Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Background Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Comparison of Postoperative Recovery after Manual and Target-Controlled Infusion of Remifentanil in Bariatric Surgery

Background and Objectives: Early postoperative recovery after surgery is a key point for patients’ safety and comfort. Moreover, operating room turnover depends on recovery time. Our aim was to assess which method of remifentanil administration, manual (MI) or target-controlled infusion (TCI), could reduce patient time in recovery room. In this study, patients’ recovery times were registered and compared among the groups. Materials and Methods: We enrolled 31 morbidly obese patients in this prospective study. All of them had undergone bariatric surgery at the Hospital of Lithuanian University of Health Sciences Kauno Klinikos in 2020. Sevoflurane/remifentanil anaesthesia was performed for all patients. The patients were randomly assigned to the manual infusion (MI) (control group) or target-controlled infusion (TCI) group for the method of the administration of remifentanil. While the patients were waking up after the surgery, we recorded spontaneous breathing and airway reflexes recovery time, time of extubation, eye opening, recovery of orientation and beginning of the following oral command. For the TCI group, we also documented remifentanil concentrations in the blood (automatic infusion pump). Results: Patients did not differ in demographic values and duration of remifentanil infusion. We found that remifentanil consumption in the TCI group was lower, p = 0.02. Despite lower remifentanil consumption in the TCI group patients, they demonstrated longer total recovery time than the control group patiens: 14 (12–20) vs. 10 (6–16), p = 0.001. Conclusions: The study showed that, upon comparing the TCI method with MI, manual infusion produced better results in postoperative patient recovery. Additionally, higher doses of remifentanil were consumed using MI. In conclusion, the dosage recommended by highly qualified anaesthesiologists is favourable for morbidly obesity patients when compared to the TCI method.

Effects of circadian rhythm on Narcotrend index and target-controlled infusion concentration of propofol anesthesia

Background The effects of circadian rhythms on drug metabolism and efficacy are being increasingly recognized. However, the extent to which they affect general anesthesia remains unclear. This study aims to investigate the effects of circadian rhythms on anesthetic depth and the concentrations of propofol target-controlled infusion (TCI). Methods Sixty patients undergoing laparoscopic surgeries were sequentially assigned to four groups. Group ND (n = 15): Propofol TCI with Narcotrend monitor during the day (8:00–18:00), Group NN (n = 15): Propofol TCI with Narcotrend monitor during the night (22:00–5:00), Group CLTD (n = 15): Propofol closed-loop TCI guided by bispectral index (BIS) during the day (8:00–18:00), Group CLTN (n = 15): Propofol closed-loop TCI guided by BIS during the night (22:00–5:00). The Narcotrend index, mean arterial pressure (MAP) and heart rate (HR) were compared between group ND and NN at 7 time points, from 5 min before induction to the end of operation. The propofol TCI concentrations, MAP and HR were compared between group CLTD and CLTN at 7 time points, from 5 min after induction to the end of operation. Results The Narcotrend index, MAP, and HR in group NN were lower than those in group ND from the beginning of mechanical ventilation to the end of operation (p < 0.05). The propofol TCI concentrations in group CLTN were lower than those in group CLTD from the beginning of operation to the end of operation (p < 0.05). Conclusion Circadian rhythms have a significant effect on the depth of anesthesia and drug infusion concentrations during propofol TCI. When using general anesthesia during night surgery, the propofol infusion concentration should be appropriately reduced compared to surgery during the day. Trial registration The present study was registered on the ClinicalTrials.gov website (NCT02440269) and approved by the Medical Ethics Committee of Southwest Hospital of Third Military Medical University (ethics lot number: 2016 Research No. 93). All patients provided informed written consent to participate in the study.

Remifentanil Target Controlled Infusion for conscious sedation in a pregnant woman: safety and efficacy

Background: Every year 2% of pregnant women undergo non-obstetric surgical interventions worldwide. According to the American College of Obstetricians and Gynaecologists Committee on Obstetric Practice, pregnant women should never be denied the most appropriate surgical treatment regardless of the trimester of pregnancy.However, additional attention should be paid during the first trimester since there is the highest risk of inducing teratogenic mutations; similarly, during the third trimester, due to the possibility of preterm birth and low weight of the new-born great care should be paid.Case presentation: We present the case of a 36-year-old woman during her 21st week of pregnancy, with a normal-sized foetus according to the gestational age on ultrasound exam and with no additional risk factors. The patient referred an increasing nasal obstruction associated with rhinorrhoea of the left nasal cavity. She also reported episodes of sleep apnoea and hyposmia.The patient received a detailed otolaryngological examination which allowed to identify a mass within the left nasal cavity. The subsequent nasal endoscopy confirmed a greyish polypoid mass lesion with a multinodular surface occupying the entire left nasal fossa. The lesion totally obliterated the left maxillary sinus resulting in obstruction of the anterior osteo-meatal unit and ethmoidal sinusitis She was referred for functional endoscopic sinus surgery (FESS) using analgosedation with Remifentanil Target Controlled Infusion.Discussion and conclusions: To the very best of our knowledge this is the first case described in English literature about the use of analgosedation with Remifentanil Target Controlled Infusion for otolaryngology surgery, specifically in FESS. It could be an interesting option to avoid the use of inhaled anaesthetics that could induce foetal damage, especially during the first months of pregnancy. Furthermore, patient intubation is not necessary, avoiding cases of difficult intubation or any trauma to the airways. An adequate informed consent and the appropriate compliance are elements of paramount importance in tailoring the anaesthetic strategy for pregnant women who need non-obstetric surgical management.

Estimation of the Loading Dose for Target-Controlled Infusion of Dexmedetomidine. Reply to Eleveld et al. Comment on “Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480”

The parameters for a three-compartment model described by Morse and colleagues [...]