Publications by authors named "Stephanie Weibel"

54 Publications

[Update on PONV-What is new in prophylaxis and treatment of postoperative nausea and vomiting? : Summary of recent consensus recommendations and Cochrane reviews on prophylaxis and treatment of postoperative nausea and vomiting].

Anaesthesist 2021 Oct 1. Epub 2021 Oct 1.

Klinik und Poliklinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie, Universitätsklinikum Würzburg, Würzburg, Deutschland.

The prophylaxis and treatment of postoperative pain to enhance patient comfort has been a primary goal of anesthesiologists for the last decades; however, avoiding postoperative nausea and vomiting (PONV) is, from a patient's perspective, a highly relevant and equally important goal of anesthesia. Recent consensus-based guidelines suggest the assessment of risk factors including female gender, postoperative opioid administration, non-smoking status, a history of PONV or motion sickness, young patient age, longer duration of anesthesia, volatile anesthetics and the type of surgery and reducing the patient's baseline risk (e.g. through the use of regional anesthesia and administration of non-opioid analgesics as part of a multimodal approach). In general, a liberal PONV prophylaxis is encouraged for adult patients and children, which should also be administered when no risk assessment is made. The basis for every adult patient should be a standard prophylaxis with two antiemetics, such as dexamethasone in combination with a 5-HT receptor antagonist. In patients at high risk, this should be supplemented by a third and potentially a fourth antiemetic prophylaxis with a different mechanism of action. A recently published comprehensive Cochrane meta-analysis comparing available antiemetic prophylaxes reported the highest effectiveness to prevent PONV for the NK receptor antagonist aprepitant (relative risk, RR 0.26), followed by ramosetron (RR 0.44), granisetron (RR 0.45), dexamethasone (RR 0.51) and ondansetron (RR 0.55), thereby revising the dogma that every antiemetic is equally effective. Adverse events of antiemetics were generally rare and reported in less than half of the included studies, yielding a low quality of evidence for these end points. In general, combinations of different antiemetics were more effective than single prophylaxes. In children above 3 years of age, the same principles should be applied as in adults. For these patients, there is a high degree of evidence for the combination of dexamethasone and 5‑HT receptor antagonists. When PONV occurs, the consensus guidelines suggest that antiemetics from a class different than given as prophylaxis should be administered. To decrease the incidence of PONV and increase the quality of care, the importance of the implementation of institutional-level guidelines and protocols as well as assessment of PONV prophylaxis and PONV incidence is highly recommended.
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http://dx.doi.org/10.1007/s00101-021-01045-zDOI Listing
October 2021

Methodological challenges for living systematic reviews conducted during the COVID-19 pandemic: a concept paper.

J Clin Epidemiol 2021 Sep 12. Epub 2021 Sep 12.

Evidence-based Oncology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Background: A living systematic review (LSR) is an emerging review type that makes use of continual updating. In the COVID-19 pandemic, we were confronted with a shifting epidemiological landscape, clinical uncertainties and evolving evidence. These unexpected challenges compelled us to amend standard LSR methodology. Objective and outline: Our primary objective is to discuss some challenges faced when conducting LSRs in the context of the COVID-19 pandemic, and to provide methodological guidance for others doing similar work. Based on our experience and lessons learned from two Cochrane LSRs and challenges identified in several non-Cochrane LSRs, we highlight methodological considerations, particularly with regards to the study design, interventions and comparators, changes in outcome measure, and the search strategy. We discuss when to update, or rather when not to update the review, and the importance of transparency when reporting changes. Lessons learned and conclusions: We learned that a LSR is a very suitable review type for the pandemic context, even in the face of new methodological and clinical challenges. Our experience showed that the decision for updating a LSR depends not only on the evolving disease or emerging evidence, but also on the individual review question and the review teams' resources.
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http://dx.doi.org/10.1016/j.jclinepi.2021.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435072PMC
September 2021

Evidence on the efficacy of ivermectin for COVID-19: another story of apples and oranges.

BMJ Evid Based Med 2021 Aug 20. Epub 2021 Aug 20.

Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wurzburg, Wurzburg, Bayern, Germany

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http://dx.doi.org/10.1136/bmjebm-2021-111791DOI Listing
August 2021

Intraoperative management of combined general anesthesia and thoracic epidural analgesia: A survey among German anesthetists.

Acta Anaesthesiol Scand 2021 Aug 12. Epub 2021 Aug 12.

Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: Evidence concerning combined general anesthesia (GA) and thoracic epidural analgesia (EA) is controversial and the procedure appears heterogeneous in clinical implementation. We aimed to gain an overview of different approaches and to unveil a suspected heterogeneity concerning the intraoperative management of combined GA and EA.

Methods: This was an anonymous survey among Members of the Scientific working group for regional anesthesia within the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) conducted from February 2020 to August 2020.

Results: The response rate was 38%. The majority of participants were experienced anesthetists with high expertise for the specific regimen of combined GA and EA. Most participants establish EA in the sitting position (94%), prefer early epidural initiation (prior to skin incision: 80%; intraoperative: 14%) and administer ropivacaine (89%) in rather low concentrations (0.2%: 45%; 0.375%: 30%; 0.75%: 15%) mostly with an opioid (84%) in a bolus-based mode (95%). The majority reduce systemic opioid doses intraoperatively if EA works sufficiently (minimal systemic opioids: 58%; analgesia exclusively via EA: 34%). About 85% manage intraoperative EA insufficiency with systemic opioids, 52% try to escalate EA, and only 25% use non-opioids, e.g. intravenous ketamine or lidocaine.

Conclusions: Although, consensus seems to be present for several aspects (patient's position during epidural puncture, main epidural substance, application mode), there is considerable heterogeneity regarding systemic opioids, rescue strategies for insufficient EA, and hemodynamic management, which might explain inconsistent results of previous trials and meta-analyses.
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http://dx.doi.org/10.1111/aas.13971DOI Listing
August 2021

Ivermectin for preventing and treating COVID-19.

Cochrane Database Syst Rev 2021 07 28;7:CD015017. Epub 2021 Jul 28.

Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting.

Objectives: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis).

Search Methods: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021.

Selection Criteria: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy.

Data Collection And Analysis: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life.

Main Results: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.  Ivermectin doses and treatment duration varied among included studies.  We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days.

Authors' Conclusions: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.
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http://dx.doi.org/10.1002/14651858.CD015017.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406455PMC
July 2021

Efficacy and adverse events of selective serotonin noradrenaline reuptake inhibitors in the management of postoperative pain: A systematic review and meta-analysis.

J Clin Anesth 2021 Jul 23;75:110451. Epub 2021 Jul 23.

Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, BG-Universitätsklinikum Bergmannsheil gGmbH, Medical Faculty of Ruhr University Bochum, Bürkle-de-la-Camp-Platz 1, Bochum, Germany.

Study Objective: Selective-serotonin-noradrenaline-reuptake inhibitors (SSNRI) might be an interesting option for postoperative pain treatment. Objective was to investigate postoperative pain outcomes of perioperative SSNRI compared to placebo or other additives in adults undergoing surgery.

Design: Systematic review of randomised controlled trials (RCT) with meta-analysis and GRADE assessment.

Setting: Acute and chronic postoperative pain treatment.

Patients: Adult patients undergoing surgery.

Interventions: Perioperative administration of SSNRI.

Measurements: Primary outcomes were postoperative acute pain at rest/during movement (measured on a scale from 0 to 10), number of patients with chronic postsurgical pain (CPSP) and with SSNRI-related adverse events.

Main Results: Fourteen RCTs (908 patients) were included. We have high-quality evidence that duloxetine has no effect on pain at rest at 2 h (MD: -0.02; 95% confidence interval (CI) -0.51 to 0.47), but probably reduces it at 48 h (MD: -1.16; 95%CI -1.78 to -0.54). There is low- and moderate-quality evidence that duloxetine has no effects on pain during movement at 2 h (MD: -0.42; 95%CI -1.53 to 0.69) and 48 h (MD: -0.91; 95% CI -2.08 to 0.26), respectively. We have very low-quality evidence that duloxetine might reduce pain at rest (MD: -0.45; 95%CI -0.74 to -0.15) and movement (MD: -1.19; 95%CI -2.32 to -0.06) after 24 h. We have low-quality evidence that duloxetine may reduce the risk of CPSP at 6 months (RR:0.35; 95%CI 0.14 to 0.90). There is moderate-quality evidence that duloxetine increases the risk of dizziness (RR:1.72; 95%CI 1.26 to 2.34).

Conclusion: At the expense of a higher risk for dizziness, SSNRI may be effective in reducing postoperative pain between 24 and 48 h after surgery. However, the results of the meta-analyses are mostly imprecise and duloxetine might only be used in individual cases. Protocol registration: CRD42018094699.
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http://dx.doi.org/10.1016/j.jclinane.2021.110451DOI Listing
July 2021

Drugs for preventing postoperative nausea and vomiting in adults after general anesthesia: An abridged Cochrane network meta-analysis.

J Evid Based Med 2021 Sep 27;14(3):188-197. Epub 2021 May 27.

Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

Objective: In this abridged version of the recently published Cochrane review on antiemetic drugs, we summarize its most important findings and discuss the challenges and the time needed to prepare what is now the largest Cochrane review with network meta-analysis in terms of the number of included studies and pages in its full printed form.

Methods: We conducted a systematic review with network meta-analyses to compare and rank single antiemetic drugs and their combinations belonging to 5HT₃-, D₂-, NK₁-receptor antagonists, corticosteroids, antihistamines, and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anesthesia.

Results: 585 studies (97 516 participants) testing 44 single drugs and 51 drug combinations were included. The studies' overall risk of bias was assessed as low in only 27% of the studies. In 282 studies, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared to placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single NK receptor antagonists were as effective as other drug combinations. Of the 10 effective single drugs, certainty of evidence was high for aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron, while moderate for fosaprepitant and droperidol. For serious adverse events (SAEs), any adverse event (AE), and drug-class specific side effects evidence for intervention effects was mostly not convincing.

Conclusions: There is high or moderate evidence for at least seven single drugs preventing postoperative vomiting. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation.
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http://dx.doi.org/10.1111/jebm.12429DOI Listing
September 2021

Drugs in anesthesia: preventing postoperative nausea and vomiting.

Curr Opin Anaesthesiol 2021 Aug;34(4):421-427

Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital of Wuerzburg, Wuerzburg, Germany.

Purpose Of Review: Postoperative nausea and vomiting (PONV) continues to be a burden for patients, medical staff and healthcare facilities because of inadequate adherence to available recommendations. This review gives an overview on recent recommendations, new evidence and remaining issues in the field of PONV management.

Recent Findings: A wide range of drugs is available for the management of PONV including corticosteroids, 5-HT3-antagonists, dopamine-antagonists, neurokinin-receptor-1 (NK1)-antagonists, antihistamines and anticholinergics. The updated PONV guidelines from 2020 recommend a universal multimodal strategy for PONV prophylaxis, which is an important paradigm shift to improve implementation of the existing evidence. A recent Cochrane network meta-analysis ranked single drugs and drug combinations for PONV prophylaxis in terms of efficacy and safety. Notably, NK1-antagonists and new 5-HT3-antagonists ranged among the most effective drugs. However, safety data on antiemetics are generally scarce.

Summary: Numerous drug (combinations) and strategies are available for PONV management. New and very effective (single) drugs could result in a simplification compared with a combination of several drugs, and thus lead to better implementation.
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http://dx.doi.org/10.1097/ACO.0000000000001010DOI Listing
August 2021

Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression.

JAMA Surg 2021 Apr 14:e210884. Epub 2021 Apr 14.

Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.

Importance: Tranexamic acid (TXA) is an efficient antifibrinolytic agent; however, concerns remain about the potential adverse effects, particularly vascular occlusive events, that may be associated with its use.

Objective: To examine the association between intravenous TXA and total thromboembolic events (TEs) and mortality in patients of all ages and of any medical disciplines.

Data Source: Cochrane Central Register of Controlled Trials and MEDLINE were searched for eligible studies investigating intravenous TXA and postinterventional outcome published between 1976 and 2020.

Study Selection: Randomized clinical trials comparing intravenous TXA with placebo/no treatment. The electronic database search yielded a total of 782 studies, and 381 were considered for full-text review. Included studies were published in English, German, French, and Spanish. Studies with only oral or topical tranexamic administration were excluded.

Data Extraction And Synthesis: Meta-analysis, subgroup and sensitivity analysis, and meta-regression were performed. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Main Outcomes And Measures: Vascular occlusive events and mortality.

Results: A total of 216 eligible trials including 125 550 patients were analyzed. Total TEs were found in 1020 (2.1%) in the group receiving TXA and 900 (2.0%) in the control group. This study found no association between TXA and risk for total TEs (risk difference = 0.001; 95% CI, -0.001 to 0.002; P = .49) for venous thrombosis, pulmonary embolism, venous TEs, myocardial infarction or ischemia, and cerebral infarction or ischemia. Sensitivity analysis using the risk ratio as an effect measure with (risk ratio = 1.02; 95% CI, 0.94-1.11; P = .56) and without (risk ratio = 1.03; 95% CI, 0.95-1.12; P = .52) studies with double-zero events revealed robust effect size estimates. Sensitivity analysis with studies judged at low risk for selection bias showed similar results. Administration of TXA was associated with a significant reduction in overall mortality and bleeding mortality but not with nonbleeding mortality. In addition, an increased risk for vascular occlusive events was not found in studies including patients with a history of thromboembolism. Comparison of studies with sample sizes of less than or equal to 99 (risk difference = 0.004; 95% CI, -0.006 to 0.014; P = .40), 100 to 999 (risk difference = 0.004; 95% CI, -0.003 to 0.011; P = .26), and greater than or equal to 1000 (risk difference = -0.001; 95% CI, -0.003 to 0.001; P = .44) showed no association between TXA and incidence of total TEs. Meta-regression of 143 intervention groups showed no association between TXA dosing and risk for venous TEs (risk difference, -0.005; 95% CI, -0.021 to 0.011; P = .53).

Conclusions And Relevance: Findings from this systematic review and meta-analysis of 216 studies suggested that intravenous TXA, irrespective of dosing, is not associated with increased risk of any TE. These results help clarify the incidence of adverse events associated with administration of intravenous TXA and suggest that TXA is safe for use with undetermined utility for patients receiving neurological care.
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http://dx.doi.org/10.1001/jamasurg.2021.0884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047805PMC
April 2021

'It's not over until it's over'.

Reg Anesth Pain Med 2021 Mar 31. Epub 2021 Mar 31.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany.

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http://dx.doi.org/10.1136/rapm-2021-102663DOI Listing
March 2021

Systematic review and meta-analysis on volume-outcome relationship of abdominal surgical procedures in Germany.

Int J Surg 2021 Feb 9;86:24-31. Epub 2021 Jan 9.

Department of General, Visceral, Transplant, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Germany; Department of Biochemistry and Molecular Biology University of Würzburg Würzburg, Germany. Electronic address:

Background: In the past, for a number of abdominal surgical interventions a correlation between treatment volume of a hospital and the patient's outcome was shown in national and international studies.

Methods: Based on a systematic literature search we analyzed the absolute and risk-adjusted in-house lethality as well as the rate of complications and the failure to rescue after abdominal surgery in Germany. The hospitals were grouped in quintiles according to the volume of treatment.

Results: 11 studies including more than 2 million patients were identified and surgeries for the treatment of 9 disease conditions were studied. The meta-analysis shows a significantly lower absolute and risk-adjusted in-house mortality for surgery in hospitals with high treatment volumes compared to low volume hospitals. In the context of subgroup analysis, this effect is demonstrated especially for complex surgical procedures. The failure to rescue in patients suffering from sepsis is significantly lower in high volume centers compared to low volume centers.

Conclusion: This systematic review and meta-analysis shows on more than 2 million patients that there is a volume-outcome relationship for the surgical treatment of abdominal diseases in Germany across various organ systems, which is particularly true for complex interventions.
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http://dx.doi.org/10.1016/j.ijsu.2020.12.010DOI Listing
February 2021

Pectoral nerve blocks for breast surgery: A meta-analysis.

Eur J Anaesthesiol 2021 04;38(4):383-393

From the Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital of Muenster, Albert-Schweitzer-Campus 1, Muenster (MM, EA, EMP-Z, AS), Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg (PK, SW) and Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, BG-Universitätsklinikum Bergmannsheil gGmbH, Medical Faculty of Ruhr University Bochum, Bürkle-de-la-Camp-Platz 1, Bochum, Germany (PKZ, CHM-F).

Background: Pectoral nerve blocks (PECS block) might be an interesting new regional anaesthetic technique in patients undergoing breast surgery.

Objective: The aim of this meta-analysis was to investigate postoperative pain outcomes and adverse events of a PECS block compared with no treatment, sham treatment or other regional anaesthetic techniques in women undergoing breast surgery.

Design: We performed a systematic review of randomised controlled trials (RCT) with meta-analysis and risk of bias assessment.

Data Sources: The databases MEDLINE, CENTRAL (until December 2019) and clinicaltrials.gov were systematically searched.

Eligibility Criteria: All RCTs investigating the efficacy and adverse events of PECS compared with sham treatment, no treatment or other regional anaesthetic techniques in women undergoing breast surgery with general anaesthesia were included.

Results: A total of 24 RCTs (1565 patients) were included. PECS (compared with no treatment) block might reduce pain at rest [mean difference -1.14, 95% confidence interval (CI), -2.1 to -0.18, moderate quality evidence] but we are uncertain regarding the effect on pain during movement at 24 h after surgery (mean difference -1.79, 95% CI, -3.5 to -0.08, very low-quality evidence). We are also uncertain about the effect of PECS block on pain at rest at 24 h compared with sham block (mean difference -0.83, 95% CI, -1.80 to 0.14) or compared with paravertebral block (PVB) (mean difference -0.18, 95% CI, -1.0 to 0.65), both with very low-quality evidence. PECS block may have no effect on pain on movement at 24 h after surgery compared with PVB block (mean difference -0.56, 95% CI, -1.53 to 0.41, low-quality evidence). Block-related complications were generally poorly reported.

Conclusion: There is moderate quality evidence that PECS block compared with no treatment reduces postoperative pain intensity at rest. The observed results were less pronounced if patients received a sham block. Furthermore, PECS blocks might be equally effective as PVBs. Due to mostly low-quality or very low-quality evidence level, further research is warranted.

Protocol Registration: CRD42019126733.
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http://dx.doi.org/10.1097/EJA.0000000000001403DOI Listing
April 2021

Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis.

Cochrane Database Syst Rev 2020 10 19;10:CD012859. Epub 2020 Oct 19.

Department of Anesthesiology and Critical Care, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects.

Objectives: • To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification).

Selection Criteria: Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded.

Data Collection And Analysis: A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo.

Main Results: We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK₁ receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353.

Authors' Conclusions: We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reduce vomiting, compared to placebo. Four of the six substance classes (5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK₁ receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT₃ receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094506PMC
October 2020

Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery.

Cochrane Database Syst Rev 2020 Aug 13;8:CD012451. Epub 2020 Aug 13.

Department of Anaesthetics, Southampton University Hospital NHS Trust, Southampton, UK.

Background: Approximately 30% of adults undergoing non-cardiac surgery suffer from preoperative anaemia. Preoperative anaemia is a risk factor for mortality and adverse outcomes in different surgical specialties and is frequently the reason for blood transfusion. The most common causes are renal, chronic diseases, and iron deficiency. International guidelines recommend that the cause of anaemia guide preoperative anaemia treatment. Recombinant human erythropoietin (rHuEPO) with iron supplementation has frequently been used to increase preoperative haemoglobin concentrations in patients in order to avoid the need for perioperative allogeneic red blood cell (RBC) transfusion.

Objectives: To evaluate the efficacy of preoperative rHuEPO therapy (subcutaneous or parenteral) with iron (enteral or parenteral) in reducing the need for allogeneic RBC transfusions in preoperatively anaemic adults undergoing non-cardiac surgery.

Search Methods: We searched CENTRAL, Ovid MEDLINE(R), Ovid Embase, ISI Web of Science: SCI-EXPANDED and CPCI-S, and clinical trial registries WHO ICTRP and ClinicalTrials.gov on 29 August 2019.

Selection Criteria: We included all randomized controlled trials (RCTs) that compared preoperative rHuEPO + iron therapy to control treatment (placebo, no treatment, or standard of care with or without iron) for preoperatively anaemic adults undergoing non-cardiac surgery. We used the World Health Organization (WHO) definition of anaemia: haemoglobin concentration (g/dL) less than 13 g/dL for males, and 12 g/dL for non-pregnant females (decision of inclusion based on mean haemoglobin concentration). We defined two subgroups of rHuEPO dosage: 'low' for 150 to 300 international units (IU)/kg body weight, and 'high' for 500 to 600 IU/kg body weight.

Data Collection And Analysis: Two review authors collected data from the included studies. Our primary outcome was the need for RBC transfusion (no autologous transfusion, fresh frozen plasma or platelets), measured in transfused participants during surgery (intraoperative) and up to five days after surgery. Secondary outcomes of interest were: haemoglobin concentration (directly before surgery), number of RBC units (where one unit contains 250 to 450 mL) transfused per participant (intraoperative and up to five days after surgery), mortality (within 30 days after surgery), length of hospital stay, and adverse events (e.g. renal dysfunction, thromboembolism, hypertension, allergic reaction, headache, fever, constipation).

Main Results: Most of the included trials were in orthopaedic, gastrointestinal, and gynaecological surgery and included participants with mild and moderate preoperative anaemia (haemoglobin from 10 to 12 g/dL). The duration of preoperative rHuEPO treatment varied across the trials, ranging from once a week to daily or a 5-to-10-day period, and in one trial preoperative rHuEPO was given on the morning of surgery and for five days postoperatively. We included 12 trials (participants = 1880) in the quantitative analysis of the need for RBC transfusion following preoperative treatment with rHuEPO + iron to correct preoperative anaemia in non-cardiac surgery; two studies were multiarmed trials with two different dose regimens. Preoperative rHuEPO + iron given to anaemic adults reduced the need RBC transfusion (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.38 to 0.80; participants = 1880; studies = 12; I = 84%; moderate-quality evidence due to inconsistency). This analysis suggests that on average, the combined administration of rHuEPO + iron will mean 231 fewer individuals will need transfusion for every 1000 individuals compared to the control group. Preoperative high-dose rHuEPO + iron given to anaemic adults increased the haemoglobin concentration (mean difference (MD) 1.87 g/dL, 95% CI 1.26 to 2.49; participants = 852; studies = 3; I = 89%; low-quality evidence due to inconsistency and risk of bias) but not low-dose rHuEPO + iron (MD 0.11 g/dL, 95% CI -0.46 to 0.69; participants = 334; studies = 4; I = 69%; low-quality evidence due to inconsistency and risk of bias). There was probably little or no difference in the number of RBC units when rHuEPO + iron was given preoperatively (MD -0.09, 95% CI -0.23 to 0.05; participants = 1420; studies = 6; I = 2%; moderate-quality evidence due to imprecision).  There was probably little or no difference in the risk of mortality within 30 days of surgery (RR 1.19, 95% CI 0.39 to 3.63; participants = 230; studies = 2; I = 0%; moderate-quality evidence due to imprecision) or of adverse events including local rash, fever, constipation, or transient hypertension (RR 0.93, 95% CI 0.68 to 1.28; participants = 1722; studies = 10; I = 0%; moderate-quality evidence due to imprecision). The administration of rHuEPO + iron before non-cardiac surgery did not clearly reduce the length of hospital stay of preoperative anaemic adults (MD -1.07, 95% CI -4.12 to 1.98; participants = 293; studies = 3; I = 87%; low-quality evidence due to inconsistency and imprecision).

Authors' Conclusions: Moderate-quality evidence suggests that preoperative rHuEPO + iron therapy for anaemic adults prior to non-cardiac surgery reduces the need for RBC transfusion and, when given at higher doses, increases the haemoglobin concentration preoperatively. The administration of rHuEPO + iron treatment did not decrease the mean number of units of RBC transfused per patient. There were no important differences in the risk of adverse events or mortality within 30 days, nor in length of hospital stay. Further, well-designed, adequately powered RCTs are required to estimate the impact of this combined treatment more precisely.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095002PMC
August 2020

[Obstetric Anesthesia During the SARS-CoV-2 Pandemic - a Brief Overview of Published Recommendations for Action by National and International Specialist Societies and Committees].

Anasthesiol Intensivmed Notfallmed Schmerzther 2020 Apr 9;55(4):266-274. Epub 2020 Apr 9.

The most common human corona viruses cause common colds. But three of these viruses cause more serious, acute diseases; Middle East Respiratory Syndrome (MERS by MERS-CoV), Severe Acute Respiratory Syndrome (SARS) by SARS-CoV and COVID-19 by SARS-CoV-2. The current outbreak was classified by the WHO as a "global public health emergency". Despite all efforts to reduce the surgical lists and to cancel or postpone non-time-critical surgical interventions, some surgical and anesthetic interventions outside of intensive care medicine are still necessary and must be performed. This is particularly true for obstetric interventions and neuraxial labor analgesia. Workload in the delivery room is presumably not going to decrease and planned cesarean sections cannot be postponed. In the meantime, the clinical course and outcome of some COVID-19 patients with an existing pregnancy or peripartum courses have been reported. There are already numerous recommendations from national and international bodies regarding the care of such patients. Some of these recommendations will be summarized in this manuscript. The selection of aspects should by no means be seen as a form of prioritization. The general treatment principles in dealing with COVID-19 patients and the recommendations for action in intensive care therapy also apply to pregnant and postpartum patients. In this respect, there are naturally considerable redundancies and only a few aspects apply strictly or exclusively to the cohort of obstetric patients. In summary, at present it must be stated that the general care recommendations that also apply to non-COVID-19 patients are initially valid with regard to obstetric anesthesia. Nevertheless, the special requirements on the part of hygiene and infection protection result in special circumstances that should be taken into account when caring for pregnant patients from an anesthetic point of view. These relate to both medical aspects, but also to a particular extent logistics issues with regard to spatial separation, staffing and material resources.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295301PMC
April 2020

Adductor canal blocks for postoperative pain treatment in adults undergoing knee surgery.

Cochrane Database Syst Rev 2019 10 26;2019(10). Epub 2019 Oct 26.

BG-Universitätsklinikum Bergmannsheil gGmbH, Department of Anaesthesiology, Intensive Care Medicine and Pain Management, Bochum, Germany.

Background: Peripheral regional anaesthesia techniques are well established for postoperative pain treatment following knee surgery. The adductor canal block (ACB) is a new technique, which can be applied as a single shot or by catheter for continuous regional analgesia.

Objectives: To compare the analgesic efficacy and adverse events of ACB versus other regional analgesic techniques or systemic analgesic treatment for adults undergoing knee surgery.

Search Methods: We searched CENTRAL, MEDLINE, and Embase, five other databases, and one trial register on 19 September 2018; we checked references, searched citations, and contacted study authors to identify additional studies.

Selection Criteria: We included all randomized controlled trials (RCTs) comparing single or continuous ACB versus other regional analgesic techniques or systemic analgesic treatment. Inclusion was independent of the technique used (landmarks, peripheral nerve stimulator, or ultrasound) and the level of training of providers.

Data Collection And Analysis: We used Cochrane's standard methodological procedures. Our primary outcomes were pain intensity at rest and during movement; rate of accidental falls; and rates of opioid-related adverse events. We used GRADE to assess the quality of evidence for primary outcomes.

Main Results: We included 25 RCTs (1688 participants) in this review (23 trials combined within meta-analyses). In 18 studies, participants underwent total knee arthroplasty (TKA), whereas seven trials investigated patients undergoing arthroscopic knee surgery. We identified 11 studies awaiting classification and 11 ongoing studies. We investigated the following comparisons. ACB versus sham treatment We included eight trials for this comparison. We found no significant differences in postoperative pain intensity at rest (2 hours: standardized mean difference (SMD) -0.56, 95% confidence interval (CI) -1.20 to 0.07, 4 trials, 208 participants, low-quality evidence; 24 hours: SMD -0.49, 95% CI -1.05 to 0.07, 6 trials, 272 participants, low-quality evidence) or during movement (2 hours: SMD -0.59, 95% CI -1.5 to 0.33; 3 trials, 160 participants, very low-quality evidence; 24 hours: SMD 0.03, 95% CI -0.26 to 0.32, 4 trials, 184 participants, low-quality evidence). Furthermore, they noted no evidence of a difference in postoperative nausea between groups (24 hours: risk ratio (RR) 1.91, 95% CI 0.48 to 7.58, 3 trials, 121 participants, low-quality evidence). One trial reported that no accidental falls occurred 24 hours postoperatively (low-quality evidence). ACB versus femoral nerve block We included 15 RCTs for this comparison. We found no evidence of a difference in postoperative pain intensity at rest (2 hours: SMD -0.74, 95% CI -1.76 to 0.28, 5 trials, 298 participants, low-quality evidence; 24 hours: SMD 0.04, 95% CI -0.09 to 0.18, 12 trials, 868 participants, high-quality evidence) or during movement (2 hours: SMD -0.47, 95% CI -1.86 to 0.93, 2 trials, 88 participants, very low-quality evidence; 24 hours: SMD 0.56, 95% CI -0.00 to 1.12, 9 trials, 576 participants, very low-quality evidence). They noted no evidence of a difference in postoperative nausea (24 hours: RR 1.22, 95% CI 0.42 to 3.54, 2 trials, 138 participants, low-quality evidence) and no evidence that the rate of accidental falls during postoperative care was significantly different between groups (24 hours: RR 0.20, 95% CI 0.04 to 1.15, 3 trials, 172 participants, low-quality evidence).

Authors' Conclusions: We are currently uncertain whether patients treated with ACB suffer from lower pain intensity at rest and during movement, fewer opioid-related adverse events, and fewer accidental falls during postoperative care compared to patients receiving sham treatment. The same holds true for the comparison of ACB versus femoral nerve block focusing on postoperative pain intensity. The overall evidence level was mostly low or very low, so further research might change the conclusion. The 11 studies awaiting classification and the 11 ongoing studies, once assessed, may alter the conclusions of this review.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814953PMC
October 2019

Pain relief during labour: challenging the use of intramuscular pethidine.

Lancet 2018 08 13;392(10148):617-619. Epub 2018 Aug 13.

Department of Anaesthesia and Critical Care, University Hospitals of Wuerzburg, 97080 Wuerzburg, Germany.

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August 2018

Efficacy and safety of dexmedetomidine in peripheral nerve blocks: A meta-analysis and trial sequential analysis.

Eur J Anaesthesiol 2018 10;35(10):745-758

Background: The duration of analgesia provided by nerve blocks is limited if local anaesthetics are administered alone. Therefore, several additives, including dexmedetomidine (DEX), have been investigated in order to prolong postoperative analgesia following single-shot regional anaesthesia.

Objectives: The aim of this meta-analysis was to assess the efficacy and safety of the addition of perineural DEX to local anaesthetics compared with local anaesthetics alone or local anaesthetics combined with systemic administration of DEX.

Design: A systematic review of randomised controlled trials (RCT) with meta-analysis, trial sequential analysis and assessment of the quality of evidence by the GRADE approach.

Data Sources: The databases MEDLINE, CENTRAL and EMBASE (to May 2017) were systematically searched.

Eligibility Criteria: All RCTs investigating the efficacy and safety of perineural DEX combined with local anaesthetics compared with local anaesthetics alone or local anaesthetics in combination with systemic DEX in peripheral nerve blocks of adults undergoing surgery were included.

Results: A total of 46 RCTs (3149 patients) were included. Patients receiving perineural DEX combined with local anaesthetics had a longer duration of analgesia than local anaesthetics alone [mean difference 4.87 h; 95% confidence interval (95% CI) 4.02 to 5.73; P < 0.001; I = 100%; moderate-quality evidence]. The most important adverse events in the DEX group were intraoperative bradycardia [risk ratio 2.83; 95% CI 1.50 to 5.33; P = 0.035; I = 40%; very low-quality evidence] and hypotension (risk ratio 3.42; 95% CI 1.24 to 9.48; P = 0.002; I = 65%; very low quality evidence). In contrast, there were no differences in the duration of analgesia between perineural or intravenous DEX combined with local anaesthetics (mean difference 0.98 h; 95% CI -0.12 to 2.08; P = 0.08; I = 0%).

Conclusion: This meta-analysis demonstrated that DEX in combination with local anaesthetics increases postoperative analgesia for around 5 h. However, there are higher risks of intraoperative hypotension and bradycardia. Findings on side effects are associated with high uncertainty. Initial evidence suggests no difference in the duration of analgesia associated with systemic or perineural DEX.

Trial Registration: CRD42016042486.
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October 2018

Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults.

Cochrane Database Syst Rev 2018 06 4;6:CD009642. Epub 2018 Jun 4.

Department of Anaesthesia and Critical Care, University of Würzburg, Oberduerrbacher Str. 6, Würzburg, Germany.

Background: The management of postoperative pain and recovery is still unsatisfactory in a number of cases in clinical practice. Opioids used for postoperative analgesia are frequently associated with adverse effects, including nausea and constipation, preventing smooth postoperative recovery. Not all patients are suitable for, and benefit from, epidural analgesia that is used to improve postoperative recovery. The non-opioid, lidocaine, was investigated in several studies for its use in multimodal management strategies to reduce postoperative pain and enhance recovery. This review was published in 2015 and updated in January 2017.

Objectives: To assess the effects (benefits and risks) of perioperative intravenous (IV) lidocaine infusion compared to placebo/no treatment or compared to epidural analgesia on postoperative pain and recovery in adults undergoing various surgical procedures.

Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, and reference lists of articles in January 2017. We searched one trial registry contacted researchers in the field, and handsearched journals and congress proceedings. We updated this search in February 2018, but have not yet incorporated these results into the review.

Selection Criteria: We included randomized controlled trials comparing the effect of continuous perioperative IV lidocaine infusion either with placebo, or no treatment, or with thoracic epidural analgesia (TEA) in adults undergoing elective or urgent surgery under general anaesthesia. The IV lidocaine infusion must have been started intraoperatively, prior to incision, and continued at least until the end of surgery.

Data Collection And Analysis: We used Cochrane's standard methodological procedures. Our primary outcomes were: pain score at rest; gastrointestinal recovery and adverse events. Secondary outcomes included: postoperative nausea and postoperative opioid consumption. We used GRADE to assess the quality of evidence for each outcome.

Main Results: We included 23 new trials in the update. In total, the review included 68 trials (4525 randomized participants). Two trials compared IV lidocaine with TEA. In all remaining trials, placebo or no treatment was used as a comparator. Trials involved participants undergoing open abdominal (22), laparoscopic abdominal (20), or various other surgical procedures (26). The application scheme of systemic lidocaine strongly varies between the studies related to both dose (1 mg/kg/h to 5 mg/kg/h) and termination of the infusion (from the end of surgery until several days after).The risk of bias was low with respect to selection bias (random sequence generation), performance bias, attrition bias, and detection bias in more than 50% of the included studies. For allocation concealment and selective reporting, the quality assessment yielded low risk of bias for only approximately 20% of the included studies.IV Lidocaine compared to placebo or no treatment We are uncertain whether IV lidocaine improves postoperative pain compared to placebo or no treatment at early time points (1 to 4 hours) (standardized mean difference (SMD) -0.50, 95% confidence interval (CI) -0.72 to -0.28; 29 studies, 1656 participants; very low-quality evidence) after surgery. Due to variation in the standard deviation (SD) in the studies, this would equate to an average pain reduction of between 0.37 cm and 2.48 cm on a 0 to 10 cm visual analogue scale . Assuming approximately 1 cm on a 0 to 10 cm pain scale is clinically meaningful, we ruled out a clinically relevant reduction in pain with lidocaine at intermediate (24 hours) (SMD -0.14, 95% CI -0.25 to -0.04; 33 studies, 1847 participants; moderate-quality evidence), and at late time points (48 hours) (SMD -0.11, 95% CI -0.25 to 0.04; 24 studies, 1404 participants; moderate-quality evidence). Due to variation in the SD in the studies, this would equate to an average pain reduction of between 0.10 cm to 0.48 cm at 24 hours and 0.08 cm to 0.42 cm at 48 hours. In contrast to the original review in 2015, we did not find any significant subgroup differences for different surgical procedures.We are uncertain whether lidocaine reduces the risk of ileus (risk ratio (RR) 0.37, 95% CI 0.15 to 0.87; 4 studies, 273 participants), time to first defaecation/bowel movement (mean difference (MD) -7.92 hours, 95% CI -12.71 to -3.13; 12 studies, 684 participants), risk of postoperative nausea (overall, i.e. 0 up to 72 hours) (RR 0.78, 95% CI 0.67 to 0.91; 35 studies, 1903 participants), and opioid consumption (overall) (MD -4.52 mg morphine equivalents , 95% CI -6.25 to -2.79; 40 studies, 2201 participants); quality of evidence was very low for all these outcomes.The effect of IV lidocaine on adverse effects compared to placebo treatment is uncertain, as only a small number of studies systematically analysed the occurrence of adverse effects (very low-quality evidence).IV Lidocaine compared to TEAThe effects of IV lidocaine compared with TEA are unclear (pain at 24 hours (MD 1.51, 95% CI -0.29 to 3.32; 2 studies, 102 participants), pain at 48 hours (MD 0.98, 95% CI -1.19 to 3.16; 2 studies, 102 participants), time to first bowel movement (MD -1.66, 95% CI -10.88 to 7.56; 2 studies, 102 participants); all very low-quality evidence). The risk for ileus and for postoperative nausea (overall) is also unclear, as only one small trial assessed these outcomes (very low-quality evidence). No trial assessed the outcomes, 'pain at early time points' and 'opioid consumption (overall)'. The effect of IV lidocaine on adverse effects compared to TEA is uncertain (very low-quality evidence).

Authors' Conclusions: We are uncertain whether IV perioperative lidocaine, when compared to placebo or no treatment, has a beneficial impact on pain scores in the early postoperative phase, and on gastrointestinal recovery, postoperative nausea, and opioid consumption. The quality of evidence was limited due to inconsistency, imprecision, and study quality. Lidocaine probably has no clinically relevant effect on pain scores later than 24 hours. Few studies have systematically assessed the incidence of adverse effects. There is a lack of evidence about the effects of IV lidocaine compared with epidural anaesthesia in terms of the optimal dose and timing (including the duration) of the administration. We identified three ongoing studies, and 18 studies are awaiting classification; the results of the review may change when these studies are published and included in the review.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513586PMC
June 2018

Hypnotic agents for induction of general anesthesia in cesarean section patients: A systematic review and meta-analysis of randomized controlled trials.

J Clin Anesth 2018 Aug 26;48:73-80. Epub 2018 May 26.

Department of Anesthesia and Pain Management, Maastricht University Medical Center, Maastricht, The Netherlands. Electronic address:

Study Objective: An ideal induction drug for cesarean section (CS) must have quick action, with minimum side effects such as awareness, hemodynamic compromise, and neonatal depression. Thiopentone is frequently used; however, no reliable evidence is available to support its use as a dedicated hypnotic agent in this setting.

Design: A systematic review and meta-analysis, using PRISMA methodology, of randomized controlled trials (RCTs), comparing women undergoing CS using thiopentone with those undergoing CS with propofol, ketamine, or benzodiazepines as hypnotic agents.

Data Sources: Comprehensive search without language restrictions of MEDLINE, EMBASE, and the Cochrane Controlled Trials Registers until May 2015, with an update in January 2017. Included trials must have reported at least one of the following variables: neonatal arterial or venous umbilical blood gas, maternal systolic blood pressure pre- and post-intubation, or Apgar score.

Main Results: A total of 911 patients from 18 RCTs were eligible for quantitative analysis. The increase in maternal systolic blood pressure was smaller in patients administered propofol, compared with those administered thiopentone (weighted mean difference [WMD]: -11.52 [-17.60, -5.45]; p = 0.0002). Induction with propofol also resulted in a significantly lower umbilical arterial pO (WMD: -0.12 [-0.20, -0.04]; p = 0.004) than induction with thiopentone. A comparison between propofol and thiopentone revealed no significant differences in other umbilical blood gas parameters or in Apgar scores. In contrast, when comparing ketamine with thiopentone, the number of neonates with a lower Apgar score (<7) at 1 and 5 min was significantly higher in the ketamine group than in the thiopentone group (p = 0.004).

Conclusion: The evidence, based on sparse and relatively old trials, indicates that propofol and thiopentone are equally suited for CS. After 1 and 5 min, ketamine yields lower Apgar scores than thiopentone. Additional well-designed trials are needed to reach firmer conclusions.
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August 2018

Total intravenous anesthesia vs single pharmacological prophylaxis to prevent postoperative vomiting in children: A systematic review and meta-analysis.

Paediatr Anaesth 2017 Dec 2;27(12):1202-1209. Epub 2017 Nov 2.

Department of Anesthesiology, University Hospital Düsseldorf, Düsseldorf, Germany.

Background: Postoperative nausea and postoperative vomiting are frequent but often missed complications after general anesthesia in pediatric patients. Because inhaled anesthetics are known to trigger postoperative vomiting, total intravenous anesthesia is often administered in high-risk children to avoid the use of inhalational anesthesia. Since inhalational anesthesia might be advantageous in some situations, the question is raised whether administration of pharmacological prophylaxis offers equal protection from postoperative vomiting compared with total intravenous anesthesia alone.

Aim: The aim of this systematic review was to compare total intravenous anesthesia with single-drug pharmacological prophylaxis for the protection of postoperative vomiting in pediatric patients.

Methods: We conducted a systematic review (EMBASE, MEDLINE, and CENTRAL) with meta-analysis on randomized controlled trials including patients <18 years of age undergoing general anesthesia, with one group receiving propofol-based total intravenous anesthesia and another group receiving inhalational anesthesia with single pharmacological prophylaxis. Primary outcome was the overall incidence for postoperative vomiting. Secondary outcomes included early and late postoperative vomiting, the need for postoperative antiemetic medication, time to first oral intake, duration of stay in the postanesthesia care unit, and any adverse events defined as such by the respective authors. Risk ratios (RR) or mean differences (MD) with 95% confidence intervals (95% CI) were calculated using a random effects model with inverse variance weighting.

Results: Four randomized controlled trials including 558 children were included in the final analysis. All patients underwent strabismus surgery. Total intravenous anesthesia and single pharmacological prophylaxis were equally effective in preventing overall postoperative vomiting (RR 0.99 [95% CI 0.77; 1.27]; 4 trials), as well as vomiting in the early (1.48 [0.78; 2.83]; 4 trials) and late (0.89 [0.56;1.42]; 2 trials) postoperative period. There was no difference in the need for postoperative antiemetic medication. Although patients resumed drinking and eating significantly earlier following total intravenous anesthesia (MD -1.40 hours [-2.01; -0.80], P < .001), the duration of PACU stay did not differ between groups. The incidence of intraoperative oculocardiac reflex was the only reported adverse event, which was more likely to occur after total intravenous anesthesia (1.86 [1.01; 3.41]).

Conclusion: Single pharmacological prophylaxis appears equally effective compared with total intravenous anesthesia in preventing postoperative vomiting in pediatric patients. However, during strabismus surgery, total intravenous anesthesia increases the risk for bradycardia due to oculocardiac reflex. Thus, when anesthesia is maintained with inhalational anesthetics, its emetogenic effects can sufficiently be compensated by the addition of a single prophylactic antiemetic medication.
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December 2017

Patient-controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour.

Cochrane Database Syst Rev 2017 Apr 13;4:CD011989. Epub 2017 Apr 13.

Department of Anaesthesia and Critical Care, University of Würzburg, Oberduerrbacher Str. 6, Würzburg, Germany.

Background: Multiple analgesic strategies for pain relief during labour are available. Recently remifentanil, a short-acting opioid, has recently been used as an alternative analgesic due to its unique pharmacological properties.

Objectives: To systematically assess the effectiveness of remifentanil intravenous patient-controlled analgesia (PCA) for labour pain, along with any potential harms to the mother and the newborn.

Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (9 December 2015), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), handsearched congress abstracts (November 2015), and reference lists of retrieved studies.

Selection Criteria: Randomised controlled trials (RCTs) and cluster-randomised trials comparing remifentanil (PCA) with another opioid (intravenous (IV)/intramuscular (IM)), or with another opioid (PCA), or with epidural analgesia, or with remifentanil (continuous IV), or with remifentanil (PCA, different regimen), or with inhalational analgesia, or with placebo/no treatment in all women in labour including high-risk groups with planned vaginal delivery.

Data Collection And Analysis: Two review authors independently assessed trials for inclusion, extracted data, and appraised study quality.We contacted study authors for additional information other than incomplete outcome data. We performed random-effects meta-analysis.To reduce the risk of random error in meta-analysis we performed trial sequential analysis. We included total zero event trials and used a constant continuity correction of 0.01 (ccc 0.01) for meta-analysis. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence.

Main Results: Twenty RCTs with 3569 women were included. Of those, 10 trials (2983 participants) compared remifentanil (PCA) to an epidural, four trials (216 participants) to another opioid (IV/IM), three trials (215 participants) to another opioid (PCA), two trials (135 participants) to remifentanil (continuous IV), and one trial (20 participants) to remifentanil (PCA, different regimen). No trials were identified for the remaining comparisons.Methodological quality of studies was moderate to poor. We assessed risk of bias as high for blinding issues and incomplete outcome data in 65% and 45% of the included studies, respectively.There is evidence of effect that women in the remifentanil (PCA) group were more satisfied with pain relief than women in the other opioids (IV/IM) group (standardised mean difference (SMD) 2.11, 95% confidence interval (CI) 0.72 to 3.49, four trials, very low-quality evidence), and that women were less satisfied compared to women in the epidural group (SMD -0.22, 95% CI -0.40 to -0.04, seven trials, very low-quality evidence).There is evidence of effect that remifentanil (PCA) provided stronger pain relief at one hour than other opioids administered IV/IM (SMD -1.58, 95% CI -2.69 to -0.48, three trials, very low-quality evidence) or via PCA (SMD -0.51, 95% CI -1.01 to -0.00, three trials, very low-quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (SMD 0.57, 95% CI 0.31 to 0.84, six trials, low-quality evidence).Data were limited on safety aspects for both the women and the newborns. Only one study analysed maternal apnoea in a comparison of remifentanil (PCA) versus epidural and reported that half of the women in the remifentanil and none in the epidural group had an apnoea (very low-quality evidence). There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for maternal respiratory depression when compared to epidural analgesia (RR 0.91, 95% CI 0.51 to 1.62, ccc 0.01, three trials, low-quality evidence) and no reliable conclusion might be reached compared to remifentanil (continuous IV) (all study arms included zero events, two trials, low-quality evidence). In one trial of remifentanil (PCA) versus another opioid (IM) three out of 18 women in the remifentanil and none out of 18 in the control group had a respiratory depression (very low-quality evidence).There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for newborns with Apgar scores less than seven at five minutes compared to epidural analgesia (RR 1.26, 95% CI 0.62 to 2.57, ccc 0.01, five trials, low-quality evidence) and no reliable conclusion might be reached compared to another opioid (IV) and compared to remifentanil (PCA, different regimen) both with zero events in all study arms (one trial, very-low quality evidence). In one trial of remifentanil (PCA) versus another opioid (PCA) none out of nine newborns in the remifentanil and three out of eight in the opioid (PCA) group had Apgar scores less than seven (very-low quality evidence).There is evidence that remifentanil (PCA) was associated with a lower risk for the requirement of additional analgesia when compared to other opioids (IV/IM) (RR 0.57, 95% CI 0.40 to 0.81, three trials, moderate-quality evidence) and that it was associated with a higher risk compared to epidural analgesia (RR 9.27, 95% CI 3.73 to 23.03, ccc 0.01, six trials, moderate-quality evidence). There is no evidence of effect that remifentanil (PCA) reduced the requirement for additional analgesia compared to other opioids (PCA) (RR 0.76, 95% CI 0.45 to 1.28, three trials, low-quality evidence).There is evidence that there was no difference in the risk for caesarean delivery between remifentanil (PCA) and other opioids (IV/IM) (RR 0.63, 95% CI 0.30 to 1.32, ccc 0.01, four trials, low-quality evidence) and epidural analgesia (RR 1.0, 95% CI 0.82 to 1.22, ccc 0.01, nine trials, moderate-quality evidence), respectively. Pooled meta-analysis revealed an increased risk for caesarean section under remifentanil (PCA) compared to other opioids (PCA) (RR 2.78, 95% CI 0.99 to 7.82, two trials, very low-quality evidence). However, a wide range of clinically relevant and non-relevant treatment effects is compatible with this result.

Authors' Conclusions: Based on the current systematic review, there is mostly low-quality evidence to inform practice and future research may significantly alter the current situation. The quality of evidence is mainly limited by poor quality of the studies, inconsistency, and imprecision. More research is needed on maternal and neonatal safety outcomes (maternal apnoea and respiratory depression, Apgar score) and on the optimal mode and regimen of remifentanil administration to provide highest efficacy with reasonable adverse effects for mothers and their newborns.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478102PMC
April 2017

Incidence and severity of chronic pain after caesarean section: A systematic review with meta-analysis.

Eur J Anaesthesiol 2016 Nov;33(11):853-865

aFrom the Department of Anaesthesia and Critical Care, University Hospital of Wuerzburg, Wuerzburg (SW, KN, YJ, NR, PK), Department of Anaesthesiology and Intensive Care, Jena University Hospital, Jena (WM) and Department of Obstetrics and Gynaecology, University Hospital of Wuerzburg, Wuerzburg, Germany (AW) *Stephanie Weibel and Katharina Neubert contributed equally to the writing of this article.

Background: The frequency of caesarean section has increased dramatically in recent decades. Despite this, robust data regarding the consequences of caesarean section in terms of developing chronic postsurgical pain (CPSP) are still lacking.

Objective: This systematic review analysed the incidence and severity of CPSP in women 3 to less than 6, 6 to less than 12, and at least 12 months after caesarean section.

Design: Systematic review of prospective and retrospective observational studies and randomised controlled trials with meta-analysis.

Data Source: We searched MEDLINE to May 2015.

Eligibility Criteria: We included all studies investigating the incidence and/or severity of CPSP at least 3 months after caesarean section. The primary outcome was chronic postsurgical wound pain (CPSP 'wound'). Secondary outcomes were persistent pain in the back area, pelvic region or reported as residual pain, and severity of 'birth-related' chronic pain.

Results: Meta-analysis using the random-effects model based on 15 studies (n = 4475) reporting CPSP 'wound' at 3 to less than 6 months after caesarean section revealed an incidence of 15.4% [95% confidence interval (CI): 9.9 to 20.9%]. For 6 to less than 12 and at least 12 months after caesarean section, the incidence of CPSP 'wound' was estimated at 11.5% (95% CI: 8.1 to 15.0%, n = 3345) and 11.2% (95% CI: 7.4 to 15.0%, n = 3451), respectively. Meta-regression analysis using the publication year as predictor revealed stable CPSP 'wound' incidences at each postoperative time slot from 2002 to the present. Of those patients who reported chronic pain, 9.6% (95% CI: 0.0 to 21.0%) had severe pain, 23.5% (95% CI: 10.0 to 37.0%) had moderate pain and 49.2% (95% CI: 18.9 to 79.4%) had mild pain at 6 months.

Limitations: Major limitations are high statistical heterogeneity of the meta-analyses and inconsistencies in reporting severity of chronic 'birth-related' pain.

Conclusion: This meta-analysis finds a clinically relevant incidence of CPSP 'wound' after caesarean section ranging from 15% at 3 months to 11% at 12 months or longer that has been largely stable in recent years.
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November 2016

Total intravenous anaesthesia versus single-drug pharmacological antiemetic prophylaxis in adults: A systematic review and meta-analysis.

Eur J Anaesthesiol 2016 Oct;33(10):750-60

From the Department of Anaesthesiology, University Hospital Düsseldorf, Düsseldorf (MSS, RK, PKIE) and Department of Anaesthesiology and Critical Care, University Hospital Würzburg, Würzburg, Germany (PKRA, SW) *Maximilian S. Schaefer and Peter Kranke contributed equally to the writing of the article.

Background: Postoperative nausea and vomiting (PONV) are among the most unfavourable anaesthetic outcomes attributed to the administration of inhaled anaesthetics. Accordingly, inhaled anaesthetics are frequently substituted by propofol when patients are at risk of PONV. As, on some occasions, inhalational anaesthesia may be favourable, the relative impact of propofol anaesthesia needs to be established based on robust data.

Objective: To compare the effectiveness of a single-drug pharmacological prophylaxis with total intravenous anaesthesia (TIVA) for prevention of PONV.

Design: Systematic review of randomised controlled trials with meta-analyses.

Data Sources: All available studies until 29 April 2015 were retrieved from MEDLINE, CENTRAL and EMBASE.

Eligibility Criteria: Randomised controlled trials on adult patients undergoing general anaesthesia with at least one group receiving propofol-based intravenous anaesthesia without further antiemetic prophylaxis, and one group receiving inhalational anaesthesia with single-drug antiemetic prophylaxis.

Results: Fourteen studies involving 2051 patients were included. Compared with TIVA, after inhalational anaesthesia and single-drug antiemetic prophylaxis, there was no difference in the overall risk of PONV [relative risk (RR) 1.06, 95% confidence interval (CI) 0.85; 1.32, GRADE rating moderate], nor was there any difference in the risk of postoperative vomiting (RR 1.17, 95% CI 0.78; 1.76), need for rescue medication (RR 1.16, 95% CI 0.68; 1.99) or early PONV (RR 1.06, 95% CI 0.88; 1.27). However, TIVA was associated with an increased risk of late PONV (RR 1.41, 95% CI 1.10; 1.79, P = 0.006). Six studies investigated other side-effects associated with anaesthesia and found no differences between the two groups. Finally, there was evidence of a publication bias that included smaller studies favouring TIVA.

Conclusion: This meta-analysis confirms the results from indirect comparisons in individual studies: instead of substituting inhalational anaesthesia with propofol-based TIVA, a similar antiemetic effect can be achieved by adding single-drug pharmacological prophylaxis to the inhalational anaesthetic.

Study Registration: This systematic review with meta-analysis was registered at PROSPERO (www.crd.york.ac.uk/PROSPERO), study number CRD42015019571.
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October 2016

Normobaric and hyperbaric oxygen therapy for the treatment and prevention of migraine and cluster headache.

Cochrane Database Syst Rev 2015 Dec 28(12):CD005219. Epub 2015 Dec 28.

Department of Anaesthesia, Prince of Wales Clinical School, University of NSW, Sydney, NSW, Australia.

Background: Migraine and cluster headaches are severe and disabling. Migraine affects up to 18% of women, while cluster headaches are much less common (0.2% of the population). A number of acute and prophylactic therapies are available. Hyperbaric oxygen therapy (HBOT) is the therapeutic administration of 100% oxygen at environmental pressures greater than one atmosphere, while normobaric oxygen therapy (NBOT) is oxygen administered at one atmosphere. This is an updated version of the original Cochrane review published in Issue 3, 2008 under the title 'Normobaric and hyperbaric oxygen for migraine and cluster headache'.

Objectives: To examine the efficacy and safety of normobaric oxygen therapy (NBOT) and hyperbaric oxygen therapy (HBOT) in the treatment and prevention of migraine and cluster headache.

Search Methods: We updated searches of the following databases up to 15 June 2015: CENTRAL (the Cochrane Library), MEDLINE, EMBASE, and CINAHL. For the original review we searched the following databases up to May 2008: CENTRAL, MEDLINE, EMBASE, CINAHL, DORCTIHM, and reference lists from relevant articles. We handsearched relevant journals and contacted researchers to identify trials.

Selection Criteria: Randomised controlled trials comparing HBOT or NBOT with one another, other active therapies, placebo (sham) interventions, or no treatment in participants with migraine or cluster headache.

Data Collection And Analysis: Three review authors independently extracted data and assessed the quality of the evidence using the GRADE approach.

Main Results: In this update, we included 11 trials with 209 participants. Five trials (103 participants) compared HBOT versus sham therapy for acute migraine, three trials compared NBOT to sham therapy or ergotamine tartrate for cluster headache (145 participants), two trials evaluated HBOT for cluster headache (29 participants), and one trial (56 participants) compared NBOT to sham for a mixed group of headache. The risk of bias varied considerably across these trials but in general trial quality was poor to moderate. One trial may not have been truly randomised and two included studies were reported as abstracts only. Seven trials did not indicate allocation concealment or randomisation method. Notably, 10 of the 11 trials used a sham comparator therapy and masked the outcome assessor to allocation.We pooled data from three trials, which suggested that HBOT was effective in relieving migraine headaches compared to sham therapy (risk ratio (RR) 6.21, 95% CI 2.41 to 16.00; 58 participants, three trials). The quality of evidence was low, having been downgraded for small crossover studies with incomplete reporting. There was no evidence that HBOT could prevent migraine episodes, reduce the incidence of nausea and vomiting, or reduce the requirement for rescue medication. There was no evidence that HBOT was effective for the termination of cluster headache (RR 11.38, 95% CI 0.77 to 167.85; P = 0.08) (one trial), but this trial had low power.NBOT was effective in terminating cluster headache compared to sham in a single small study (RR 7.88, 95% CI 1.13 to 54.66), but not superior to ergotamine administration in another small trial (RR 1.17, 95% CI 0.94 to 1.46; P = 0.16). A third trial reported a statistically significant difference in the proportion of attacks successfully treated with oxygen (117 of 150 attacks were successfully treated with NBOT (78%) versus 30 of 148 attacks treated with NBOT (20%)). The proportion of responders was consistent across these three trials, and suggested more than 75% of headaches were likely to respond to NBOT.No serious adverse events during HBOT or NBOT were reported.

Authors' Conclusions: Since the last version of this review, two new included studies have provided additional information to change the conclusions. There was some evidence that HBOT was effective for the termination of acute migraine in an unselected population, and some evidence that NBOT was similarly effective in cluster headache. Given the cost and poor availability of HBOT, more research should be done on patients unresponsive to standard therapy. NBOT is cheap, safe, and easy to apply, so will probably continue to be used despite the limited evidence in this review.
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December 2015

The transparent clinical trial: Why we need complete and informative prospective trial registration.

Eur J Anaesthesiol 2016 Feb;33(2):72-4

From the Department of Anaesthesia and Critical Care, University Hospitals of Würzburg, Würzburg, Germany (SW, PK), and Department of Anaesthesiology, Geneva University Hospitals, Institute of Global Health, University of Geneva, Geneva, Switzerland (NE).

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February 2016

Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery.

Cochrane Database Syst Rev 2015 Jul 16(7):CD009642. Epub 2015 Jul 16.

Department of Anaesthesia and Critical Care, University of Würzburg, Oberdürrbacher Str. 6, Würzburg, Germany, 97080.

Background: The management of postoperative pain and recovery is still unsatisfactory in clinical practice. Opioids used for postoperative analgesia are frequently associated with adverse effects including nausea and constipation. These adverse effects prevent smooth postoperative recovery. On the other hand not all patients may be suited to, and take benefit from, epidural analgesia used to enhance postoperative recovery. The non-opioid lidocaine was investigated in several studies for its use in multi-modal management strategies to reduce postoperative pain and enhance recovery.

Objectives: The aim of this review was to assess the effects (benefits and risks) of perioperative intravenous lidocaine infusion compared to placebo/no treatment or compared to epidural analgesia on postoperative pain and recovery in adults undergoing various surgical procedures.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 5 2014), MEDLINE (January 1966 to May 2014), EMBASE (1980 to May 2014), CINAHL (1982 to May 2014), and reference lists of articles. We searched the trial registry database ClinicalTrials.gov, contacted researchers in the field, and handsearched journals and congress proceedings. We did not apply any language restrictions.

Selection Criteria: We included randomized controlled trials comparing the effect of continuous perioperative intravenous lidocaine infusion either with placebo, or no treatment, or with epidural analgesia in adults undergoing elective or urgent surgery under general anaesthesia. The intravenous lidocaine infusion must have been started intraoperatively prior to incision and continued at least until the end of surgery.

Data Collection And Analysis: Trial quality was independently assessed by two authors according to the methodological procedures specified by the Cochrane Collaboration. Data were extracted by two independent authors. We collected trial data on postoperative pain, recovery of gastrointestinal function, length of hospital stay, postoperative nausea and vomiting (PONV), opioid consumption, patient satisfaction, surgical complication rates, and adverse effects of the intervention.

Main Results: We included 45 trials involving 2802 participants. Two trials compared intravenous lidocaine versus epidural analgesia. In all the remaining trials placebo or no treatment was used as a comparator. Trials involved participants undergoing open abdominal (12), laparoscopic abdominal (13), or various other surgical procedures (20).The risk of bias was low with respect to selection bias (random sequence generation), performance bias, attrition bias, and detection bias in more than 50% of the included studies. For allocation concealment and selective reporting the quality assessment yielded low risk of bias for only approximately 20% of the included studies.We found evidence of effect for intravenous lidocaine on the reduction of postoperative pain (visual analogue scale, 0 to 10 cm) compared to placebo or no treatment at 'early time points (one to four hours)' (mean difference (MD) -0.84 cm, 95% confidence interval (CI) -1.10 to -0.59; low-quality evidence) and at 'intermediate time points (24 hours)' (MD -0.34 cm, 95% CI -0.57 to -0.11; low-quality evidence) after surgery. However, no evidence of effect was found for lidocaine to reduce pain at 'late time points (48 hours)' (MD -0.22 cm, 95% CI -0.47 to 0.03; low-quality evidence). Pain reduction was most obvious at 'early time points' in participants undergoing laparoscopic abdominal surgery (MD -1.14, 95% CI -1.51 to -0.78; low-quality evidence) and open abdominal surgery (MD -0.72, 95% CI -0.96 to -0.47; moderate-quality evidence). No evidence of effect was found for lidocaine to reduce pain in participants undergoing all other surgeries (MD -0.30, 95% CI -0.89 to 0.28; low-quality evidence). Quality of evidence is limited due to inconsistency and indirectness (small trial sizes).Evidence of effect was found for lidocaine on gastrointestinal recovery regarding the reduction of the time to first flatus (MD -5.49 hours, 95% CI -7.97 to -3.00; low-quality evidence), time to first bowel movement (MD -6.12 hours, 95% CI -7.36 to -4.89; low-quality evidence), and the risk of paralytic ileus (risk ratio (RR) 0.38, 95% CI 0.15 to 0.99; low-quality evidence). However, no evidence of effect was found for lidocaine on shortening the time to first defaecation (MD -9.52 hours, 95% CI -23.24 to 4.19; very low-quality evidence).Furthermore, we found evidence of positive effects for lidocaine administration on secondary outcomes such as reduction of length of hospital stay, postoperative nausea, intraoperative and postoperative opioid requirements. There was limited data on the effect of IV lidocaine on adverse effects (e.g. death, arrhythmias, other heart rate disorders or signs of lidocaine toxicity) compared to placebo treatment as only a limited number of studies systematically analysed the occurrence of adverse effects of the lidocaine intervention.The comparison of intravenous lidocaine versus epidural analgesia revealed no evidence of effect for lidocaine on relevant outcomes. However, the results have to be considered with caution due to imprecision of the effect estimates.

Authors' Conclusions: There is low to moderate evidence that this intervention, when compared to placebo, has an impact on pain scores, especially in the early postoperative phase, and on postoperative nausea. There is limited evidence that this has further impact on other relevant clinical outcomes, such as gastrointestinal recovery, length of hospital stay, and opioid requirements. So far there is a scarcity of studies that have systematically assessed the incidence of adverse effects; the optimal dose; timing (including the duration of the administration); and the effects when compared with epidural anaesthesia.
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July 2015

Microglia and astrocytes attenuate the replication of the oncolytic vaccinia virus LIVP 1.1.1 in murine GL261 gliomas by acting as vaccinia virus traps.

J Transl Med 2015 Jul 7;13:216. Epub 2015 Jul 7.

Department of Biochemistry, Biocenter, University of Wuerzburg, Am Hubland, 97074, Würzburg, Germany.

Background: Oncolytic virotherapy is a novel approach for the treatment of glioblastoma multiforme (GBM) which is still a fatal disease. Pathologic features of GBM are characterized by the infiltration with microglia/macrophages and a strong interaction between immune- and glioma cells. The aim of this study was to determine the role of microglia and astrocytes for oncolytic vaccinia virus (VACV) therapy of GBM.

Methods: VACV LIVP 1.1.1 replication in C57BL/6 and Foxn1(nu/nu) mice with and without GL261 gliomas was analyzed. Furthermore, immunohistochemical analysis of microglia and astrocytes was investigated in non-, mock-, and LIVP 1.1.1-infected orthotopic GL261 gliomas in C57BL/6 mice. In cell culture studies virus replication and virus-mediated cell death of GL261 glioma cells was examined, as well as in BV-2 microglia and IMA2.1 astrocytes with M1 or M2 phenotypes. Co-culture experiments between BV-2 and GL261 cells and apoptosis/necrosis studies were performed. Organotypic slice cultures with implanted GL261 tumor spheres were used as additional cell culture system.

Results: We discovered that orthotopic GL261 gliomas upon intracranial virus delivery did not support replication of LIVP 1.1.1, similar to VACV-infected brains without gliomas. In addition, recruitment of Iba1(+) microglia and GFAP(+) astrocytes to orthotopically implanted GL261 glioma sites occurred already without virus injection. GL261 cells in culture showed high virus replication, while replication in BV-2 and IMA2.1 cells was barely detectable. The reduced viral replication in BV-2 cells might be due to rapid VACV-induced apoptotic cell death. In BV-2 and IMA 2.1 cells with M1 phenotype a further reduction of virus progeny and virus-mediated cell death was detected. Application of BV-2 microglial cells with M1 phenotype onto organotypic slice cultures with implanted GL261 gliomas resulted in reduced infection of BV-2 cells, whereas GL261 cells were well infected.

Conclusion: Our results indicate that microglia and astrocytes, dependent on their activation state, may preferentially clear viral particles by immediate uptake after delivery. By acting as VACV traps they further reduce efficient virus infection of the tumor cells. These findings demonstrate that glia cells need to be taken into account for successful GBM therapy development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492094PMC
July 2015

Hyperbaric oxygen therapy for chronic wounds.

Cochrane Database Syst Rev 2015 Jun 24(6):CD004123. Epub 2015 Jun 24.

Department of Anaesthesia and Critical Care, University of Würzburg, Oberdürrbacher Str. 6, Würzburg, Germany, 97080.

Background: Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing.

Objectives: To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb.

Search Methods: For this second update we searched the Cochrane Wounds Group Specialised Register (searched 18 February 2015); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 1); Ovid MEDLINE (1946 to 17 February 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 17 February 2015); Ovid EMBASE (1974 to 17 February 2015); and EBSCO CINAHL (1982 to 17 February 2015).

Selection Criteria: Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy).

Data Collection And Analysis: Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion.

Main Results: We included twelve trials (577 participants). Ten trials (531 participants) enrolled people with a diabetic foot ulcer: pooled data of five trials with 205 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 2.35, 95% confidence interval (CI) 1.19 to 4.62; P = 0.01) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We identified one trial (30 participants) which enrolled patients with non-healing diabetic ulcers as well as venous ulcers ("mixed ulcers types") and patients were treated for 30 days. For this "mixed ulcers" there was a significant benefit of HBOT in terms of reduction in ulcer area at the end of treatment (30 days) (MD 61.88%, 95% CI 41.91 to 81.85, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers.

Authors' Conclusions: In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias.
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http://dx.doi.org/10.1002/14651858.CD004123.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055586PMC
June 2015

Intratumoral INF-γ triggers an antiviral state in GL261 tumor cells: a major hurdle to overcome for oncolytic vaccinia virus therapy of cancer.

Mol Ther Oncolytics 2015 24;2:15009. Epub 2015 Jun 24.

Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany; Rudolf Virchow Center for Experimental Biomedicine and Institute for Molecular Infection Biology, University of Wuerzburg, Wuerzburg, Germany; Department of Radiation Medicine and Applied Sciences, Rebecca & John Moores Comprehensive Cancer Center, University of California, San Diego, California, USA; Genelux Corporation, San Diego Science Center, San Diego, California, USA.

Oncolytic vaccinia virus (VACV) therapy is an alternative treatment option for glioblastoma multiforme. Here, we used a comparison of different tumor locations and different immunologic and genetic backgrounds to determine the replication efficacy and oncolytic potential of the VACV LIVP 1.1.1, an attenuated wild-type isolate of the Lister strain, in murine GL261 glioma models. With this approach, we expected to identify microenvironmental factors, which may be decisive for failure or success of oncolytic VACV therapy. We found that GL261 glioma cells implanted subcutaneously or orthotopically into Balb/c athymic, C57BL/6 athymic, or C57BL/6 wild-type mice formed individual tumors that respond to oncolytic VACV therapy with different outcomes. Surprisingly, only Balb/c athymic mice with subcutaneous tumors supported viral replication. We identified intratumoral IFN-γ expression levels that upregulate MHCII expression on GL261 cells in C57BL/6 wild-type mice associated with a non-permissive status of the tumor cells. Moreover, this IFN-γ-induced tumor cell phenotype was reversible.
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http://dx.doi.org/10.1038/mto.2015.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782962PMC
April 2016
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