Characteristics Of Dexmedetomidine Metabolism In Morbidly Obese Patients And The Effect Dose Of Dexmedetomidine Blunting Responses To The Insertion Of The Laryngeal Mask

Obesity seems to be an important factor for pharmacokinetics and pharmacodynamics of intravenous anesthetics. The metabolic characteristics of many kinds of intravenous anesthetics of normal weight patients is different from obese patients. The body mass index (BMI) was always used to assess the degree of obesity (BMI≥28 kg/m2 was considered to be obese, BMI≥40 kg/m2 was considered to be morbidly obese. In the 21st century, the incidence of obesity was significantly increased in the United States and many Asian countries, including China. Approximately 14% of American adults have class II obesity (BMI ≥40 kg/m2) and 6% are morbidly obese. At the same time,6.3% of the adult was also overweight or obese in China, in a research in five province. Dex is a highly selective α2-adrenoreceptor agonist, which possesses hypnotic, sedative, anxiolytic, sympatholytic and analgesic properties without producing significant respiratory depression. It has been described as an useful and safe adjunct in many clinical applications with a wide safety margin and moderate analgesic properties. Morbidly obese patients are at an increased risk of developing postoperative obstructive sleep apnea and opioid-induced ventilatory depression. Since Dex possesses an opioid-sparing effect without causing respiratory depression, it has been increasingly used in bariatric surgery. In addition, Dex has an advantage to reduce volatile anesthetic requirements, and attenuate the fluctuation of hemodynamic when used in laparoscopic bariatric surgery. Although the pharmacology of Dex had been well studied, few PK and PD clinical trials of obese patients was available to guide therapy, particularly the trials about the morbid obesity patients. The conventional dose of Dex in morbidly obese patients was still based on the clinical trail of normal weight subjects. Understanding the clinical pharmacology characteristic of Dex in these patients is crucial. Obesity in general can alter drug pharmacokinetics and disp- -osition because of altered volume of distribution, regional blood flow, total body clearance, and plasma protein binding. In our previous study, compared the pharmacokinetics of Dex in obesity patients (35kg·m-2≥BMI≥28kg·m-2) with normal body mass, we found that the AUC,Cmax, CLz, V1 were significantly increased in the obese. But this research still had some shortages. Firstly, the BMI in the research was relatively small, which was not up to the standard of morbid obesity. Secondly, the previous studies did not set up a control group. The previous research results compared with other related literature results at the same time instead of a control group. Thirdly, only pharmacokinetics data was recorded. The aim of this study was to investigate the PK and PD of intravenous Dex in the morbid obesity patients using an open-label, single-dose, parallel group comparison study design in morbidly obese patients and normal weight patients.Dexmedetomidine has been regularly used as a co-induction agent to facilitate laryngeal mask airway (LMA) insertion. Although the mechanical stimulation of LMA insection was small, sympathetic stimulation of throat can not be avoided. And then the blood pressure and heart rate increased through hypothalamus-pituitary-adrenal cortex axis and sympathetic nervous system. For successful laryngeal mask airway (LMA) insertion, a sufficient anaesthesia depth are required in order to reduce the reflexes of the upper airway and to avoid the unwanted events of gagging, coughing and laryngospasm. Fentanyl, sufentanil and other opioid agents have been studied to prevent cardiovascular changes due to interventions associated with anesthesia. But the complications of perioperative respiratory complications and anesthesia recovery increase, with the increasing total dose of the opioid agents. Dexmedetomidine can prevent hypertension and tachycardia, with a dose-dependent effect. Therefore, dexmedetomidine may be a useful co-induction agent to facilitate LMA insertion with minimal effects on respiratory function. The modified Dixon’s up-and-down method was used to determine the ED50 of dexmedetomidine blunting cardiovascular responses to the insertion of the laryngeal mask in patients undergoing gynecological laparoscopic surgery induced by propofol.OBJECTIVE1. To determine the PK and PD of intravenous Dex in the morbid obesity patients using an open-label, single-dose, parallel group comparison study design in morbidly obese patients and normal weight patients.2. To determine the ED50 and ED95 of dexmedetomidine blunting cardiovascular responses to the insertion of the laryngeal mask in patients undergoing gynecological laparoscopic surgery induced by propofol.METHODSAfter obtaining institutional approval (Guangzhou Hospital,Guangzhou) and registered at ClinicalTrials.gov(ID:NCT02386462,2014/11/01), the patients ready for elective laparoscopic gastric surgery aged 18-60 years old with American society of Anesthesiology (ASA) physical status from I to III were eligible for this enrollment. Eight morbidly obese patients and eight normal weight patients were enrolled.A 12-lead electrocardiogram should not be shown significant abnormalities (including conduction abnormalities) in all subjects. Fasting patients had the following monitors applied:continuous electrocardiogram monitoring, SpO2 and intermittent noninvasive blood pressure (NIBP). The SBP, DBP, HR and SpO2 were monitored continuously. An infusion of lactated Ringer’s solution (1 mL·kg-1·h-1) was started in one arm, and a catheter was inserted in a radial artery in the same arm for blood sampling.After the control vital signs were obtained, Dex diluted to 4 μg/mL was administered through the Agilia syringe pump with the dose of 1 μg/kg over 10 minutes. The SBP, DBP, HR and SpO2 were recorded every 5 minutes from the baseline (immediately before the start of the Dex infusion) to 30 min after the start of the infusion. The OAA/S scores were administered just once on a scale from 1 (no response to mild prodding or shaking) to 5 (responds readily to name spoken in normal tone) at 26 min after the start of the Dex infusion. Propofol (1.5 mg/kg), rocuronium (0.8mg/kg) and fentanyl (4μg/kg) were used successively for endotracheal intubation at 30 min after the start of the Dex infusion. Anesthesia was maintained with sevoflurane (1.5 to 4.0 vol%) and remifentanil (0.2 to 1.0 μgkg-1·min-1). Rocuronium was administered for further muscle relaxation as clinically indicated.Arterial blood samples (3 mL) were collected before the infusion and at 5,10,15, 20,25,30,45,60,90,120,180,240,360 and 480 min after the start of Dex infusion respectively. Blood samples were drawn into potassium ethylenediaminetetraacetic acid (EDTA) tubes, and centrifuged immediately afterwards. Plasma was separated and stored at a -80℃ upright ultra-low temperature freezer until it was assayed by HPLC-MS/MS system in two weeks.The individual plasma Dex concentrations were fitted to the following multiexponential function with the aid of DRUG AND STATISTICS software (DAS, version 2.1.1, Mathematical Pharmacology Professional Committee of China) by noncompartmental and compartmental modeling approaches.Patients undergoing elective gynecological laparoscopic surgery, whose American Society of Anesthesiologists physical status was I or II with ages between 18 and 55 years, were enrolled. After an injection of bolus dose of dexmedetomidine over 10 min, anaesthesia was induced with target-controled propofol, and then bolus of vecuronium 0.1 mg/kg was injected when the BIS was between 45 and 55. LMA insertion was conducted 3 minutes after the vecuronium injection.The modified Dixon’s up-and-down method was used to determine the bolus dose of dexmedetomidine, starting from 1.0μg/kg (step size:0.1μg/kg). Cardiovascular response was defined as an increase in SBP and/or HR by 15% of baseline within 2 min after insertion of the laryngeal mask. The study would ended at least 7 crossovers (successive ’response’ or ’not response’) had been obtained. Probit analysis was used to calculate ED50, ED95 and 95% confidence interval (CI)RESULTSSixteen of 18 patients enrolled completed the study. There were no significant differences between the groups in age, sex, height or serum albumin.The plasma Dex concentrations versus time relationships were best described by a two-compartment pharmacokinetic model.There were significantly differences in these parameters between the two groups. The Cmax, AUC0-∞, AUC0-t and T1/2β of Dex were significantly larger in morbidly obese patients (P<0.05). The T1/2α has no significant difference (P>0.05). The CL of Dex was higher in morbidly obese patiens, however TBW-normalized CL was significantly smaller instead. There is a high correlation between Cnax and BMI, a moderate correlation between Vz, AUC0-∞, AUCo-t, CL and BMI, and a low correlation between ti/20 and BMI.The sedation level was deeper in morbidly obese patients, and significantly more patients achieved an OAA/S score of 2. There was a significant decline of SBP, DBP, HR and SpO2 in the 30 min when compared with the baseline in both of the two groups, but this largest decline of SBP and DBP had no difference between the two groups. The decline range of HR and SpO2 in the 30 min had a significantly difference (P<0.05) between the two groups. A positive correlation (R2=0.737) between the decrease of heart rate and the Cmax of Dex was found in the 30 min.The research was stopped when the eighth inflexion point was appeared. A total of 26 patients were finally included in the study. Two of 28 patients were excluded the research because of a severe bradycardia (HR<50 bpm). There were no significant differences between the groups in age(38.23±7.7 years old), weight (57.30±6.95 kig) and height (161.00±4.15). The number of patients with positive cardiovascular reaction was 12, and the number of patients with negative cardiovascular reaction was 14. The probit regression equation, according to Probit regression analysis method, was Probit(P)= 3.600-2.331lg(dose).The value of regression equation was a linear trend(χ2=0.495,P=0.992).The ED50 and ED95 (95% confidence interval) of dexmedetomidine for blunting cardiovascular responses to the insertion of the laryngeal mask airway was 0.65μg/kg (0.44～ 0.80μg/kg) and 0.94μg/kg(0.79～2.47μg/kg).CONCLUSIONThe PK and PD of Dex in morbidly obese patients was significantly different with normal weight patients. Morbidly obese patients have a deeper sedation level, more obvious decline of HR and SpO2 with a larger plasma concentration of Dex from the baseline to 30 min after the start of the infusion with the same dose of 1.0 μg/kg. Because of these alterations, much more attention should be taken to the sedation level, HR and SpO2 when Dex was used in morbidly obese patients.The single dose of dexmedetomidine for successful blunting cardiovascular responses to the insertion of the laryngeal mask airway to be feasible in 50% and 95% of patients was 0.65μg/kg and 0.94μg/kg during anaesthesia induction with target-controled propofol in female patients.