The Effect of Obesity in Dexmedetomidine Metabolic Clearance

Study Overview
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Brief Summary
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The purpose of this study is to study the effect of obesity in dexmedetomidine pharmacokinetics and pharmacodynamic profile.

Detailed Description
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The investigators expect to find an inverse correlation between the amount of fat mass and liver blood flow or with the enzymatic metabolic capacity. Results will be based on a population pharmacokinetic modeling analysis performed in NONMEM program. The investigators will first account for the effect of different measured size scalars on volumes and clearances and then they will search for plausible covariates (liver blood flow, enzymatic capacity, degree of hepatic steatosis, etc) on dexmedetomidine metabolic clearance. A pharmacokinetic model capable of characterizing clearance changes in the obese using more plausible biological covariates will be tried to be defined.

Official Title
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The Effect of Obesity in Dexmedetomidine Metabolic Clearance

Conditions
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Obesity

Intervention / Treatment
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* Drug: Dexmedetomidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for obese patients: American Society of Anesthesiology classification I-III patients. Both genders. Age between 18 - 60 years. Body mass index higher than 40 Kg/m2. Inclusion Criteria for non-obese patients: American Society of Anesthesiology classification I-II patients Both genders. Age between 18 - 60 years Body mass index lower than 30 Kg/m2. Exclusion Criteria: Known allergy to study drugs Uncontrolled hypertension. Heart block greater than first degree. Chronic hepatic and kidney disease. Patients taking any drug acting in the central nervous system within 24 hrs before surgery. Patients taking drugs that induce overexpression of liver cytochrome P450-complex enzymes (Carbamazepine, Phenytoin, Phenobarbital, Rifampicin, Dexamethasone, Griseofulvin, Terbinafine, Prednisone, Hydrocortisone, Modafinil).) Known addiction to illicit drugs. Pregnancy. Current or past oncologic disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obese<br>Body composition measurement before surgery using Dual energy X-ray absorptiometry. Dexmedetomidine infusion during surgery. Venous blood sampling for dexmedetomidine plasmatic levels during and after surgery. Liver blood flow indirect non-invasive assessment after surgery using indocyanine. Liver biopsy during surgery. | Drug: Dexmedetomidine<br>* Dexmedetomidine 0.5 μg/kg over 10 minutes and then, 0.5 mcg/kg/h throughout surgery.<br>* Other names: Precedex;|
| Experimental: Non-obese<br>Body composition measurement before surgery using Dual energy X-ray absorptiometry. Dexmedetomidine infusion during surgery. Venous blood sampling for dexmedetomidine plasmatic levels during and after surgery. Liver blood flow indirect non-invasive assessment after surgery using indocyanine. Liver biopsy during surgery. | Drug: Dexmedetomidine<br>* Dexmedetomidine 0.5 μg/kg over 10 minutes and then, 0.5 mcg/kg/h throughout surgery.<br>* Other names: Precedex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dexmedetomidine plasmatic levels | Measured by high performance liquid chromatography | From start of infusion (min): 5, 10, 20, 30, 45, 60, 90, 120, 150, 180; from end of infusion (min): 5, 10, 20, 30, 60, 90, 120, 240, 360, 720 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steatohepatitis score | Using liver biopsy, a score for steatohepatitis will be applied on samples from all patients | 3 months after liver biopsy specimen collection | 
| Plasma disappearance rate of indocyanine | Using indocyanine green and LiMON monitor (Pulsion Medical Systems) surrogate measures of liver blood flow will be registered. | 2 hours after arrival to Post-Anesthesia Care Unit | 
| Enzyme expression | Liver samples will be analyzed for UGT2B10 and UGT1A4 expression (involved in dexmedetomidine metabolization) | 3 months after liver biopsy specimen collection | 
| Hemodynamics | Heart rate and arterial pressure will be recorded during anesthesia | Recorded at every blood sample collection (5, 10, 20, 30, 45, 60, 90, 120, 150, 180 min) during anesthesia | 
| Anesthetic depth | Using a bispectral index monitor, anesthetic depth will be monitorized through out surgery. | Recorded at every blood sample collection (5, 10, 20, 30, 45, 60, 90, 120, 150, 180 min) during anesthesia | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dexmedetomidine, pharmacokinetic, obesity