Pharmacodynamics Comparison Of Vercuronium Administrated According To Fat-free Mass And Real Body Weight In Obese Patients

According the World Health Organization (WHO), obesity is defined as a body mass index (BMI) greater than30kg/m2, and morbid obesity is defined as body mass index (BMI) greater than40kg/m2, or greater than35kg/m2with associated comorbidites such as diabetes mellitus and hypertension. Many studies have described the effects of obesity on metabolic, cardiovascular, and pulmonary function, and have documented the increased risk of anaesthesia in these subjects. The physiological and anthropometric changes associated with obesity alter the pharmacokinetic (PK) properties of most drugs. Obese subjects have both an increased amount of fat and lean body weight (LBW) when compared with non-obese subjects of similar age, height, and gender. The increase in LBW can account for as much as20-40%of the excess total body weight (TBW).These changes markedly affect the apparent volume of distribution of some drugs in obese patients. Additionally, increases in cardiac output, total blood volume, and changes in regional blood flow can affect peak plasma concentration, clearance and elimination half-life of many anesthetic agents. morbid obesity also alters pharmacodynamic (PD) properties of some drugs.Despite the growing recognition of the impact of obesity on the PK/PD properties of pharmaceutical agents, obesity individuals are often excluded from clinical trials during the drug development process. As a result, dosing information in package inserts is usually based on a kilogram of RBW, which result in incorrect doses when applied to the obesity patients.At present, the dose of muscle relaxant is mainly calculated by body weight and the ED95We found that both obese patients and normal body weight are administrated according to body weight, and in the obese patients onset time is faster and the effect of muscle relaxant is stronger, particularly in longer aging. The reason may be that the apparent volume of distribution of obesity is decreasing and the dose calculated by body weight is too much.Usually the pharmacological effects of the drug effectiveness depends on the drug in a target cell concentration,Drug effect is proportional to its plasma concentration,Compared with normal body mass of people, obese patient musculature and adipose tissue is increasing, but adipose tissue increased more than muscle tissue. Obese patients per kilogram of body quality have less muscle tissue and more adipose tissue. Usually flows through the blood flow less fat, accounting for approximately5%of heart, and blood flows through visceral is accounted for73%, muscle is22%. This indicates the lean body mass is more closely related to blood volume. Many formulas measure lean body mass, including James’ equation and Janmahasatian’ equation. But James’equation is commonly used to calculate LBW, yet at the obesity, this equation underestimates LBW and can even yield negative values. Janmahasatian equations for estimating LBW are more accurate in estimating LBW for obesity patients. Would the muscle relaxant administered according to lean body mass according Janmahasatian quations calculate free fat mass (FFM).reduce the individual differences of obesity? Firstly, establish the dose-response curve of vercuronium to evaluate the ED95in patients administrated according to real body weight and the free fat mass of non-obese patients. Comparelly the clinical efficacy and individual differences of vercuronium administered according to real body weight and the free fat mass of obese patients. There will be a reference for study and application in clinical.Part one The dose-effect relationship of vercuronium administered according to real body weight and the free fat mass of non-obese patientsObjective To establish the dose-response curve of vercuronium and to evaluate the ED95of vercuronium in non-obese patients administrated according to real body weight and the free fat mass.Methods160patients (American Society of Anesthesiologists, ASA physical status Ⅰ-Ⅱ, aged18-65years, body mass index18-24.9kg/m2)undergoing elective surgery under general anesthesia were enrolled in this study. Patients with neuromuscular disease were excluded and no patient was taking any drug that might influence the effect of muscle relaxant. Standard monitoring was used throughout the study, including ECG, heart rate (lead Ⅱ) and pulse oximetry. In all patients, the EEG was monitored using the Narcotrend monitor. General anaesthesia was induced with target-controlled infusion propofol Cp3～4μg/ml and remifentanil Ce3～6μg/ml to maintain NTI40～60.160subjects were randomized into two groups:group RBW and group FFM, every group into four subgroup. The four subgroups of group RBW patients were randomized divided to receive vercuronium10μg/kg、20μg/kg、30μg/kg,40μg/kg according real body weight, and another four subgroups of group FFM patients were also randomized to receive vercuronium20μg/kg、30μg/kg、40μg/kg、50μg/kg according fat-free mass, Neuromuscular function was monitored with TOF-Watch(?) SX monitor. The temperature of the tenor eminence surface was maintained at32～34℃and body temperature at36.0～36.9℃and room temperature at22～25℃during the induction of anesthesia. The responses of adductor pollicis muscle were defined in terms of the percentages of maximal suppression in T1of train-of-four (TOF) stimulation of ulnar nerve. According to log-probit transformation of the data of dose and response, the dose-response curve of vercuronium was established through linear regression. The onset time of vercuronium was also observed.Results No significant difference in sex, age, body weight, height, and body mass index among8subgroups (P>0.05).The percentages of maximal suppression of T1rised when increasing the dose of vercuronium (P<0.05) in group RBW and FFM. There was no a significant change in onset time among8subgroups(P>0.05),mean (251±30S).The ED95of vercuronium in group RBW and FFM were42.86μg/kg and50.58μg/kg respectively. Conclusion The ED95of vercuronium in group RBW and FFM were42.86μg/kg and50.58μg/kg respectively. The onset time of vercuronium was not significantly shorter while increasing dosage when the drug is less than ED95.Part two Pharmacodynamics comparison of vercuronium administrated according to free fat mass and real body weight in obese patientsObjective To compare the clinical efficacy and individual differences of vercuronium administered according to free fat mass and real body weight.Methods undergoing elective surgery under general anesthesia patients40cases, ASA Ⅰ～Ⅲ grade, age between18～60years, according to the different BMI patients were divided into obesity group (group O,30<BMI<35,20cases) and control group (group N,18≤BMI<24.9,20cases),The O group was randomly divided into two subgroup group OR (according to the real body weight of ED95administration) and group OF (according to the fat-free mass of ED95administration), each subgroup of10cases;N group were randomly divided into group NR (according to real body weight of ED95administration) and group NF(according to fat-free mass ED95administration),each subgroup of10patients, as control group.Routine monitoring was used throughout the study similar part Ⅰ.All airway management equipment was available including fiberoptic endoscopes, laryngeal mask airway (LMA), intubating LMA, and instrumentation for transtracheal ventilation and cricothyrotomy. A surgeon familiar with surgical airways was readily available. General anaesthesia was induced with target-controlled infusion(obese patients setting weight according FFM) propofol Cp3～4μg/ml and remifentanil Ce3-6ng/ml. vercuronium0.13mg/Kg (group OR and NR) or0.15mg/Kg (group OF and NF).The responses of adductor pollicis to train of four(TOF) stimulation of ulnar nerve were monitored by TOF-Watch(?) SX monitor. Recording intubating conditions, onset time, T1maximum inhibition, the clinical role of time, recovery index, pharmacological effects of time. Analyses were performed using SPSS13.0statistical software. All data are reported as the mean±standard deviation. Age, body weight, height, BMI and FFM with single factor analysis of variance(one-way ANOVA), using LSD multiple comparison method, variance not neat using the method of Welch and Dunnett’s T3, and vercuronium dosage, onset time, time of clinical effects, time of pharmacological effects, recovery index using two factors analysis of variance analysis of single effect due to the design, comparison between groups by the independent sample t test. Gender, intubation conditions using nonparametric test a plurality of samples. Differences were considered significant at P<0.05.Results1. There was no significant difference among the groups were age, gender, height, intubation conditions (P>0.05), there were significant differences in body weight, BMI and FFM between group obese and normal body weight,(P<0.05), and compared to normal body weight groups, obesity groups have a high BMI,weight and FFM.(P<0.05).2. Vercuronium dosageAccording to factorial analysis, main effect results show the factors of body weight and type of administration are not statistically significant (P>0.05). But interactive effect of body weight and type of administration had a statistical significance (P<0.05), Fixed normal body weight, there were significant differences between the two level type of administration (P<0.05), and fixed obese weight, there were significant differences between the two level type of administration (P<0.05). Fixed type of administration, vercuronium dosage of normal weight and obese weight had significant difference (P<0.05).3. Comparison of onset time among groupsAccording to factorial analysis,main effect and interaction effect results show the factors of body weight and type of administration are not statistically significant(P>0.05).4. Comparison of time of clinical effects among groupsAccording to factorial analysis, main effect results show the factors of body weight and type of administration are not statistically significant (P>0.05),But interactive effect of two factors had a statistical significance (P<0.05), Fixed normal body weight, there were no significant differences between the two level type of administration (P>0.05), and fixed obese weight, there were significant differences between the two level type of administration (P<0.05). Fixed RBW of administration, the time of clinical effects of normal weight and obese weight had a statistical significance (P<0.05);Fixed FFM of administration, there were no significant differences in time of clinical effects between groups normal weight and obese weight (P>0.05).5. Comparison of time of pharmacological effects among groupsAccording to factorial analysis, main effect results show the factors of body weight and type of administration are not statistically significant (P>0.05),But interactive effect of two factors had a statistical significance (P<0.05), Fixed normal body weight, there were no significant differences between the two level type of administration (P>0.05), and fixed obese weight, there were significant differences between the two level type of administration (P<0.05). Fixed RBW of administration, the time of pharmacological effects of normal weight and obese weight had a statistical significance (P<0.05);Fixed FFM of administration, there were no significant differences in time of pharmacological effects between groups normal weight and obese weight (P>0.05)6. Comparison of recovery index among groupsAccording to factorial analysis, main effect and interaction effect results show the factors of body weight and type of administration are not statistically significant (P>0.05),Fixed normal body weight, there were no significant differences between the two level type of administration (P>0.05), and fixed obese weight, there were significant differences between the two level type of administration (P<0.05). Fixed RBW of administration, recovery index of normal weight and obese weight had a statistical significance (P<0.05);Fixed FFM of administration, there were no significant differences in recovery index between groups normal weight and obese weight (P>0.05).Conclusion vercuronium administrated according to free fat mass in obese patients can be obtained similar to the effects of muscle relaxation-including time of clinical effects, time of pharmacological effects and recovery index-with normal weight according to the actual weight of drug, but the onset time would be lengthen slightly. It also can reduce individual differences of muscle relaxation block in obesity, while reducing the dosage of muscle relaxant. In the absence of neuromuscular monitoring during operation of obesity, vercuronium administrated according to fat-free mass, we can better predict the effect of muscle relaxation, be more reasonable application of vecuronium, guide the time of postoperative antagonistic of muscle relaxant, reduce the incidence of postoperative residual neuromuscular blockade of obesity, and avoid the occurrence of postoperative respiratory complications. Therefore, obese patients using vecuronium administrated according to free fat mass are safely and effectively, more economical on anesthetic management, pharmacodynamic behaviors be more predictability.