Association of intraoperative dexmedetomidine use with postoperative hypotension in unilateral hip and knee arthroplasties: a historical cohort study.

PURPOSE: Dexmedetomidine is frequently used as a sedative agent for orthopedic surgery patients undergoing total hip or knee arthroplasty. Although the benefits of dexmedetomidine are well described in the literature, there is also potential for harm, especially regarding the hemodynamic effects of dexmedetomidine in the postoperative setting. METHODS: This historical cohort study included all primary unilateral total hip or knee arthroplasties conducted from April 2017 to February 2020 in a single, university-affiliated, tertiary care centre (Jewish General Hospital, Montreal, QC, Canada). We used multivariable logistic regression to analyze the predictors for postoperative hypotension, defined as a systolic blood pressure < 90 mm Hg or any systolic blood pressure while on a vasopressor infusion in the postanesthesia care unit. Models were validated using calibration and discrimination with bootstrapping technique. RESULTS: One thousand five hundred and eighty-eight patients were included in this study. Postoperative hypotension occurred in 413 (26%) patients. Statistically significant predictors for postoperative hypotension included female sex (adjusted odds ratio [aOR], 3.24; 95% confidence interval [CI], 2.29 to 4.58), a history of transient ischemic attack or cerebrovascular accident (aOR, 1.97; 95% CI, 1.04 to 3.72), and intraoperative dexmedetomidine use (aOR, 2.61; 95% CI, 1.99 to 3.42). Moreover, the risk of postoperative hypotension was approximately two times higher than baseline, with a total intraoperative dexmedetomidine dose above 50 µg (relative risk, 1.99; 95% CI, 1.63 to 2.44; P < 0.001). A higher preoperative systolic blood pressure (aOR, 0.98; 95% CI, 0.97 to 0.99) was a protective factor for postoperative hypotension. CONCLUSION: In this historical cohort study, dexmedetomidine was a strong risk factor for postoperative hypotension in total hip or knee arthroplasty patients. Dexmedetomidine, and particularly at high cumulative doses above 50 µg, should be administered judiciously in high-risk surgical patients to minimize the risk of postoperative hypotension.

RéSUMé: OBJECTIF: La dexmédétomidine est fréquemment utilisée comme agent sédatif pour les patients en chirurgie orthopédique bénéficiant d'une arthroplastie totale de la hanche ou du genou. Bien que les avantages de la dexmédétomidine soient bien décrits dans la littérature, il existe également un potentiel de préjudice, en particulier en ce qui touche aux effets hémodynamiques de la dexmédétomidine dans un contexte postopératoire. MéTHODE: Cette étude de cohorte historique comprenait toutes les arthroplasties totales unilatérales primaires de la hanche ou du genou réalisées entre avril 2017 et février 2020 dans un seul centre de soins tertiaires universitaire (Hôpital général juif, Montréal, QC, Canada). Nous avons utilisé la régression logistique multivariable pour analyser les prédicteurs d'hypotension postopératoire, définie comme une tension artérielle systolique < 90 mmHg ou toute tension artérielle systolique pendant une perfusion de vasopresseurs en salle de réveil. Les modèles ont été validés à l'aide de l'étalonnage et de la discrimination avec une technique d'auto-amorçage. RéSULTATS: Mille cinq cent quatre-vingt-huit patients ont été inclus dans cette étude. Une hypotension postopératoire est survenue chez 413 (26 %) patients. Les prédicteurs statistiquement significatifs d'une hypotension postopératoire comprenaient le sexe féminin (rapport de cotes ajusté [RCA], 3,24; intervalle de confiance [IC] à 95 %, 2,29 à 4,58), des antécédents d'accident ischémique transitoire ou d'accident vasculaire cérébral (RCA, 1,97; IC 95 %, 1,04 à 3,72) et l'utilisation peropératoire de dexmédétomidine (RCA, 2,61; IC 95 %, 1,99 à 3,42). De plus, le risque d'hypotension postopératoire était environ deux fois plus élevé que la valeur initiale, avec une dose peropératoire totale de dexmédétomidine supérieure à 50 µg (risque relatif, 1,99; IC 95 %, 1,63 à 2,44; P < 0,001). Une tension artérielle systolique préopératoire plus élevée (RCA, 0,98; IC 95 %, 0,97 à 0,99) était un facteur protecteur contre l'hypotension postopératoire. CONCLUSION: Dans cette étude de cohorte historique, la dexmédétomidine était un facteur de risque important d'hypotension postopératoire chez les patients bénéficiant d'une arthroplastie totale de la hanche ou du genou. La dexmédétomidine, et en particulier à des doses cumulatives élevées supérieures à 50 µg, devrait être administrée judicieusement chez les patients chirurgicaux à haut risque afin de minimiser le risque d'hypotension postopératoire.

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1.

Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the Slco2b1 gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced C max by 80% and 88%, respectively, while the AUC0-last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine C max and AUC0-last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT: A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

Validation of the Critical-Care Pain Observation Tool (CPOT) in pediatric patients undergoing orthopedic surgery.

Background: Postoperative pain cannot be measured accurately among many children with intellectual and developmental disabilities, resulting in underrecognition or delay in recognition of pain. The Critical-Care Pain Observation Tool (CPOT) is a pain assessment tool that has been widely validated in critically ill and postoperative adults. Aims: The objective of this study was to validate the CPOT for use with pediatric patients able to self-report and undergoing posterior spinal fusion surgery. Methods: Twenty-four patients (10-18 years old) scheduled to undergo surgery were consented to this repeated-measure, within-subject study. To examine discriminative and criterion validation, CPOT scores and patients' self-reports of pain intensity were collected prospectively by a bedside rater before, during, and after a nonnociceptive and nociceptive procedure on the day following surgery. Patients' behavioral reactions were video recorded at the bedside and retrospectively viewed by two independent video raters to examine interrater and intrarater reliability of CPOT scores. Results: Discriminative validation was supported with higher CPOT scores during the nociceptive procedure than during the nonnociceptive procedure. Criterion validation was supported with a moderate positive correlation between the CPOT scores and the patients' self-reported pain intensity during the nociceptive procedure. A CPOT cutoff score of ≥2 was associated with the maximum sensitivity (61.3%) and specificity (94.1%). Reliability analyses revealed poor to moderate agreement between bedside and video raters and moderate to excellent consistency within video raters. Conclusions: These findings suggest that the CPOT may be a valid tool to detect pain in pediatric patients in the acute postoperative inpatient care unit after posterior spinal fusion.

Contexte: La douleur postopératoire ne peut pas être mesurée avec précision chez de nombreux enfants atteints de déficience intellectuelle et développementale, entraînant ainsi une méconnaissance ou un retard dans la reconnaissance de la douleur. Le Critical-Care Pain Observation Tool (CPOT) est un outil d'évaluation de la douleur qui a été largement validé chez les adultes gravement malades et postopératoires.Objectifs: L'objectif de cette étude était de valider le CPOT pour une utilisation auprès de patients pédiatriques capables d'autoévaluation et subissant une chirurgie de fusion vertébrale postérieure.Méthodes: Dans le cadre d'une étude intra-sujet, un consentement à cette mesure répétée a été obtenu pour vingt-quatre patients (10­18 ans) devant subir une intervention chirurgicale. Pour examiner la validation discriminante et de critère, les scores CPOT et les autoévaluations des patients concernant l'intensité de la douleur ont été collectés de manière prospective par un évaluateur au chevet du patient avant, pendant et après une procédure non nociceptive et nociceptive le lendemain de la chirurgie. Les réactions comportementales des patients ont été enregistrées sur vidéo au chevet du patient et visionnées rétrospectivement par deux des évaluateurs vidéo indépendants pour examiner la fiabilité des scores CPOT inter-évaluateurs et intra-évaluateurs.Résultats: La validation discriminante a été confirmée par l'obtention de scores plus élevés à l'échelle CPOT pendant la procédure nociceptive que pendant la procédure non nociceptive. La validation de critère a été confirmée par une corrélation positive modérée entre les scores sur l'échelle CPOT et l'intensité de la douleur autoévaluée par les patients pendant la procédure nociceptive. Un score-seuil ≥ 2 sur l'échelle CPOT a été associé à la sensibilité et la spécificité maximales (61,3 % et 94,1 %, respectivement). Les analyses de fiabilité ont révélé une concordance faible à modérée entre les évaluateurs de chevet et les évaluateurs vidéo, et une cocordance modérée à excellente parmi les évaluateurs vidéo.Conclusions: Ces résultats indiquent que le CPOT peut être un outil valide pour détecter la douleur chez les enfants patients de l'unité de soins hospitaliers postopératoires aigus après une fusion rachidienne postérieure.

Experience and Management of the Adverse Effects of Analgesics After Surgery: A Pediatric Patient Perspective.

After surgery, the adverse effects (AEs) of analgesics are common and critical factors influencing the postoperative experience of pediatric patients. Inadequate management of AEs has been found to prolong hospital stay, increase readmission rates and decrease satisfaction with care. The aim of this qualitative descriptive study was to better understand the AEs of analgesics from the perspective of adolescent patients with idiopathic scoliosis after spinal surgery. A total of 7 patients participated in the study. Semistructured interviews were conducted at discharge and 1 week after discharge. Transcribed data were analyzed using qualitative content analysis and themes were identified. Overall, participants most frequently reported gastrointestinal and cognitive AEs, with constipation being the most persistent and bothersome. The pediatric participants used a combination of 3 strategies to mitigate analgesic AEs, namely pharmacologic, nonpharmacologic, and reduction of analgesic intake. Participants demonstrated a lack of understanding of AEs and involvement in their own care. Future studies should be conducted to evaluate the efficacy of nonpharmacological strategies in managing analgesic AEs for pediatric patients after surgery.

Predicting Acute Postoperative Pain Trajectories and Long-Term Outcomes of Adolescents after Spinal Fusion Surgery.

Objectives: Acute pain trajectories are associated with long-term outcomes such as persistent pain and functional disability in adults. However, there are limited data on acute postoperative pain trajectories in the pediatric population. The aims of this study were to investigate acute postoperative pain trajectories, their predictors, and their impact on long- term outcomes in adolescents with idiopathic scoliosis. Methods: We evaluated the preoperative pain intensity, use of analgesics, psychosocial measures and physical functioning of adolescents scheduled to undergo spinal fusion, and their average 6-hour self-reported pain intensity scores for their entire hospital stay. Six months after surgery, baseline variables were reassessed. We used growth mixture modeling to conduct acute postoperative pain trajectory analysis and to identify predictors of pain trajectories. Generalized linear models were conducted to determine whether acute pain trajectories predict long-term outcomes. Results: One hundred and six patients were included in the best-fitted acute pain trajectory model that included four classes that differed in initial pain intensity and rates of change over time. Preoperative pain catastrophizer status and use of analgesics significantly predicted pain trajectory membership. Furthermore, at the 6-month follow-up, patients experiencing moderate-to-severe pain in the acute postoperative period were more likely to report higher levels of pain severity, use pain medication, and miss a greater number of school/work days due to back pain in the last three months. Discussion. Preoperative assessment and analyzing the progression of pain in the acute postoperative period can help identify those at risk of negative long-term outcomes after surgery.