Anesthesia in the obese patient: Pharmacokinetic considerations

Casati, Andrea; Putzu, Marta

doi:10.1016/j.jclinane.2004.01.009

Cited by 178 publications

(136 citation statements)

References 108 publications

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“…An increase in the volume of distribution most likely results from the increased fat and lean masses of obese individuals (Casati and Putzu, 2005). Propofol clearance is blood flow dependent (Peeters et al, 2008b).…”

Section: Resultsmentioning

confidence: 99%

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Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction

Dong

Peng

Liu

et al. 2016

Drug Metabolism and Disposition

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The prevalence of obesity has markedly increased worldwide. Obese patients pose significant challenges to anesthesiologists with regard to accurate dosing of anesthetics due to potentially altered pharmacokinetics (PK). Here we determined the PK and pharmacodynamics (PD) of propofol for anesthesia induction in morbidly obese (MO) subjects (body mass index >35 kg/m 2 ) at two dosing regimens: dosing based on total body weight and lean body weight (LBW), respectively. The propofol pharmacokinetic profile was well fitted with a twocompartment model. Both elimination clearance (223%-243% of controls, who had a body mass index <25 kg/m 2 ; P < 0.01) and peripheral compartment volume (156%-180% of controls; P < 0.01) were significantly increased in MO subjects, resulting in an equal or decreased propofol level in plasma (total body weight-based dosing).Furthermore, propofol PD (measured by the bispectral index) was adequately described by a PK/PD model that linked an effect compartment to the two-compartment PK model through a sigmoidal E max model. All PD parameters except EC 50 values (the half maximal effect concentration) were similar (P > 0.05) between MO subjects and controls. Morbid obesity led to a significant decrease (37.9%-38.6%; P < 0.01) in EC 50 values, which suggests increased brain sensitivity to propofol in the MO population. Moreover, dose reduction (i.e., dosing based on LBW) generated identical anesthetic effects in MO subjects compared with controls. In conclusion, morbid obesity significantly altered both PK and PD of propofol. LBW was a better weight-based dosing scalar for anesthesia induction with propofol in MO subjects.

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Section: Resultsmentioning

confidence: 99%

“…However, the exact reasons why MO subjects were more sensitive to the anesthetic effects remain unknown. Nevertheless, it was speculated that the increased sensitivity to propofol was associated with changes in cardiovascular and respiratory function (Casati and Putzu, 2005;Ingrande and Lemmens, 2010).…”

Section: Resultsmentioning

confidence: 99%

Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction

Dong

Peng

Liu

et al. 2016

Drug Metabolism and Disposition

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“…In the morbidly obese, the dosing of intravenous anaesthetics can be based on Ideal Body Weight [26], Corrected Body Weight [27] or Total Body Weight [28]. We used CBW for the calculation of the dosage of propofol [27].…”

Section: Discussionmentioning

confidence: 99%

Porównanie wartości BIS podczas całkowitego znieczulenia dożylnego z zastosowaniem propofolu i znieczulenia wziewnego sewofluranem u otyłych pacjentów

Gaszyński

Wieczorek²

2016

Anaesthesiol Intensive Ther

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Background: Intraoperative awareness is a rarely occurring phenomenon. Obesity is considered as one of the factors increasing the probability of intraoperative awareness due to problems with the dosing of anaesthetics. In a randomized prospective study we compared bispectral index (BIS) recordings during propofol-based total intravenous anaesthesia (TIVA) and sevoflurane-based inhalation anaesthesia in morbidly obese patients as a sign of possible intraoperative awareness. Methods: 120 morbidly obese patients were randomly allocated into two subgroups: TIVA or SEVO. Propofol TIVA was performed following the Servin formula, while sevoflurane was administered based on the age of the patients. The physician administering anaesthesia was blinded to the BIS recordings while the evaluation of the depth of anaesthesia was conducted based on the clinical symptoms of adequate anaesthesia. BIS recordings were evaluated for periods of BIS > 60. Blinded structured interviews were conducted 2 hours after anaesthesia was administrated. Results: The incidence of BIS > 60 occurred in 90% vs. 91.67% of patients while the mean duration of periods of BIS > 60 was 13.74 ± 21.74% vs. 14.21 ± 18.78% of the duration of anaesthesia in TIVA and SEVO groups, respectively (P > 0.05). There was no correlation between the BMI value and the duration of elevated BIS values observed during anaesthesia in both studied methods of anaesthesia, nor between the total time of anaesthesia and the duration of elevated BIS values above 60 in this study. No patient complained of intraoperative awareness when asked in the post-operative period, probably due to the administration of midasolam. Conclusions: Although the incidence of BIS > 60 are very common in obese patients, true awareness during anaesthesia infrequent in this group of patients despite the type of anaesthesia, whether intravenous or inhalation.

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“…Apart from the dysregulation of microsomal P450 enzymes, lipid accumulation in adipose tissue can increase the volume of distribution and decrease drug f u and clearance (Blouin and Warren, 1999). In general, therapy with basic lipophilic drugs, such as benzodiazepines, anesthetics, and other central nervous system-active drugs, is complicated in obese subjects (Abernethy et al, 1983;Casati and Putzu, 2005). Dose adjustment may be required with drugs such as CLZ because it has a highly significant toxicity profile and because close monitoring of plasma concentrations during therapy is mandatory.…”

Section: Discussionmentioning

confidence: 99%

“…Drug clearance may also be impaired in humans with obesity, early steatosis, and NASH (Fiatarone et al, 1991;Blouin and Warren, 1999;Cheymol, 2000). However, changes in the extrahepatic distribution of lipophilic drugs in obese subjects may alter their pharmacokinetic and pharmacodynamic profiles and necessitate dose adjustments (Casati and Putzu, 2005). Sequestration in adipose tissue of obese subjects may decrease the unbound concentrations of basic drugs that are available for biotransformation by P450 enzymes (McLure et al, 2000).…”

mentioning

confidence: 99%

Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis

Zhang

Ramzan²,

Murray³

2007

J Pharmacol Exp Ther

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Hepatic lipid infiltration (steatosis) is a complication of the metabolic syndrome and can progress to nonalcoholic steatohepatitis and severe liver injury. Microsomal cytochrome P450 (P450) drug oxidases are down-regulated in experimental steatosis. In this study we evaluated the separate and combined effects of lipid accumulation and P450 down-regulation on the microsomal oxidation of the antipsychotic agent clozapine (CLZ), the use of which is associated with an increased incidence of the metabolic syndrome. Several important drug oxidizing P450s were down-regulated, and the formation of Ndesmethyl-CLZ (norCLZ) and CLZ N-oxide was decreased in microsomal fractions from orotic acid-induced early steatotic rat liver. Inclusion of lipids extracted from steatotic, but not control, liver decreased the free concentration of CLZ in microsomes and suppressed norCLZ formation; CLZ N-oxidation was unchanged. Triglycerides increased in steatotic liver to 15-fold of control, whereas increases in the monounsaturated oleic acid to 10-fold of control and total polyunsaturated and saturated fatty acids to 4-and 5-fold of control also occurred. Addition of triglycerides containing esterified -6 and -3 fatty acids inhibited the microsomal formation of norCLZ but not that of CLZ N-oxide; triglycerides esterified with unsaturated and monounsaturated fatty acids were inactive. Thus, drug oxidation may be suppressed in steatosis by P450 down-regulation and the accumulation of polyunsaturated fatty esters. In contrast, the activity of the flavin-containing monooxygenase that mediates CLZ N-oxidation was unimpaired. Lipid deposition in livers of patients with the metabolic syndrome may necessitate dosage adjustments for toxic drugs, including CLZ.

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Anesthesia in the obese patient: Pharmacokinetic considerations

Cited by 178 publications

References 108 publications

Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction

Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction

Porównanie wartości BIS podczas całkowitego znieczulenia dożylnego z zastosowaniem propofolu i znieczulenia wziewnego sewofluranem u otyłych pacjentów

Impaired Microsomal Oxidation of the Atypical Antipsychotic Agent Clozapine in Hepatic Steatosis

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