1.02, high-certainty evidence] and probably does not reduce the risk for 'hospitalization or death' (RR 0.81, 95% CI 0.55-1.20, moderate-certainty evidence) by Day 28 in COVID-19 outpatients. We are uncertain whether molnupiravir increases symptom resolution by Day 14 (RR 1.20, 95% CI 1.02-1.41, very-low-certainty evidence) but it may make no difference by Day 28 (RR 1.05, 95% CI 0.92-1.19, low-certainty evidence). In inpatients, molnupiravir may increase mortality by Day 28 compared with placebo (RR 3.78, 95% CI 0.50-28.82, low-certainty evidence). There is little to no difference in serious adverse and adverse events during the study period in COVID-19 inpatients/outpatients treated with molnupiravir compared with placebo/SoC (moderate- to high-certainty evidence). CONCLUSIONS: In a predominantly immunized population of COVID-19 outpatients, molnupiravir has no effect on mortality, probably none on 'hospitalization or death' and effects on symptom resolution are uncertain. Molnupiravir was safe during the study period in outpatients although a potential increase in inpatient mortality requires careful monitoring in ongoing clinical research. Our analysis does not support routine use of molnupiravir for COVID-19 treatment in immunocompetent individuals.

Postoperative/postdischarge nausea and vomiting: evidence-based prevention and treatment.

PURPOSE OF REVIEW: Postoperative/postdischarge nausea and vomiting (PONV/PDNV) remains a relevant issue in perioperative care. Especially in outpatient surgery, PONV can prevent discharge or lead to unplanned readmission. RECENT FINDINGS: Evidence on prophylaxis and treatment of PONV is growing, but implementation remains poor. SUMMARY: A liberal, universal PONV management is now endorsed by the guidelines. Specific evidence concerning prevention and (at-home) treatment of PDNV is still scarce.

Pragmatic and open science-based solution to a current problem in the reporting of living systematic reviews.

Living systematic reviews (LSRs) are an increasingly common approach to keeping reviews up to date, in which new relevant studies are incorporated as they become available, so as to inform healthcare policy and practice in a timely manner. While journal publishers have been exploring the publication of LSRs using different updating and publishing approaches, readers cannot currently assess if the evidence underpinning a published LSR is up to date, as neither the search details, the selection process, nor the list of identified studies is made available between the publication of updates. We describe a new method to transparently report the living evidence surveillance process that occurs between published LSR versions. We use the example of the living Cochrane Review on nirmatrelvir combined with ritonavir (Paxlovid) for preventing and treating COVID-19 to illustrate how this can work in practice. We created a publicly accessible spreadsheet on the Open Science Framework platform, linking to the living Cochrane Review, that details the search and study selection process, enabling readers to track the progress of eligible ongoing or completed studies. Further automation of the evidence surveillance process should be explored.

Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis.

Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing "Risk of Bias" aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.