Pediatrics

Emily C. Benefield and Jacquelyn F. Ouellette

Introduction

Based on the Centers for Disease Control and Prevention (CDC) statistics, childhood obesity has more than doubled in children and quadrupled in adolescents in the past 30 years.¹ In the United States, from 1980 to 2012 the prevalence of obesity increased from 7% to 18% in children 6 to 11 years old and from 5% to >20% in adolescents 12 to 19 years old.^1,2 Despite a stabilization between 2003 to 2004 and 2009 to 2010, approximately 17% of all children in the United States are considered obese.^2-4

In pediatrics, the terms overweight and obesity are defined differently than in adults because the body composition of children varies by age and sex. Body mass index (BMI) is determined by calculating the total body weight (TBW) (in kg) divided by the square of height (in m).^1-4 A BMI between the 85th and 95th percentile on the CDC growth charts is defined as overweight, where a BMI at or above the 95th percentile is defined as obese, and a BMI greater than the 99th percentile is considered severely obese in children 2 to 19 years old.^1,2 A BMI can still be calculated for pediatric patients <2 years old; however, the CDC sex-specific, BMI-for-age growth charts are generally used as a comparison in children and adolescents 2 to 19 years old.¹ In children younger than 2 years old, recumbent length is measured and compared against weight using the World Health Organization (WHO) weight for recumbent length growth charts.¹ A measurement at or above the 95th percentile is considered excess weight for this age group; however, there are no specific definitions for overweight or obese.¹ Both the CDC and the WHO growth charts can be found on the CDC website at www.cdc.gov/growthcharts/index.htm.

BMI does not differentiate fat and muscle, measure total body adiposity, or predict body fat distribution.³ Because of these discrepancies, BMI may overestimate in an athletic child with increased muscle mass, and it may underestimate a less active child with reduced muscle mass.³ Caution should be used when interpreting values without considering the body habitus of the child.

Ideal body weight (IBW) is commonly calculated and used to help estimate renal function when dosing specific medications and to predict pharmacokinetics in obese and morbidly obese adult patients. The use of IBW for medication dosing in pediatric patients has been extrapolated from the adult literature. Currently, no widely accepted IBW calculation is used in the pediatric population; however, a simple way to calculate IBW in children utilizes the BMI for the 50th percentile based on age and sex (Equation 7-1).^5,6 Often in a trauma or emergency, drug dosing is based on estimated weight, which can be calculated with a length-based tape. Initially developed in 1988 by Broselow, length-based tapes were based on information obtained from the National Health Center for Statistics (NHCS) to correctly correlate the IBW of a child with their length.⁷ When using the length-based tape, weight is determined based on length according to specific color-coded sections. Each color-coded section estimates the 50th percentile weight for length; therefore, estimating the pediatric patient’s IBW. The length-based tape has been updated to incorporate the most current data from the National Health and Nutrition Examination Survey (NHANES). The healthcare provider should also visually inspect the patient to determine if an overweight child should be moved up one color section on the tape to provide for more accurate drug dosing.

Equation 7-1⁶

IBW (kg) = BMI at the 50th percentile × ht (in m)²

Example calculation⁸

9-year-old female, TBW 51 kg, height 138 cm, BMI at the 50th percentile 16.25 kg/m²

(16.25 kg/m²) × (1.38 m)² = 30.9 kg

Pharmacokinetic Principles in Obese Pediatric Patients

Pediatric patients encompass several different stages of development with corresponding pharmacokinetic changes to consider. In general, the first year of life is when the vast majority of changes occur as renal and hepatic function develops at differing rates during this time period.⁹ Following the first year of life, renal function continues to improve and will exceed that of otherwise healthy adults. This continues to gain efficiency until adolescence. As such, this affects the renal clearance (Cl) of many medications throughout the age continuum. Hepatic metabolic function including the cytochrome P450 system develops at differing rates dependent on each isoenzyme; however, function typically will reach or exceed adult levels within the first year of life.

In obese pediatric patients, many pharmacokinetic parameters may be altered. The two factors that have been associated with necessitating medication dosage adjustment in this population are volume of distribution (V_d) and Cl.^10-12 Both lean body mass and fat mass are increased in obese children compared to normal-weight children; however, lean body mass per kg of TBW is reduced and fat mass per kg of TBW is larger.^9,12 Having a higher proportion of adipose tissue, a higher V_d for lipophilic medications in overweight and obese pediatric patients is expected.^10-13 Additionally, V_d of hydrophilic medications may vary but is less well defined. With an increase in fat-free mass and corresponding increase in hydration seen in obese patients, an adjusted body weight may be necessary for hydrophilic medications with a low V_d to account for these changes.¹² In a study examining the body composition of children based on weight classification, it was shown that obese children had increased water content of their lean body weight, likely due to higher extracellular water content.¹⁴ As a result, dosing parameters may be altered to achieve goal serum concentrations in this population. Metabolism and excretion of medications may also be altered in obese pediatric patients; however, it has not been clearly studied at this time. One metabolic pathway that has been shown to be enhanced in obese pediatric patients is xanthine oxidase.¹³

Pediatric medication dosing regimens frequently utilize weight-based or body surface area (BSA) dosing strategies to reflect the variance in V_d and Cl in pediatric patients due to growth and developmental changes. Additionally, age-based dosing may be recommended. BSA in children is typically calculated by using the Mosteller formula (see Equation 6-5, Table 6-1, in Chapter 6: Dosing Antineoplastic Medications in Obese Patients), which has been validated in children between 1 month and 14 years of age.¹⁵ Obese children have been shown to be taller than normal-weight children, which could play a part in their higher BSA as well.¹⁴ The observed increased height in obese children can be attributed to excess energy intake; however, this is not observed in patients with underlying genetic pathology, such as Prader-Willi syndrome.¹⁴ Often, pediatric patients require higher dosing than adults when assessed on a mg/kg basis, which results in patients reaching adult maximum dosing in much younger obese children and a potential area for error.⁹ Similar to adults, concerns arise when determining if TBW, IBW, or adjusted body weight should be utilized when calculating medication dosing in overweight and obese pediatric patients.

With the increasing overweight and obese pediatric population, medication dosing becomes even more complex. It is recommended that adult dosing should be considered when TBW equals or exceeds 40 kg.¹⁶ Close consideration should be taken to ensure that the adult maximum dose is not exceeded if using the pediatric dosage strategies described previously.^16,17 If dosing exceeds adult maximum recommendations, risk for medication-related toxicities increases. Conversely, if pediatric patients receive medications based on adult dosing strategies that do not account for age-related higher Cl rates, risk of underdosing certain medications and reduced clinical effectiveness increases. Either error could result in significant morbidity and mortality.

Sedatives, Analgesics, and Paralytics

Medications used to treat pain and facilitate sedation in children bring along inherent risks, which may be heightened in the overweight and obese population. Oversedation and respiratory depression could occur with overdosing sedative and opioid medications, while incomplete anesthesia and poor pain control associated with underdosing could result in poor outcomes. Several studies have investigated various types of sedation and analgesia regimens in overweight and obese children.

Fentanyl is a lipophilic medication with a large V_d. In a retrospective review of overweight and obese children receiving continuous infusion fentanyl for sedation and analgesia in the pediatric intensive care setting, a nonsignificant difference in the number of dose changes per day (overweight/obese: 0.92 versus normal weight: 0.69; p = 0.16) and the number of additional bolus doses needed to maintain sedation (overweight/obese: 45.6 versus normal weight: 22.9; p = 0.19) were observed in the overweight and obese children.¹⁹ Additionally, two patients in the overweight and obese group were initiated on continuous infusion fentanyl at a dose that exceeded the adult initial maximum of 100 mcg/hr. Considering adult dosing at a weight of 40 kg could help prevent exceeding adult maximum dosing. Like other synthetic opioids with large V_d, fentanyl may require higher initial bolus doses to achieve appropriate analgesia in obese patients with lower maintenance dosing.¹⁸

Burke and colleagues investigated potential over- and underdosing of commonly utilized sedatives, analgesics, and neuromuscular blockers in overweight and obese children.²⁰ Overdose was defined as >10% of the maximum recommended dose, and underdose was defined as >10% below the minimum recommended dose. The overweight and obese children were 3.5 times more likely to experience an overdose of morphine. Actual morphine doses received were evaluated with IBW based on expert opinion.²¹ This potential overdose could result in excessive sedation and respiratory depression for this patient population. Additionally, the authors found that overweight and obese children were twice as likely to be prescribed an underdosage of succinylcholine, which may result in inadequate paralysis during intubation or other procedures. Administered succinylcholine doses were assessed with TBW.

In a review of the effects of obesity on sedation for pediatric dental procedures, concerns for respiratory, gastrointestinal, and cardiac adverse effects were discussed.²² Of particular concern is the link between obesity and restrictive lung disease, which may increase the likelihood of complications with minimal sedation, such as hypoxia or inability to maintain a patent airway. A retrospective evaluation of adverse effects—including oxygen desaturation, apnea, vomiting, or prolonged sedation following sedation with standard regimen of meperidine (1.5 mg/kg), chloral hydrate (50 mg/kg), and hydroxyzine (25 mg) in children based on weight and BMI percentiles—was performed in dental procedures.²³ Although no results reached statistical significance, patients experiencing greater than or equal to one adverse effect had a higher BMI percentile than those without adverse effects (70th percentile versus 61st percentile). Of patients with BMI data, 18% of overweight and obese patients experience greater than or equal to one adverse effect compared to 12% of normal-weight patients. Unfortunately, this study was underpowered to identify a difference. It does, however, identify areas of opportunity for further study and warrant appropriate monitoring in place when caring for overweight and obese children in this setting.

The highly lipophilic anesthetic, propofol, was investigated in two studies using the same patient cohort. These studies evaluated the use of propofol for anesthesia during procedures lasting at least 60 minutes in obese children. Propofol Cl in obese children was best correlated with TBW in a pharmacokinetic modeling study, where Cl = 1.7 × (TBW/70)^0.8.²⁴ In the clinical evaluation, vital signs remained relatively stable during the propofol infusion, declining by 20% from baseline with subsequent recovery in approximately 40 minutes.²⁵ Additionally, as BMI increased so did the likelihood of experiencing a respiratory adverse event following anesthesia. Sedation also was prolonged, which the authors suggest was secondary to higher total dosing achieved by the TBW-based dosing scheme used in the study. This suggests, along with expert opinion, that dosing of propofol using TBW should be started at the lower end of the dosing range to account for its large V_d; however, titrating to effect to avoid adverse effects associated with prolonged sedation and overdosing is warranted.²⁶

Succinylcholine, a depolarizing skeletal muscle relaxant, is rapidly hydrolyzed resulting in its short duration of action. Only one study investigating neuromuscular blockade with succinylcholine in obese pediatric patients has been identified. Rose and colleagues assessed three succinylcholine dosing regimens in children 9 to 15 years old with a BMI >30 kg/m².²⁷ Patients received standardized anesthesia with either 0.1 mg/kg, 0.15 mg/kg, or 0.25 mg/kg of succinylcholine and were subsequently monitored using train of four (TOF) until maximal response.²⁷ A supplemental dose of succinylcholine was then given to equal a total dose of 2 mg/kg. The percent depression in the TOF monitoring was significantly different between each group (0.1 mg/kg: 20.2%, 0.15 mg/kg: 39.5%, 0.25 mg/kg: 80.1%; p <0.001).²⁷ Additionally, assessment of three different descriptions of the dosing used (mcg/kg, mcg/BSA, and mcg/BMI) were evaluated for correlation with the probit percent depression in TOF monitoring. Both the mcg/kg (r² = 0.680) and mcg/BSA (r² = 0.626) were found to have a significantly stronger correlation to the TOF decrease compared to the mcg/BMI (r²= 0.110) dosing (p <0.0003 and p

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