Analysis of Remifentanil with Liquid Chromatography-Tandem Mass Spectrometry and an Extensive Stability Investigation in EDTA Whole Blood and Acidified EDTA Plasma

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.

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“…The supernatants were stored at −80 °C until subsequent assay. The remifentanil assay procedures were followed as previously described 35 .…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation

Yang

Noh

Hahn

et al. 2017

Sci Rep

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“…26 Dexmedetomidine and remifentanil concentrations were measured using ultra-high-performance liquid chromatography-mass spectrometry (Supplemental Digital Content 2, http://links.lww.com/ALN/C13). 23,26 The lower and upper limits of quantification were 0.05 and 20 ng/ml for both compounds with a coefficient of variation of less than 8% for dexmedetomidine and less than 9% for remifentanil (within the entire range of the quality control samples of 0.075 to 7.5 ng/ml). Samples that were thought to be above the upper limit of quantification were diluted with blank human plasma before the sample treatment.…”

Section: Storage and Analysis Of Blood Samplesmentioning

confidence: 99%

Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy

et al. 2019

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Background: Dexmedetomidine is a sedative with modest analgesic efficacy, whereas remifentanil is an opioid analgesic with modest sedative potency. Synergy is often observed when sedative-hypnotics are combined with opioid analgesics in anesthetic practice. A three-phase crossover trial was conducted to study the pharmacodynamic interaction between remifentanil and dexmedetomidine. Methods: After institutional review board approval, 30 age-and sex-stratified healthy volunteers were studied. The subjects received consecutive stepwise increasing target-controlled infusions of dexmedetomidine, remifentanil, and remifentanil with a fixed dexmedetomidine background concentration. Drug effects were measured using binary (yes or no) endpoints: no response to calling the subject by name, tolerance of shaking the patient while shouting the name ("shake and shout"), tolerance of deep trapezius squeeze, and tolerance of laryngoscopy. The drug effect was measured using the electroencephalogram-derived "Patient State Index." Pharmacokinetic-pharmacodynamic modeling related the administered dexmedetomidine and remifentanil concentration to these observed effects. results: The binary endpoints were correlated with dexmedetomidine concentrations, with increasing concentrations required for increasing stimulus intensity. Estimated model parameters for the dexmedetomidine EC50 were 2.1 [90% CI, 1.6 to 2.8], 9.2 [6.8 to 13], 24 [16 to 35], and 35 [23 to 56] ng/ml, respectively. Age was inversely correlated with dexmedetomidine EC50 for all four stimuli. Adding remifentanil did not increase the probability of tolerance of any of the stimuli. The cerebral drug effect as measured by the Patient State Index was best described by the Hierarchical interaction model with an estimated dexmedetomidine EC 50 of 0.49 [0.20 to 0.99] ng/ml and remifentanil EC 50 of 1.6 [0.87 to 2.7] ng/ml. conclusions: Low dexmedetomidine concentrations (EC 50 of 0.49 ng/ml) are required to induce sedation as measured by the Patient State Index. Sensitivity to dexmedetomidine increases with age. Despite falling asleep, the majority of subjects remained arousable by calling the subject's name, "shake and shout," or a trapezius squeeze, even when reaching supraclinical concentrations. Adding remifentanil does not alter the likelihood of response to graded stimuli.

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“…To prevent ex vivo remifentanil metabolism, blood was immediately injected into potassium EDTA vacutainers (BD Vacutainer, USA) and plasma separation, acidification, and −80°C storage were performed within an hour of blood draw. 20 Samples were centrifuged at 3,000 rotations per minute at 4°C for 5 min to separate plasma. Plasma (500 μl) was acidified with 3 μl of a nearly saturated 1 g/ml citric acid solution and stored at −80°C until analysis.…”

Section: Analyticalmentioning

confidence: 99%

“…Venous plasma remifentanil concentrations were determined by liquid chromatography-tandem mass spectrometry, using a modification of a previous method. 20 Protein precipitation was used to prepare samples. An aliquot of 100 μl of thawed patient plasma, calibrator, or quality control plasma was pipetted into discrete wells of a 96-well 2.2ml polypropylene plate.…”

Section: Analyticalmentioning

confidence: 99%

Opioid Sensitivity in Children with and without Obstructive Sleep Apnea

et al. 2019

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C hildhood obstructive sleep apnea, defined by periodic, partial or complete obstruction of the upper airway during sleep, is a common disorder in pediatric patients, with a prevalence as high as 5.7%. 1,2 Children with obstructive sleep apnea often present for surgery and other procedures that require general anesthesia. In fact, the treatment of obstructive sleep apnea is the primary indication for more than 75% of children undergoing tonsillectomy with or without adenoidectomy. 3 Tonsillectomy is the most common pediatric operation performed in the United States, with more than 500,000 tonsillectomies performed annually. 4 Unfortunately, children at high risk for obstructive sleep apnea are three times more likely to have posttonsillectomy respiratory complications and apneic adverse events than children at low risk for obstructive sleep apnea, 5,6 and the rate of complications in patients with obstructive sleep apnea posttonsillectomy (16 to 27%) is substantially increased compared to that of the general pediatric postoperative population (0 to 1.3%). 7-11 These complications include oxygen desaturation, hypercapnia, obstructive apneas requiring continuous positive airway pressure or airway instrumentation, unexpected intensive care unit admission, and in rare cases, death. Concerns for a heightened risk of opioid induced respiratory depression make the perioperative use of opioids in children with obstructive sleep apnea particularly challenging, if not controversial. It has been suggested that they may be at risk from overdose if administered what would otherwise be considered a normal dose of opioid. 6 Indeed, some pediatric surgical centers automatically reduce by half aBStract Background: Opioids are a mainstay of perioperative analgesia. Opioid use in children with obstructive sleep apnea is challenging because of assumptions for increased opioid sensitivity and assumed risk for opioid-induced respiratory depression compared to children without obstructive sleep apnea. These assumptions have not been rigorously tested. This investigation tested the hypothesis that children with obstructive sleep apnea have an increased pharmacodynamic sensitivity to the miotic and respiratory depressant effects of the prototypic μ-opioid agonist remifentanil. Methods: Children (8 to 14 yr) with or without obstructive sleep apnea were administered a 15-min, fixed-rate remifentanil infusion (0.05, 0.1, or 0.15 μg • kg-1 • min-1). Each dose group had five patients with and five without obstructive sleep apnea. Plasma remifentanil concentrations were measured by tandem liquid chromatography mass spectrometry. Remifentanil effects were measured via miosis, respiratory rate, and end-expired carbon dioxide. Remifentanil pharmacodynamics (miosis vs. plasma concentration) were compared in children with or without obstructive sleep apnea. results: Remifentanil administration resulted in miosis in both nonobstructive sleep apnea and obstructive sleep apnea patients. No differences in the relationship between remifentanil concentra...

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Analysis of Remifentanil with Liquid Chromatography-Tandem Mass Spectrometry and an Extensive Stability Investigation in EDTA Whole Blood and Acidified EDTA Plasma

Cited by 17 publications

References 16 publications

Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation

Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation

Pharmacodynamic Interaction of Remifentanil and Dexmedetomidine on Depth of Sedation and Tolerance of Laryngoscopy

Opioid Sensitivity in Children with and without Obstructive Sleep Apnea

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