Klaus T. Olkkola

Purpose: Methylprednisolone is used during paediatric cardiac surgery with cardiopulmonary bypass to attenuate the systemic inflammatory response. However, developmental differences in drug disposition and cardiopulmonary bypass–related factors contribute to pharmacokinetic variability in this population. We aimed to develop a population pharmacokinetic model of methylprednisolone in neonates and paediatric patients undergoing cardiac surgery with cardiopulmonary bypass and to identify factors associated with its pharmacokinetic variability. Methods: Data were pooled from four prospective clinical studies including 93 patients aged 1 to 574 days undergoing cardiac surgery with cardiopulmonary bypass. Methylprednisolone was administered as an intravenous bolus after anaesthesia induction or into the cardiopulmonary bypass circuit at 5 or 30 mg/kg. Plasma concentrations were measured perioperatively. A nonlinear mixed-effects model was developed using NONMEM. Covariate effects were evaluated. Model evaluation included goodness-of-fit plots, normalized prediction distribution errors, sampling importance resampling, and prediction-corrected visual predictive checks. Results: A one-compartment model with first-order elimination adequately described the data. The final model identified body weight, an empirical postmenstrual-age effect on clearance, and operation-group differences in the apparent volume of distribution as significant determinants of methylprednisolone pharmacokinetics. Interindividual variability was estimated for clearance (48.1%) and volume of distribution (19.9%). Model evaluation supported the predictive performance of the final model. Conclusion: We developed a population pharmacokinetic model for methylprednisolone in paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. The model identifies body weight, postmenstrual age and operation group as determinants of pharmacokinetic variability. It provides a descriptive framework for characterizing methylprednisolone disposition in this heterogeneous population. Trial registration number and date: EudraCT 2008-007413-76 2008-12-23.

Tramadol is a widely used analgesic whose bioactivation to O‐desmethyltramadol is primarily mediated by cytochrome P450 2D6 (CYP2D6). Genetic variability and drug–drug interactions affecting CYP2D6 may influence tramadol pharmacokinetics and pharmacological effects. Cyclooxygenase‐2 inhibitors are frequently co‐administered with tramadol in multimodal analgesia, but their potential to affect tramadol disposition and effects remains incompletely characterised. Celecoxib has been reported to act as a weak inhibitor of CYP2D6 in vivo. This randomised, single‐blind, placebo‐controlled crossover study evaluated the effects of 8‐day pretreatment with celecoxib or etoricoxib (200 and 120 mg once daily, respectively), compared with placebo, on the pharmacokinetics and pharmacological effects of a single 100 mg oral dose of tramadol in 12 healthy volunteers. Plasma concentrations of tramadol and O‐desmethyltramadol were measured, and pharmacological effects were assessed using visual analogue scales, psychomotor testing (digit symbol substitution test) and cold pressor pain models. Celecoxib pretreatment did not change tramadol exposure but reduced the formation of O‐desmethyltramadol, decreasing the geometric mean AUC ratio (GMR) of O‐desmethyltramadol to tramadol (AUC _m /AUC _p ) by 24% relative to placebo (90% CI, 0.69–0.84; p < 0.001). Etoricoxib had minimal effects on tramadol exposure or metabolism (GMR 0.92; 90% CI, 0.84–1.02; p = 0.13). In conclusion, celecoxib modestly inhibited the bioactivation of tramadol, but not etoricoxib. Differences in pharmacological effects were negligible.

Background and Objective Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine. Methods We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development. Results Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers. Conclusions Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine.

Background: We investigated whether a universal predictive risk index for persistent postsurgical pain (PPP) is applicable to patients who undergo total knee arthroplasty (TKA).Methods: In this cohort study, 392 participants of a randomized study investigating the effects of anaesthesia methods and tourniquet use on TKA were divided into low‐, moderate‐, and high‐risk groups for PPP, as suggested in the previous risk index study. Patients reported pain using the Oxford Knee Score pain subscale and Brief Pain Inventory–short form preoperatively and 3 and 12 months postoperatively. We compared the pain scores of the low‐ to moderate‐ and high‐risk groups at respective time points and investigated changes in pain scores and the prevalence of PPP at 3 and 12 months after surgery.Results: The high‐risk group reported more pain 3 and 12 months after TKA than the low‐ to moderate‐risk group. However, of seven variables, only a single difference reached the threshold for minimal clinical importance between the groups at 12 months. Additionally, at 12 months, the low‐ to moderate‐risk group reported slightly worse improvements in three of seven pain variables than the high‐risk group. Depending on the definition, the prevalence of PPP ranged from 2% to 29% in the low‐ to moderate‐risk group and 4% to 41% in the high‐risk group 12 months postoperatively.Conclusions: Although the investigated risk index might predict clinically important differences in PPP between the risk groups at 3 months after TKA, it seems poorly applicable for predicting PPP at 12 months after TKA.Significance: Although many risk factors for persistent postsurgical pain after total knee arthroplasty have been identified, predicting the risk of this pain has remained a challenge. Results of the current study suggest that accumulation of previously presented modifiable risk factors might be associated with increased postsurgical pain at 3 months, but not at 12 months after total knee arthroplasty.

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.

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.

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. Editor’s Perspective: What We Already Know about This Topic: What This Article Tells Us That Is New: