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Anne-Lene Kjældgaard,1,2 Katrine Pilely,1 Karsten Skovgaard Olsen,2 Anne Øberg Lauritsen,2 Stephen Wørlich Pedersen,3 Kirsten Svenstrup,3,4 Merete Karlsborg,4 Helle Thagesen,5 Morten Blaabjerg,5 Ásta Theódórsdóttir,6 Elisabeth Gundtoft Elmo,3 Anette Torvin Møller,7 Niels Anker Pedersen,8 Niels Kirkegaard,8 Kirsten Møller,2,9 Peter Garred1,9 1Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Diagnostic Centre, Rigshospitalet, Copenhagen, Denmark; 2Department of Neuroanaesthesiology Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark; 3Department of Neurology, Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark; 4Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark; 5Department of Neurology, Roskilde University Hospital, Roskilde, Denmark; 6Department of Neurology, Odense University Hospital, Odense, Denmark; 7Department of Neurology, Aarhus Hospital, Copenhagen, Denmark; 8Department of Anaesthesiology, Private Hospital Gildhøj, Brondby, Denmark; 9Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Anne-Lene KjældgaardLaboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Diagnostic Centre, Rigshospitalet, Ole Maaloesvej 26, Copenhagen, DK-2200, DenmarkTel +45 35457631Fax +45 35398766Email anne-lene.kjaeldgaard@regionh.dkBackground: The complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients.Methods: This observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, − 2, and − 3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time.Results: Compared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios.Conclusion: ALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS.Keywords: amyotrophic lateral sclerosis, innate immunity, complement, lectin pathway, cerebrospinal fluid, pathophysiology, observational cohort study

Abstract Background Chronic fatigue syndrome is an idiopathic syndrome widely suspected of having an infectious or immune etiology. We applied an unbiased metagenomic approach to try to identify known or novel infectious agents in the serum of 45 cases with chronic fatigue syndrome or idiopathic chronic fatigue. Controls were the unaffected monozygotic co-twins of cases, and serum samples were obtained at the same place and time. Results No novel DNA or RNA viral signatures were confidently identified. Four affected twins and no unaffected twins evidenced viremia with GB virus C (8.9% vs. 0%, p = 0.019), and one affected twin had previously undetected hepatitis C viremia. An excess of GB virus C viremia in cases with chronic fatigue requires confirmation. Conclusions Current, impairing chronic fatigue was not robustly associated with viremia detectable in serum.

Abstract Background The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.

Abstract Background The aim was to ascertain whether thrombocyte MAO (trbc-MAO) activity and depressed state are genetically associated with the MAO locus on chromosome X (Xp11.3 – 11.4). We performed novel sequencing of the MAO locus and validated genetic variants found in public databases prior to constructing haplotypes of the MAO locus in a Swedish sample (N = 573 individuals). Results Our results reveal a profound SNP desert in the MAOB gene. Both the MAOA and MAOB genes segregate as two distinct LD blocks. We found a significant association between two MAOA gene haplotypes and reduced trbc-MAO activity, but no association with depressed state. Conclusion The MAO locus seems to have an effect on trbc-MAO activity in the study population. The findings suggest incomplete X-chromosome inactivation at this locus. It is plausible that a gene-dosage effect can provide some insight into the greater prevalence of depressed state in females than males.

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for pain treatment after elective hip and knee arthroplasties. However, evidence regarding the incidence of adverse effects with short-term NSAID treatment following surgery is limited. We, therefore, aim to assess the adverse effects with an eight-day postoperative treatment with ibuprofen after elective hip and knee arthroplasties., Methods and Analysis: PERISAFE is a randomized, placebo-controlled, blinded multicenter trial with 90-day and one-year follow-up. Eligible patients undergoing elective hip or knee arthroplasty are allocated 1:1 to either ibuprofen 400 mg ×3/day or identical placebo ×3/day for eight days after surgery. The primary outcome is a composite of either death, acute myocardial infarction, stroke, pulmonary embolism, deep venous thrombosis, renal failure, major bleeding, re-operation, gastrointestinal ulcer, or readmission within 90 days postoperatively. Secondary outcomes are hospital-free days within 90 days postoperatively, a composite of ibuprofen and opioid-related adverse reactions based on eight-day postoperative diary, and health related quality of life after 90 days postoperatively. A total of 2904 patients are needed to demonstrate a relative risk reduction of 33% in the placebo group, accepting a risk of type I error of 5% and type II error of 20% and a proportion of serious adverse events in the ibuprofen group of 8%. The primary analysis will be in the modified intention-to-treat population., Ethics and Dissemination: The trial is approved by the Danish Medicine Agency and the Research Ethics Committee (EU CT no. 2022-502, 502-32-00). We plan to submit for publication in a major international peer-reviewed journal and present results at scientific meetings., (© 2025 Acta Anaesthesiologica Scandinavica Foundation.)

The DEXamethasone twice for pain treatment after Total Knee Arthroplasty (DEX-2-TKA) trial showed that adding one and two doses of 24 mg intravenous dexamethasone to paracetamol, ibuprofen and local infiltration analgesia, reduced morphine consumption (primary outcome) within 48 h after TKA. We aimed to explore the differences in the effect of dexamethasone on morphine consumption in different subgroups. Quantile regression adjusted for site was used to test for significant interaction between the predefined dichotomised subgroups and treatment group. The subgroups were defined based on baseline data: sex (male/female), age (≤65 years/>65 years), American Society of Anaesthesiologists (ASA)-score (ASA I + II/III), visual analogue score of preoperative pain at rest (≤30 mm/>30 mm), pain during mobilisation (≤30 mm/>30 mm), type of anaesthesia (spinal anaesthesia/general anaesthesia and spinal converted to general anaesthesia), and prior daily use of analgesics (either paracetamol and/or NSAID/neither). These analyses were supplemented with post hoc multivariate linear regression analyses. Test of interaction comparing sex in the pairwise comparison between DX2 (dexamethasone [24 mg] + dexamethasone [24 mg]) versus placebo (p = .02), showed a larger effect of dexamethasone on morphine consumption in male patients compared to females. Test of interaction comparing age in the pairwise comparison between DX1 (dexamethasone [24 mg] + placebo) versus placebo (p = .04), showed a larger effect of dexamethasone on morphine consumption in younger patients (≤65 years) compared to older. All remaining subgroup analyses showed no evidence of a difference. The supplemental multivariate analyses did not support any significant interaction for sex (p = .256) or age (p = .730) but supported a significant interaction with the type of anaesthesia (p < .001). Our results from the quantile regression analyses indicate that the male sex and younger age (≤65 years) may be associated with a larger analgesic effect of dexamethasone than the effects in other types of patients. However, this is not supported by post-hoc multivariate linear regression analyses. The two types of analyses both supported a possible interaction with the type of anaesthesia., (© 2024 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty., Methods: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873., Findings: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group., Interpretation: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen., Funding: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund., Competing Interests: Declaration of interests THL has been chair at an advisory board meeting (3 h, June 2023) for Paion, concerning Byfavo. SO has received personal payment from Johnson & Johnson for a lecture, and institutional payment has been made by Heraeus due to this author's role as lecturer and course moderator. CV has had travel expenses paid to their institution from Stryker. ML-L is Chairman at Danish Knee Arthroplasty Register. All other authors declare no other competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The DEX-2-TKA trial demonstrated that one and two doses of 24 mg intravenous dexamethasone reduced opioid consumption and pain after total knee arthroplasty (TKA). We aimed to investigate the prolonged effects of dexamethasone after the 48-h intervention period., Design: This was a prospective, pre-planned questionnaire follow-up on postoperative days 3-7 of patients in the DEX-2-TKA trial that randomly received: DX1 (dexamethasone 24 mg + placebo), DX2 (dexamethasone 24 mg + dexamethasone 24 mg), and placebo (placebo + placebo) perioperatively and 24 h later., Setting: A multicenter trial performed at five Danish hospitals., Participants: We analyzed 434 of 485 adult participants enrolled in the DEX-2-TKA trial., Outcome Measures: Primary outcome was difference between groups in average of all numerical rating scale (NRS) pain scores reported in the morning, at bedtime, and the daily average pain on postoperative days 3-7. Secondary outcomes were sleep quality and patient satisfaction., Results: The median (interquartile range) pain intensity levels for postoperative days 3-7 were: DX2 3.2 (2.1-4.3); DX1 3.3 (2.3-4.1); and placebo 3.3 (2.5-4.7). Hodges-Lehmann median differences between groups were: 0 (95% confidence interval - 0.54 to 0.2), P = 0.38 between DX1 and placebo; 0.1 (-0.47 to 0.33), p = .87 between DX1 and DX2; and 0.1 (-0.6 to 0.13), p = .20 between DX2 and placebo. We found no relevant differences between groups on sleep quality on postoperative days 3-7 nor for patient satisfaction with the analgesic treatment., Conclusions: We found that neither one nor two doses of 24 mg intravenous dexamethasone demonstrated prolonged effects on overall pain or sleep quality on postoperative days 3-7 after total knee arthroplasty. We also found that dexamethasone had no effect on patient satisfaction., Trial Registration Number: Clinicaltrials.gov NCT03506789 (main result trial)., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen that causes a wide range of infections. Its resistance to β-lactam antibiotics complicates treatment due to the limited number of antibiotics with activity against MRSA. To investigate development of alternative therapeutics, the mechanisms that mediate antibiotic resistance in MRSA need to be fully understood. In this study, MRSA cells were subjected to antibiotic stress from methicillin in combination with three cannabinoid compounds and analyzed using proteomics to assess the changes in physiology. Subjecting MRSA to nonlethal levels of methicillin resulted in an increased production of penicillin-binding protein 2 (PBP2). Exposure to cannabinoids showed antibiotic activity against MRSA, and differential proteomics revealed reduced levels of proteins involved in the energy production as well as PBP2 when used in combination with methicillin.

Objective: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty., Design: Randomised, blinded, placebo controlled trial with follow-up at 90 days., Setting: Five Danish hospitals, September 2018 to March 2020., Participants: 485 adult participants undergoing total knee arthroplasty., Intervention: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia., Main Outcome Measures: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain., Results: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone., Conclusion: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain., Trial Registration: Clinicaltrials.gov NCT03506789., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Næstved, Slagelse, and Ringsted Hospitals’ Research Fund and the Department of Anaesthesiology at Næstved, Slagelse and Ringsted Hospitals for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Optimization of post-operative pain treatment is of upmost importance. Multimodal analgesia is the main post-operative pain treatment principle, but the evidence on optimal analgesic combinations is unclear. With the "DEXamethasone twice for pain treatment after TKA" trial, we aim to investigate the role of one or two doses of glucocorticoid for post-operative pain treatment after total knee arthroplasty. To ensure transparency and minimization of bias, we present this article with a detailed statistical analysis plan, to be published before the last participant is enrolled., Methods: "DEXamethasone twice for pain treatment after TKA" (DEX-2-TKA) is a randomized, blinded, three-group multicentre clinical trial. Participants will be randomized to one of three intervention groups: single dose of iv dexamethasone 24 mg, two consecutive doses of iv dexamethasone 24 mg or matching iv placebo. All three intervention groups will receive paracetamol, NSAID (ibuprofen) and local infiltration analgesia. Participants, treatment providers, outcome assessors, data managers, statisticians and conclusion drawers will be blinded to the allocated intervention. The primary outcome is total opioid consumption (iv morphine milligram equivalents) 0-48 hours post-operatively. Secondary outcomes are (1) visual analogue scale pain levels: (a) during active 45 degrees flexion of the knee at 24 and 48 hours post-operatively, (b) at rest at 24 and 48 hours post-operatively, and (c) during 0-24 hours (highest score) and 24-48 hours post-operatively (highest score); and (2) the proportion of participants with one or more adverse events within 48 hours post-operatively., Discussion: The DEX-2-TKA trial will provide high quality data regarding benefits and harms of adding one or two high-doses of dexamethasone to a multimodal analgesic regimen., Trial Registration: EudraCT: 2018-001099-39 (08/06-18); ClinicalTrials.gov: NCT03506789 (24/04-2019)., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: The "Paracetamol and Ibuprofen in Combination" (PANSAID) trial showed that combining paracetamol and ibuprofen resulted in lower opioid consumption than each drug alone and we did not find an increase in risk of harm when using ibuprofen vs paracetamol. The aim of this subgroup analysis was to investigate the differences in benefits and harms of the interventions in different subgroups. We hypothesized that the intervention effects would differ in subgroups with different risk of pain or adverse events., Methods: In these pre-planned subgroup analyses of the PANSAID trial population, we assessed subgroup heterogeneity in intervention effects between (a) subgroups (sex, age, use of analgesics, American Society of Anesthesiologists (ASA) score, and type of anesthesia) and morphine consumption, and (b) subgroups (sex, age, use of non-steroidal anti-inflammatory drugs (NSAIDs), and ASA score) and serious adverse events., Results: Test of interaction between age and the pairwise comparison between paracetamol 1 g vs paracetamol 0.5 g + ibuprofen 200 mg (P = .009) suggested lower morphine consumption in patients >65 years. However, post hoc analyses of related outcomes showed no interaction for this pairwise comparison. All other tests of interaction regarding both benefit and harm were not statistically significant., Conclusion: These pre-planned subgroup analyses did not suggest that patients in the investigated subgroups benefitted differently from a basic non-opioid analgesic regimen consisting of paracetamol and ibuprofen. Further, there was no evidence of subgroup heterogeneity regarding harm and use of ibuprofen. Because of reduced statistical power in subgroup analyses, we cannot exclude clinically relevant subgroup heterogeneity., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Multimodal analgesia is considered the leading principle for post-operative pain treatment, but no gold standard after total knee arthroplasty (TKA) exists., Aim: To investigate the beneficial and harmful effects of one or two doses of 24 mg intravenous dexamethasone (DXM) as part of a multimodal analgesic regimen (paracetamol, NSAID and perioperative local infiltration analgesia) after TKA. We hypothesize that addition of DXM will reduce post-operative opioid consumption., Methods: DEXamethasone twice for pain treatment after TKA is a randomized, blinded, three-group multicentre clinical trial. Participants will be randomized to one of three groups: placebo, single dose of DXM or two consecutive doses of DXM. Participants, treatment providers and investigators will be blinded to the allocated intervention. The primary outcome is total opioid consumption (units of morphine equivalents) 0-48 hours post-operatively., Inclusion Criteria: unilateral, primary TKA; age ≥18 years; American Society of Anesthesiologists-Score 1-3; Body Mass Index ≥18 and ≤40; for women-not pregnant; and written informed consent., Exclusion Criteria: allergy or contraindications against trial medication; daily use of high dose opioid and/or use of methadone/transdermal opioids; daily use of systemic glucocorticoids; dysregulated diabetes; and patients suffering from alcohol and/or drug abuse. Four-hundred-and-eighty-six eligible participants are needed to detect or discard a difference of 10 mg morphine equivalents 0-48 hours post-operatively maintaining a familywise error rate of 0.05 and a power of 90% for the three possible pairwise comparisons., Discussion: Recruiting is planned to commence September 2018 and expected to finish March 2020., Trial Registration: EudraCT: 2018-001099-39 (08/06-18); ClinicalTrials.gov: NCT03506789 (24/04-2019). Editorial Comment This is the protocol for the largest randomized clinical trial investigating the effect of one or two doses of dexamethasones on pain treatment after total knee arthroplasty. Due to the pragmatic and rigerous design this study will deliver results of high quality and external validity., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Importance: Multimodal postoperative analgesia is widely used but lacks evidence of benefit., Objective: Investigate beneficial and harmful effects of 4 nonopioid analgesics regimens., Design, Setting, and Participants: Randomized, blinded, placebo-controlled, 4-group trial in 6 Danish hospitals with 90-day follow-up that included 556 patients undergoing total hip arthroplasty (THA) from December 2015 to October 2017. Final date of follow-up was January 1, 2018., Interventions: Participants were randomized to receive paracetamol (acetaminophen) 1000 mg plus ibuprofen 400 mg (n = 136; PCM + IBU), paracetamol 1000 mg plus matched placebo (n = 142; PCM), ibuprofen 400 mg plus matched placebo (n = 141; IBU), or half-strength paracetamol 500 mg plus ibuprofen 200 mg (n = 140; HS-PCM + IBU) orally every 6 hours for 24 hours postoperatively, starting 1 hour before surgery., Main Outcomes and Measures: Two co-primary outcomes: 24-hour morphine consumption using patient-controlled analgesia in pairwise comparisons between the 4 groups (multiplicity-adjusted thresholds for statistical significance, P < .0042; minimal clinically important difference, 10 mg), and proportion of patients with 1 or more serious adverse events (SAEs) within 90 days (multiplicity-adjusted thresholds for statistical significance, P < .025)., Results: Among 559 randomized participants (mean age, 67 years; 277 [50%] women), 556 (99.5%) completed the trial and were included in the analysis. Median 24-hour morphine consumption was 20 mg (99.6% CI, 0-148) in the PCM + IBU group, 36 mg (99.6% CI, 0-166) for PCM alone, 26 mg (99.6% CI, 2-139) for IBU alone, and 28 mg (99.6% CI, 2-145) for HS-PCM + IBU. The median difference in morphine consumption between the PCM + IBU group vs PCM alone was 16 mg (99.6% CI, 6.5 to 24; P < .001); for the PCM-alone group vs HS-PCM + IBU, 8 mg (99.6% CI, -1 to 14; P = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, -2 to 16; P = .002). The difference in morphine consumption was not statistically significant for the PCM + IBU group vs HS-PCM + IBU (8 mg [99.6% CI, -2 to 16]; P = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, -2 to 16]; P = .004) after adjustment for multiple comparisons and 2 co-primary outcomes. There was no significant difference between the IBU-alone group vs HS-PCM + IBU (2 mg [99.6% CI, -10 to 7]; P = .81). The proportion of patients with SAEs in groups receiving IBU was 15%, and in the PCM-alone group, was 11%. The relative risk of SAE was 1.44 (97.5% CI, 0.79 to 2.64; P = .18)., Conclusions and Relevance: Among patients undergoing THA, paracetamol plus ibuprofen significantly reduced morphine consumption compared with paracetamol alone in the first 24 hours after surgery; there was no statistically significant increase in SAEs in the pooled groups receiving ibuprofen alone vs with paracetamol alone. However, the combination did not result in a clinically important improvement over ibuprofen alone, suggesting that ibuprofen alone may be a reasonable option for early postoperative oral analgesia., Trial Registration: ClinicalTrials.gov Identifier: NCT02571361.

Background: Effective postoperative pain management is essential for the rehabilitation of the surgical patient. The PANSAID trial evaluates the analgesic effects and safety of the combination of paracetamol and ibuprofen. This paper describes in detail the statistical analysis plan for the primary publication to prevent outcome reporting bias and data-driven analysis results., Methods/design: The PANSAID trial is a multicentre, randomised, controlled, parallel, four-group clinical trial comparing the beneficial and harmful effects of different doses and combinations of paracetamol and ibuprofen in patients having total hip arthroplastic surgery. Patients, caregivers, physicians, investigators, and statisticians are blinded to the intervention. The two co-primary outcomes are 24-h consumption of morphine and proportion of patients with one or more serious adverse events within 90 days after surgery. Secondary outcomes are pain scores during mobilisation and at rest at 6 and 24 h postoperatively, and the proportion of patients with one or more adverse events within 24 h postoperatively., Discussion: PANSAID will provide a large trial with low risk of bias regarding benefits and harms of the combination of paracetamol and ibuprofen used in a perioperative setting., Trial Registration: ClinicalTrials.org identifier: NCT02571361 . Registered on 7 October 2015.

Background: Anaesthesia followed by positioning in the prone position takes time and may have complications., Objective: The hypothesis was that self-positioning in the prone position followed by anaesthesia and introduction of a laryngeal mask airway (LM method) would be faster with fewer complications than positioning after tracheal intubation (ET method)., Design: Randomised, controlled trial., Setting: University Hospital, March 2009 to March 2011., Patients: One hundred forty patients scheduled for spinal surgery were allocated to the LM or the ET method. Exclusion criteria were surgery expected to last more than 2 h, American Society of Anesthesiologists status more than II, age more than 70 years, abnormal neck, throat, and mouth anatomy and function, Mallampati score III-IV, BMI more than 35 kg m, anticipated difficult airway/mask ventilation and decreased neck mobility., Interventions: Patients in the LM group placed themselves in the prone position, anaesthesia was induced and a laryngeal mask was introduced. Patients in the ET group were anaesthetised, intubated and then placed in the prone position., Main Outcome Measures: Time taken from identification of the patient at the outset to readiness for radiographic examination following anaesthesia and positioning. Airway problems, sore throat, hoarseness and pain from muscles and joints were also noted., Results: One hundred and forty patients were randomised to LM (n = 70) and ET (n = 70). Data from 64 and 67 patients were analysed. Values are expressed as median (interquartiles) [range]. The primary outcome time was 25 min (23 to 29) [16 to 44] in the LM group and 30 min (26 to 33) [17 to 47] in the ET group (P <0.001). In two patients in group LM, a complete seal could not be obtained; one was intubated, and the other had surgery cancelled due to arterial hypotension. There were fewer cases with sore throat, hoarseness and pain from muscles and joints in the LM group at 3 h, but not at 24 h postoperatively., Conclusion: Self-positioning and induction of anaesthesia in the prone position saves time. More patients should be studied to confirm safety and examine whether the method reduces the number of severe complications associated with the prone position., Trial Registration: www.clinicaltrials.gov identifier: NCT01041352.

Introduction: The Toronto Extremity Salvage Score (TESS) questionnaire is a self-administered questionnaire designed to assess physical disability in patients having undergone surgery of the extremities. The aim of this study was to validate a Danish translation of the TESS., Material and Methods: The TESS was translated according to international guidelines. A total of 22 consecutive patients attending the regular outpatient control programme were recruited for the study. To test their understanding of the questionnaires, they were asked to describe the meaning of five randomly selected questions from the TESS. The psychometric properties of the Danish version of TESS were tested for validity and reliability. To assess the test-retest reliability, the patients filled in an extra TESS questionnaire one week after they had completed the first one., Results: Patients showed good understanding of the questionnaire. There was a good internal consistency for both the upper and lower questionnaire measured by Cronbach's alpha. A Bland-Altman plot showed acceptable limits of agreement for both questionnaires in the test-retest. There was also good intraclass correlation coefficients for both questionnaires. The validity expressed as Spearman's rank correlation coefficient comparing the TESS with the QLQ-C30 was 0.89 and 0.90 for the questionnaire on upper and lower extremities, respectively., Conclusion: The psychometric properties of the Danish TESS showed good validity and reliability., Funding: not relevant., Trial Registration: not relevant.

Background: Magnetic resonance imaging (MRI) of children is generally performed under sedation or with general anaesthesia (GA), but the ideal regimen has not been found. The aim of this study was to see if propofol-remifentanil would be a suitable alternative for the maintenance of anaesthesia in this category of patients., Patients and Methods: Children aged 1-10 years, American Society of Anesthesiologists physical status 1-2 were included. After induction with thiopental or sevoflurane, the children were randomised to maintenance of anaesthesia with an infusion of propofol and remifentanil (group PR) (56 μg/kg/min of propofol and 0.06 μg/kg/min of remifentanil) or with sevoflurane 1.3 MAC (group S). A binasal catheter was placed in group PR and a laryngeal mask airway in group S. The children breathed spontaneously. The Paediatric Anaesthesia Emergence Delirium (PAED) score (primary end point), the number of movements during MRI, and the length of stay in the recovery room (secondary endpoints) were recorded., Results: Sixty children were included in each group. A lower level of emergence delirium (measured as a lower PAED score) was found in group PR compared with group S, and the children in group PR were discharged earlier from the recovery room than the children in group S. However, 15 children in group PR vs. 0 in group S moved during the scan (P < 0.001)., Conclusion: The PR infusion ensured a satisfactory stay in the recovery room, but additional boluses were necessary during the MRI. Sevoflurane was reliable during the MRI, but emergence delirium was a concern., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: There have been few studies describing wound infiltration with additional intraarticular administration of multimodal analgesia for total knee arthroplasty (TKA). In this study, we assessed the efficacy of wound infiltration combined with intraarticular regional analgesia with epidural infusion on analgesic requirements and postoperative pain after TKA., Methods: 40 consecutive patients undergoing elective, primary TKA were randomized into 2 groups to receive either (1) intraoperative wound infiltration with 150 mL ropivacaine (2 mg/mL), 1 mL ketorolac (30 mg/mL), and 0.5 mL epinephrine (1 mg/mL) (total volume 152 mL) combined with intraarticular infusion (4 mL/h) of 190 mL ropivacaine (2 mg/mL) plus 2 mL ketorolac (30 mg/mL) (group A), or (2) epidural infusion (4 mL/h) of 192 mL ropivacaine (2 mg/mL) combined with 6 intravenous administrations of 0.5 mL ketorolac (30 mg/mL) for 48 h postoperatively (group E). For rescue analgesia, intravenous patient-controlled-analgesia (PCA) morphine was used. Morphine consumption, intensity of knee pain (0–100 mm visual analog scale), and side effects were recorded. Length of stay and corrected length of stay were also recorded (the day-patients fulfilled discharge criteria)., Results: The median cumulated morphine consumption, pain scores at rest, and pain scores during mobilization were reduced in group A compared to group E. Corrected length of stay was reduced by 25% in group A compared to group E., Interpretation: Peri- and intraarticular analgesia with multimodal drugs provided superior pain relief and reduced morphine consumption compared with continuous epidural infusion with ropivacaine combined with intravenous ketorolac after TKA.

Background: Mivacurium is hydrolyzed by plasma cholinesterase (pChe). The purpose of this study was to evaluate the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium in patients phenotypically heterozygous for the usual and the atypical pChe variant (UA)., Methods: Thirty-two patients were included in a dose-response study, in which the patients received one of four doses of mivacurium. An additional bolus dose of mivacurium, to a total of 0.1 mg kg-1, was given followed by a continuous infusion adjusted to maintain 91-99% neuromuscular block. The times to different levels of recovery following the infusion were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Twelve of the patients with an estimated duration of anaesthesia of more than 90 min were (randomly) selected for the pharmacokinetic part of the study. Venous samples were taken for determination of the three isomers of mivacurium. These results were compared with results from a previous study in phenotypically normal patients (UU)., Results: The estimated ED50 and ED95 were 24 and 69 microg kg-1, respectively. The median (range) infusion rate was 3.7 microg kg-1 min-1 (1.2-2.9) and the time to a TOF ratio of 0.7 was 29.8 min (16.1-44.8). The median clearances of the cis-cis, cis-trans and trans-trans isomers were 3.7, 29 and 28 ml kg-1 min-1, respectively. The elimination half-lives of the isomers were 45, 6.7 and 6.3 min, respectively., Conclusion: In patients heterozygous for the usual and the atypical variant (UA), the potency of mivacurium is higher, the infusion requirements lower and the rate of spontaneous recovery prolonged, compared with phenotypically normal patients. The clearances of the active isomers are significantly lower and the elimination half-lives longer in heterozygous patients than in phenotypically normal patients (UU). The pharmacokinetics of the inactive cis-cis isomer was not affected.

Background: Mivacurium is hydrolyzed by plasma cholinesterase, and is therefore less dependent on liver metabolism and renal elimination than other neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients. The purpose of this study was to compare the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium and their metabolites in young adult and elderly patients., Methods: Sixty-four patients were included in a dose-response study, in which 32 young adults and 32 elderly patients received one of four doses of mivacurium. An additional bolus dose of mivacurium to a total of 0.1 mg/kg was given followed by a continuous infusion adjusted to maintain a 91-99% neuromuscular block. The times to maximum block and different levels of recovery were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Thirty-two patients were randomly selected for the pharmacokinetic study. Venous samples were taken for determination of the three mivacurium isomers and the metabolites., Results: The estimated ED95 were 0.053 and 0.061 mg/kg in young adults and elderly patients, respectively (NS). The median infusion rate did not differ, but duration to a TOF ratio of 0.7 was significantly longer in elderly patients than in young adult patients (21.0 vs. 16.5 min). No statistically significant difference between the age groups in clearance and elimination half-life of the isomers was seen. The half-lives of the metabolites were significantly prolonged in the elderly patients., Conclusion: There were no significant differences in the potency or infusion requirements between the adult and elderly patients, but the rate of recovery was significantly, though only moderately prolonged, in the elderly patients. No significant difference in clearance was seen but the elimination half-lives of the metabolites was longer in the elderly patients.

Introduction: The aim of this investigation was to compare the use of a continuous infusion of mivacurium or atracurium guided by tactile evaluation of the neuromuscular block., Materials and Methods: Forty-five patients were randomly allocated to three groups of patients. Group M and MN received a bolus dose of mivacurium 0.15 mg/kg followed by a continuous infusion and group AN a bolus dose of atracurium 0.4 mg/kg followed by an infusion., Results: The neuromuscular blockade recovered spontaneously in group M and was antagonised in group MN and AN. The level of block was quantified by tactile evaluation. The time to full recovery was significantly shorter in patients receiving mivacurium compared to patients given atracurium, 14.5, 12.0 and 18.0 min, respectively. Further, reversal with neostigmine significantly enhanced recovery following mivacurium., Conclusion: A continuous infusion of mivacurium and atracurium can easily be performed, guided by tactile evaluation of the neuromuscular block and the effect can be reversed by neostigmine.

Background: The short duration of action of mivacurium results from its rapid hydrolysis by plasma cholinesterase. Bambuterol, an oral bronchodilator, has an inhibiting effect on plasma cholinesterase. The purpose of this study was to evaluate the effect of bambuterol-induced low plasma cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium., Methods: Fourteen patients received 20 mg bambuterol and 14 patients received placebo orally 2 h before induction of anesthesia. During anesthesia the neuromuscular block was monitored at the thumb using train-of-four nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery after 0.2 mg/kg mivacurium were measured. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured using high-performance liquid chromatography., Results: Plasma cholinesterase activity was inhibited a median of 90% (range, 67-97%) after bambuterol. The time to first response to train-of-four nerve stimulation was 15 min (range, 9-21 min) and 59 min (range, 32-179 min) in patients receiving placebo and bambuterol, respectively. The estimated clearances of the isomers were significantly lower and the elimination half-lives of all three isomers significantly prolonged in patients receiving bambuterol. No difference was seen in elimination half-lives of the metabolites. The elimination rate constant from the effect compartment and the potency of mivacurium was not affected by bambuterol., Conclusion: A 90% inhibition of plasma cholinesterase activity significantly reduced clearance of the isomers of mivacurium. Correspondingly, the duration of action of 0.2 mg/kg mivacurium was prolonged three- to fourfold, compared with patients not administered bambuterol.

Plasma cholinesterase is a glycoprotein synthesized in the liver and is found in plasma, liver, intestinal mucosa and other tissues. Six percent to 7% of patients in most surgical populations have an abnormal plasma cholinesterase activity and about 65% of all cases of prolonged neuromuscular blockade following succinylcholine are due to genetic factors. This review focuses on the causes and clinical significance of plasma cholinesterase for the hydrolyses of succinylcholine. Diagnosis and treatment of prolonged response to succinylcholine in phenotypically normal patients, heterozygous abnormal patients and patients homozygous for the atypical gene is mentioned. Also presented is the relationship between plasma cholinesterase and the new relaxant mivacurium, and bambuterol, a prodrug to terbutaline. Additionally, the recent developments in the identification of the plasma cholinesterase genotypes are presented.

The porphyrias are a group of disorders of haem metabolism. A knowledge of which anaesthetic can precipitate an acute attack of porphyria is important, since an accumulation of metabolites can result in life threatening symptoms, such as abdominal pain, vomiting, photophobia, neuropathy, bulbar paresis and respiratory failure. Treatment consists primarily of adequate calorie intake e.g. glucose, but is otherwise symptomatic. Anaesthetic drug recommendations are based both on animal experiments and patient experience, primarily case histories. An array of local anaesthetics, hypnotics, sedatives, neuroleptics, analgesics, muscle relaxants, inhalation anaesthetics and some antibiotics are reviewed. Patients with a history of porphyria should be in an optimal condition and maintain a high calorie intake perioperatively. The pre-operative fast should be a minimum and iv-glucose is advisable while fasting. There are anaesthetic agents that are safe for both regional and general anaesthesia.