Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children
Anesthesia Analgesia
Submitted June 2024 by Dr Mark Moll
Read by 321 Journal Watch subscribers
Background:
Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of many medications. Fentanyl is commonly used in paediatric anaesthesia, but there is a paucity in the pharmacokinetics of bolus dose fentanyl data in obese children.
Study:
30 children aged between 2 to 12 years of age, half of whom presented with obesity (defined as >95th percentile body mass index (BMI) for their age and sex) undergoing elective tonsillectomy & adenoidectomy.
After induction, subjects had two intravenous lines placed in two different extremities:
One for medications and IV fluids and one for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes.
Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters.
Mean fentanyl concentrations at 5 minutes was 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, a difference of 0.35 ng/mL (95% CI, 0.08–0.61 ng/mL; P = .01).
Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. 1 mcg/kg fentanyl dose based on TBW resulted in approximately a 60% higher peak fentanyl effect site concentration than dosing based on FFM.
A few salient points and confounders need to be mentioned here:
- The primary preoperative indication for the procedure was sleep-disordered breathing, excluded patients who had previously documented hypersensitivity to opioids, preexisting respiratory disease with the exception of sleep disordered breathing, hepatic disease, renal disease, pregnancy, Tanner stages 2 to 5, and chromosomal abnormalities.
- The mean age of the obese cohort was 8.9 years with mean TBW of 38 kg. The mean age of the nonobese cohort was 3.9 years with mean TBW of 15.8 kg.
- No additional doses of fentanyl for the procedure or in the post-anaesthesia care unit.
- Additional opioid and anaesthetic medications were administered at the discretion of the anaesthetist. Additional opioids administered during the case and in the post anaesthesia care unit were tracked and converted to morphine milligram equivalents for analysis.
- Adverse respiratory events requiring bag mask ventilation were concurrently recorded.
Commentry:
Adenotonsillectomy is one of the most common surgeries performed in children. Fentanyl is one of most common analgesics used in these surgeries and there is a well known interplay between children with obesity related co-morbid disease and adverse post operative consequences namely respiratory depression of which opioids have a significant role.
The study has achieved its aim of determining the peak concretions of fentanyl in obese and non-obese children. Finding that at 5 minutes after the bolus dose there is approximately 60% greater concentration. It appears that recommendation dosing of lipophilic drugs like fentanyl have many differing opinions in the literature, some suggesting that dosing based on ideal body weight, total body weight and adjusted body weight being the more common ones. In my opinion this study is useful in the clinical context of choosing a bolus dose of fentanyl in which it is preferential to keep the patient breathing i.e. remain below the apneic threshold threshold as seen in the below figure. This of course comes with the acknowledgement of the confounders: the difference in age between obese and non-obese children and its effect on PK; the change physiology of the respiratory drive system in obesity and how that influences propensity for apnea; and interplay with other medications.
Whilst not a major aim of the study the authors do note some clinical effects of dosing based on TBW—adverse respiratory events requiring bag mask ventilation and additional opioid administration. They note no difference in bag mask ventilation but do note that the non obese children required higher average amount of additional opioids - as represented by morphine milligram equivalents per kilogram - than obese subjects through the procedure and into their recovery time in the post anaesthesia care unit.
This may just indicate that obese children with higher effect site concentrations are just better analgesed due to the higher peak concentrations. There was no mention of comparing non-opioid medications between the two groups, such as ketamine, alpha-2 agonists etc.
The authors concluded that dosing based on FFM was the most likely to not “overshoot” goal analgesic concentrations. One of the major problems is that the calculation of FFM is not a common calculation and requires the input of many variables limiting its use in clinical anaesthesia.
The authors rightly conclude that more research into this topic to develop FFM based calculations and protocols to bolus dose fentanyl in the obese child.
