The Effect of Obesity on the ED95 of Propofol for Loss of Consciousness in Children and Adolescents

Olutoye, Olutoyin A.; Yu, Xiaoying; Govindan, Kalyani; Tjia, Imelda; East, Deborah L.; Spearman, Renee; Garcia, Priscilla J.; Coulter-Nava, Crystal; Needham, Jennifer; Abrams, Stephanie H.; Kozinetz, Claudia A.; Andropoulos, Dean B.; Watcha, Mehernoor F.

doi:10.1213/ane.0b013e318256858f

Cited by 43 publications

(34 citation statements)

References 34 publications

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“…Hence clinical trials for evaluating propofol dosing in obese children is necessary. A recent retrospective study concluded that overweight/obese children are more likely to receive doses of common anesthetic medications outside recommended doses potentially adding risk of adverse outcomes in these children [61]. Ingrande et.…”

Section: ) Propofol Pharmacokinetics (Pk) and Pharmacodynamics (Pd) mentioning

confidence: 99%

Propofol: A Review of its Role in Pediatric Anesthesia and Sedation

2015

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Propofol is an intravenous agent used commonly for induction and maintenance of anesthesia, procedural and critical care sedation in children. The mechanisms of action on the central nervous system involve interactions at various neurotransmitter receptors, especially gamma-aminobutyric acid A receptor. Approved for use in the United States by the Federal Drugs and Administration (FDA) in 1989, its use for induction of anesthesia in children less than 3 years of age still remains off-label. Despite its wide use in pediatric anesthesia, there is conflicting literature about its safety and serious adverse effects in particular subsets of children. Particularly as children are not “little adults”, in this review, we emphasize the maturational aspects of propofol pharmacokinetics. Despite the myriad of propofol pharmacokinetic-pharmacodynamic studies and the ability to use allometrical scaling to smooth out differences due to size and age, there is no optimal model that can be used in target controlled infusion pumps for providing closed loop total intravenous anesthesia in children. As the commercial formulation of propofol is a nutrient-rich emulsion, the risk for bacterial contamination exist despite the FDA mandating addition of antimicrobial preservative, calling for manufacturers’ directions to discard open vials after six hours. While propofol has advantages over inhalation anesthesia like less postoperative nausea and emergence delirium in children, pain on injection remains a problem even with newer formulations. Propofol is known to depress mitochondrial function by its action as an uncoupling agent in oxidative phosphorylation. This has implications for children with mitochondrial diseases and the occurrence of propofol-related infusion syndrome, a rare but seriously life-threatening complication of propofol. At the time of this review, there is no direct evidence in humans for propofol induced neurotoxicity to the infant brain; however, current concerns of neuroapoptosis in developing brains induced by propofol persist and continue to be a focus of research.

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Section: ) Propofol Pharmacokinetics (Pk) and Pharmacodynamics (Pd) mentioning

confidence: 99%

Propofol: A Review of its Role in Pediatric Anesthesia and Sedation

2015

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“…Examples of BCD in anesthesia studies include identifying the minimum effective dose of lidocaine or ropivacaine needed to effectively block the femoral nerve in 90% of subjects. Pediatric anesthesia examples include determining the speed of a propofol bolus at induction preserving respiration , finding an ED 95 dose of remifentanil allowing extubation without coughing post tonsillectomy , or determining the effect of obesity on ED 95 for propofol during induction .…”

Section: Sequential Design Methodsmentioning

confidence: 99%

Sequential allocation trial design in anesthesia: an introduction to methods, modeling, and clinical applications

Görges

Zhou

Brant

et al. 2017

Pediatric Anesthesia

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Summary Estimation of the dose–response curve for new anesthetic protocols typically focuses on identifying minimum effective doses. The application of a sequential experimental method is appropriate, as it minimizes sample size requirements by updating dose assignments based on information accrued from successive subjects. One approach is the up‐and‐down method for estimating the median effective dose in a patient population (ED50). Designs better suited for achieving greater than 50% effectiveness, include the biased coin approach, and continual reassessment method. In this review we introduce different sequential design methods, provide examples of their use, and show through simulation how the method employed influences sample size and the accuracy of the estimated dose. Simulation studies are presented to illustrate the effects of dose parameter and stopping rule choice for up‐and‐down method and biased coin approach. For continual reassessment method, the effects of assumed dose–response model, prior guess, and cohort size are simulated. A binary response regression curve was fit to the data in Saidman and Eger's endtidal halothane dose‐finding study to provide a dose–response curve for generating simulations. A range of options exist when designing a study using sequential allocation with biased coin approach or continual reassessment method. Method choice influences the required sample size and confidence in estimated effect. In the halothane example, up‐and‐down method decreases the required sample size by 20–30% when the choice of design parameters is optimal. For both up‐and‐down method and biased coin approach designs, greater sample sizes, arising from adjusted stopping criteria, might be required to achieve reliable estimates. The continual reassessment method is only efficient if a limited range of doses can be chosen a priori. In conclusion the up‐and‐down method can be more efficient than nonsequential designs for the estimation of the median dose/intervention level for a given intervention (ED50). The biased coin approach or continual reassessment method are preferred for the estimation of higher or lower tail quantiles such as ED90 or ED10. Continual reassessment method may be superior if knowledge of the dose–response relationship is available for the drug of interest.

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“…4 When evaluating the alterations of pharmacokinetics on the drug propofol, obese children require significantly less propofol for loss of lash reflex than do lean children; obese children are given a lower dose of propofol on the basis of actual body weight than their nonobese peers. 10 Clearance of propofol appears to be linearly related to lean body weight rather than to total body weight. 5 It is recommended that the dose of propofol for both induction and maintenance of anesthesia should be based on actual body weight in obese individuals analogous to their lean counterparts.…”

Section: Management Of Anesthesia Of the Obese Patient Inductionmentioning

confidence: 96%

Nutritional Disease

Snyder

2014

Canine and Feline Anesthesia and Co‐Existing Disease

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The World Health Organization's definition of obesity is an abnormal or excessive fat accumulation in adipose tissue to the extent that health is impaired. 1 -3 An excess of adipose tissue occurs when the caloric intake surpasses the caloric expenditure. 4 Owing to the prevalence of obesity in the human population, the World Health Organization has classified obesity into simple obesity (body mass index [BMI] 30-34.9 kg m −2 ), severe obesity (35-39.9 kg m −2 ), morbid obesity (40-49.9 kg m −2 ), and super morbid obesity (≥40 kg m −2 ). 5 PathophysiologyObesity is the most common medical condition in companion animals and is associated with a number of comorbidities. 2 Approximately 55% of dogs and 53% of cats in the USA are considered to be overweight or obese. 6 Worldwide, 22-40% of dogs are considered to be obese. 2 Coincident with obesity in humans comes an increase in morbidity, such as diabetes and musculoskeletal conditions. 6 The criteria for obesity are not as clear-cut in veterinary patients as with human patients, as optimal body weights have not been established for our species and varying breeds. However, it is still concluded that when a patient's weight is 15% above normal for its breed, it is "overweight," and when a patient's weight is 30% above normal, it is "obese." 2 Risk factors for the development of obesity in veterinary patients have been identified. There is a link between certain breeds and their genetic predisposition for obesity. genetically predisposed to obesity. Likewise, particular breeds appear to be resistant to obesity, such as the sight hound group. 2 Aging is associated with an increase in the likelihood of obesity. With aging, the lean body mass decreases, resulting in a decrease in the total daily energy needs of the animal. In conjunction with a decrease in total daily energy needs, the animal's voluntary activity is typically decreased, possibly because of comorbidities of aging, such as osteoarthritis. The decrease in total daily energy needs combined with a decrease in activity can lead to weight gain if caloric intake is not decreased as well. 2 Excessive weight can have a major impact on the overall health of the animal. In humans, morbid obesity (BMI of ≥ 40-44.9 kg m −2 ) is associated with an increased likelihood of diabetes mellitus, 7 respiratory failure, hypertension, left ventricular hypertrophy, atherosclerosis, myocardial ischemia, and some forms of cancer compared to nonobese patients. 4 Mild to moderate hypertension is described in up to 60% of obese human patients, whereas 5-10% of obese human patients have severe hypertension. With time, hypertension can lead to left ventricular dilation, increased left ventricular wall stress, compensatory left ventricular hypertrophy, and left ventricular diastolic dysfunction. 4 An increase in body adipose tissue alters cardiopulmonary physiology, leading to an increase in cardiac output (CO), oxygen consumption, and closing capacity and a decrease in functional residual capacity (FRC). In humans, these alterations ca...

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The Effect of Obesity on the ED95 of Propofol for Loss of Consciousness in Children and Adolescents

Cited by 43 publications

References 34 publications

Propofol: A Review of its Role in Pediatric Anesthesia and Sedation

Propofol: A Review of its Role in Pediatric Anesthesia and Sedation

Sequential allocation trial design in anesthesia: an introduction to methods, modeling, and clinical applications

Nutritional Disease

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