Elimination Clearance of Dexmedetomidine: Cross-examining What the Data Say

Henthorn, Thomas K.; Krejcie, Tom C.; Avram, Michael J.

doi:10.1097/aln.0000000000004087

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“…If different target concentrations are desired, these relationships should be proportional if the clearances are, indeed, first order and stationary. 23 Caveats to these dosing recommendations include using these parameter estimates beyond the 12 h of data collection, beyond the fractions of remaining liver studied in this sample of patients (0.26 to 0.84) and the preliminary nature of these results, based on only 15 patients with 5 plasma lidocaine/metabolite measurements per patient. Follow-up studies to correlate lidocaine plasma concentrations with postoperative pain scores should be combined with these pharmacokinetic results to implement a safe and more rational lidocaine dosing regimen for reduction of postoperative pain after donor hepatectomy.…”

Section: Discussionmentioning

confidence: 99%

Lidocaine Intraoperative Infusion Pharmacokinetics during Partial Hepatectomy for Living Liver Donation

et al. 2022

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Background. Postoperative pain associated with open partial hepatectomy can be intense and persistent. Our multimodal approach to lessen this problem includes an intraoperative intravenous infusion of lidocaine hydrochloride. Decreased hepatic metabolism after resection raises concerns about safe lidocaine dosing in this patient population. We hypothesized that the elimination clearance of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), is reduced after a partial hepatectomy, as reflected by observed plasma concentrations that are higher and have a longer half-life than expected based on pharmacokinetic modeling (estimated for normal liver function). Secondarily, we postulated that plasma concentrations of lidocaine, MEGX and GX do not reach toxic concentrations with our institutional protocol up to 24 hours after surgery. Methods. Blood samples were collected from fifteen patients undergoing a partial hepatectomy for living liver donation, at these specific time points: before and immediately after induction of anesthesia, during hepatectomy, 30 minutes after hepatectomy completion, at case end and 24 hours after the end of surgery. Plasma concentrations of lidocaine and metabolites were measured by liquid chromatography-mass spectrometry (LC-MS/MS). We estimated population lidocaine pharmacokinetics and evaluated total body weight and the fraction of remaining liver mass as potential model covariates. We evaluated the detection of any lidocaine, MEGX or GX toxic plasma concentrations at any time point during and after hepatectomy. Results. The typical value for lidocaine elimination clearance was 0.55 ± 0.12 L/min (±Standard Error of Estimate) which, on average, was reduced to about one third of the baseline clearance, 0.17 ± 0.02 L/min, once the donor graft was surgically isolated, and remained so for 24 hours according to the current data and model. The fraction of remaining liver was a significant covariate for the post-hepatectomy lidocaine clearance such that if 50% of the liver is removed the clearance is reduced by approximately 60%. Plasma concentrations of lidocaine and its metabolites remained below their theoretical combined toxic threshold concentrations throughout the surgical and post-operative course in all patients, with one exception obtained near induction of anesthesia. Plasma lidocaine concentrations decreased at case end and postoperatively while metabolite concentrations continued to rise at the end of surgery with reduction postoperatively. Pharmacokinetic modeling revealed the only significant covariate in the model was the fraction of liver remaining after isolation of the donor graft. Conclusions. Intravenous lidocaine infusions are an acceptable option for multimodal pain management in patients undergoing a hepatectomy for living donation if the lidocaine infusion is stopped when the liver resection is complete. Clearance of lidocaine is decreased proportionally to the remaining liver mass, which should guide lidocaine infusion administration or dosing adjustments for patients undergoing liver resection surgery.

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Section: Discussionmentioning

confidence: 99%