Influence of clinical and genetic factors on propofol dose requirements: A genome-wide association study.

BACKGROUND: Propofol is a widely used intravenous hypnotic. Dosing is mostly based on weight with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, gender, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. METHODS: We studied 1000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy TM. Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study (GWAS). Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. RESULTS: BMI, smoking status, alcohol use, remifentanil dose (ln(mgkg -1min -1)), and average state entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5×10 -8). The most significant associations were for SNPs rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding Kir2.1 potassium channel showed suggestive association (P = 4.7×10 -7). None of these SNPs are coding variants but possibly affect the regulation of nearby genes. None of the SNPs previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in our data. CONCLUSION: In this first GWAS exploring propofol requirements, we discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN and KCNJ2 in propofol anesthesia warrant further studies.

Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers.

BACKGROUND: Subanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers. METHODS: In this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC) 0-24 of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests ( tmax ) or paired t -tests on log-transformed variables (other variables). RESULTS: While the AUC 0-24 was similar between the 2 phases, S-ketamine reduced the AUC 0-1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15-0.65; P = .0171) and increased its tmax from 0.5 (range, 0.50-1.5) to 1.0 hour (range, 0.50-4.0; P = .010). The AUC 0-1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07-0.37; P = .0025) and maximum plasma concentration ( Cmax ) by 43% (0.57; 90% CI, 0.40-0.81; P = .0155), while its tmax was increased from 1.5 (range, 1.0-2.0) to 4.0 (range, 1.0-8.0; P = .0094) hours by S-ketamine. Similarly, the AUC 0-1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05-0.43; P = .0083), and tmax increased from 1.0 (range, 0.5-1.5) to 4.0 hours (range, 1.0-8.0; P = .0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39-0.71; P = .0033) and 52% (0.48; 90% CI, 0.27-0.85; P = .0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78-0.92; P = .0057) and 10% (0.90; 90% CI, 0.83-0.98; P = .0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase. CONCLUSIONS: Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.

ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

BACKGROUND: The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline "ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation." The guideline can provide guidance to Nordic anaesthesiologists on the perioperative use of cardiac biomarkers in patients undergoing non-cardiac surgery.

Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

BACKGROUND: Awake proning in spontaneously breathing patients with hypoxemic acute respiratory failure was applied during the coronavirus disease 2019 (COVID-19) pandemic to improve oxygenation while avoiding tracheal intubation. An updated systematic review and meta-analysis on the topic was published. METHODS: The Clinical practice committee (CPC) of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) assessed the clinical practice guideline "Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline" for possible endorsement. The Appraisal of Guidelines for REsearch and Evaluation (AGREE) II tool was used. RESULTS: Four out of six SSAI CPC members completed the appraisal. The individual domain totals were: Scope and Purpose 90%; Stakeholder Involvement 89%; Rigour of Development 74%; Clarity of Presentation 85%; Applicability 75%; Editorial Independence 98%; Overall Assessment 79%. CONCLUSION: The SSAI CPC endorses the clinical practice guideline "Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline". This guideline serves as a useful decision aid for clinicians caring for critically ill patients with COVID-19-related acute hypoxemic respiratory failure and can be used to provide guidance on use of prone positioning in this group of patients.

Saudi Critical Care Society clinical practice guidelines on the prevention of venous thromboembolism in adults with trauma: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Saudi Critical Care Society clinical practice guidelines on the prevention of venous thromboembolism in adults with trauma: reviewed for evidence-based integrity and endorsed by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. This clinical practice guideline serves as a useful decision aid for Nordic anaesthesiologists managing adult trauma patients in the operating room and in the intensive care unit.

ISTH guidelines for antithrombotic treatment in COVID-19: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the ISTH guidelines for antithrombotic treatment in COVID-19. This evidence-based guideline serves as a useful decision aid for Nordic anaesthesiologists caring for patients with COVID-19.

Clinical and genetic factors associated with post-operative nausea and vomiting after propofol anaesthesia.

BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.

Regional anaesthesia in patients on antithrombotic drugs - a joint ESAIC/ESRA guideline: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Regional anaesthesia in patients on antithrombotic drugs - a joint ESAIC/ESRA guideline. This clinical practice guideline serves as a useful decision aid for Nordic anaesthesiologists providing regional anaesthesia to adult patients on antithrombotic drugs.

Therapeutics and COVID-19-A living WHO guideline: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the Living WHO guideline on therapeutics and COVID-19. This trustworthy continuously updated guideline serves as a highly useful decision aid for Nordic anaesthesiologists caring for patients with COVID-19.

Transfusion strategies in bleeding critically ill adults: A clinical practice guideline from the European Society of Intensive Care Medicine: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. This trustworthy clinical practice guideline serves as a useful decision aid for Nordic anaesthesiologists caring for critically ill patients with bleeding.

Surviving sepsis campaign: International guidelines for management of sepsis and septic shock in adults 2021 - endorsement by the Scandinavian society of anaesthesiology and intensive care medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. The guideline serves as a useful bedside decision aid for clinicians managing adults with suspected and confirmed septic shock and sepsis-associated organ dysfunction.

Anesthesia Method, Tourniquet Use, and Persistent Postsurgical Pain after Total Knee Arthroplasty: A Prespecified Secondary Analysis of a Randomized Trial.

BACKGROUND: Persistent postsurgical pain after total knee arthroplasty is a common problem and a major reason for patient dissatisfaction. This secondary analysis aimed to investigate the effects of anesthesia (spinal vs. general) and tourniquet use on persistent pain after total knee arthroplasty. METHODS: In this secondary analysis of a previously presented parallel, single-center, randomized trial, 404 patients scheduled for total knee arthroplasty were randomized to spinal versus general anesthesia and no-tourniquet versus tourniquet groups. Patients assessed pain using the Brief Pain Inventory-short form preoperatively and 3 and 12 months postoperatively. The prespecified main outcome was the change in "average pain" measured with numerical 0 to 10 rating scale 1 yr postoperatively. The threshold for clinical importance between groups was set to 1.0. RESULTS: The change in average pain scores 1 yr postoperatively did not differ between the spinal and general anesthesia groups (-2.6 [SD 2.5] vs. -2.3 [SD 2.5], respectively; mean difference, -0.4; 95% CI, -0.9 to 0.1; P = 0.150). The no-tourniquet group reported a smaller decrease in the average pain scores than the tourniquet group (-2.1 [SD 2.7] vs. -2.8 [SD 2.3]; mean difference, 0.6; 95% CI, 0.1 to 1.1; P = 0.012). After 1 yr, the scores concerning the mean of four pain severity variables (numerical rating scale) decreased more in the spinal than in the general anesthesia group (-2.3 [SD 2.2] vs. -1.8 [SD 2.1]; mean difference, -0.5; 95% CI, -0.9 to -0.05; P = 0.029) and less in the no-tourniquet than in the tourniquet group (-1.7 [SD 2.3] vs. -2.3 [SD 2.0]; mean difference, 0.6; 95% CI, 0.2 to 1.0; P = 0.005). None of the differences in pain scores reached the threshold for clinical importance. CONCLUSIONS: The type of anesthesia (spinal vs. general) or tourniquet use has no clinically important effect on persistent postsurgical pain after total knee arthroplasty.

Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

AIMS: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry-based enantiomer-specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S- and R-ketorolac exposure. RESULTS: S- and R-ketorolac PK were best described with a 3- and a 2-compartment model, respectively. The allometry-based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S-ketorolac concentration of 0.057 mg/L, but a mean S-ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S-ketorolac-concentration (0.057 mg/L) in typical infants, the EC50-racemic should be increased to 0.41 mg/L. CONCLUSION: Enantiomer-specific changes in ketorolac PK yield different concentrations and S- and R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.

First genome-wide association study on rocuronium dose requirements shows association with SLCO1A2.

BACKGROUND: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. METHODS: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 µg kg-1 min-1) and remifentanil (0.05-0.25 µg kg-1 min-1). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. RESULTS: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P=5.3e-11) and rs11045995 (P=1.4e-10), and the clinical variables accounted for 41% of the variability in rocuronium dosage. CONCLUSIONS: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.

Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers.

BACKGROUND: Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin. METHODS: In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes. RESULTS: Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters. CONCLUSIONS: Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Clinical practice guideline on the management of septic shock and sepsis-associated organ dysfunction in children: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

BACKGROUND: The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children. The guideline can serve as a useful decision aid for clinicians managing children with suspected and confirmed septic shock and sepsis-associated organ dysfunction.

Clinical practice guideline on gastrointestinal bleeding prophylaxis for critically ill patients: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Scandinavian Society of Anaesthesiology and Intensive Care Medicine Clinical practice Committee endorses the BMJ Rapid Recommendation Gastrointestinal bleeding prophylaxis for critically ill patients-a clinical practice guideline. The guideline serves as a useful decision aid for clinicians caring for critically ill patients, and can be used together with clinical experience to decide whether a specific critically ill patient may benefit from gastrointestinal bleeding prophylaxis.

Clinical practice guideline on spinal stabilisation of adult trauma patients: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the clinical practice guideline New clinical guidelines on the spinal stabilisation of adult trauma patients-consensus and evidence based. The guideline can serve as a useful decision aid for clinicians caring for patients with traumatic spinal cord injury. However, it is important to acknowledge that the overall certainty of evidence supporting the guideline recommendations was low, implying that further research is likely to have an important impact on the confidence in the estimate of effect.

Ability of prehospital NEWS to predict 1-day and 7-day mortality is reduced in older adult patients.

BACKGROUND: National Early Warning Score (NEWS) does not include age as a parameter despite age is a significant independent risk factor of death. The aim of this study was to examine whether age has an effect on predictive performance of short-term mortality of NEWS in a prehospital setting. We also evaluated whether adding age as an additional parameter to NEWS improved its short-term mortality prediction. METHODS: We calculated NEWS scores from retrospective prehospital electronic patient record data for patients 18 years or older with sufficient prehospital data to calculate NEWS. We used area under receiver operating characteristic (AUROC) to analyse the predictive performance of NEWS for 1 and 7 day mortalities with increasing age in three different age groups: <65 years, 65-79 years and ≥80 years. We also explored the ORs for mortality of different NEWS parameters in these age groups. We added age to NEWS as an additional parameter and evaluated its effect on predictive performance. RESULTS: We analysed data from 35 800 ambulance calls. Predictive performance for 7-day mortality of NEWS decreased with increasing age: AUROC (95% CI) for 1-day mortality was 0.876 (0.848 to 0.904), 0.824 (0.794 to 0.854) and 0.820 (0.788 to 0.852) for first, second and third age groups, respectively. AUROC for 7-day mortality had a similar trend. Addition of age as an additional parameter to NEWS improved its ability to predict short-term mortality when assessed with continuous Net Reclassification Improvement. CONCLUSIONS: Age should be considered as an additional parameter to NEWS, as it improved its performance in predicting short-term mortality in this prehospital cohort.

Effects of anaesthesia method and tourniquet use on recovery following total knee arthroplasty: a randomised controlled study.

BACKGROUND: We investigated the effects of spinal and general anaesthesia and surgical tourniquet on acute pain and early recovery after total knee arthroplasty (TKA). METHODS: Patients (n=413) were randomised to four parallel groups: spinal anaesthesia with or without tourniquet, and general anaesthesia with or without tourniquet. The primary outcome was patient-controlled i.v. oxycodone consumption over 24 postoperative hours. RESULTS: Results from 395 subjects were analysed. Median i.v. oxycodone consumption did not differ between the four groups (spinal anaesthesia without [36.6 mg] and with tourniquet [38.0 mg], general anaesthesia without [42.3 mg] and with tourniquet [42.5 mg], P=0.42), between spinal (37.7 mg) and general anaesthesia (42.5 mg) groups (median difference -3.1, 95% confidence interval [CI] -7.4 to 1.2, P=0.15) and between tourniquet and no-tourniquet groups (40.0 vs 40.0 mg, median difference -0.8, CI -5.1 to 3.5, P=0.72). Vomiting incidence was higher with spinal than with general anaesthesia (21% [42/200] vs 13% [25/194], CI 1.05 to 3.1, P=0.034). The mean haemoglobin decrease was greater without than with tourniquet (-3.0 vs -2.5 g dl-1, mean difference -0.48, CI -0.65 to -0.32, P<0.001). No differences were observed in pain, pain management, incidences of blood transfusions, in-hospital complications, or length of hospital stay. CONCLUSIONS: For TKA, spinal and general anaesthesia with or without tourniquet did not differ in 24-h postoperative opioid consumption, pain management, blood transfusions, in-hospital complications, and length of hospital stay. Vomiting incidence was higher in the spinal than in the general anaesthesia group. Tourniquet use caused smaller decreases in haemoglobin levels. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002035-15.