Award Winning Abstracts

Population Pharmacokinetics of Intraperitoneal Bupivacaine Using Atomization versus Nebulization and Opioid Requirements in Young Children

Petra M. Meier, MD, DEAA; Luis Pereira, PhD; David Zurakowski, MS, PhD; Constance S. Houck, MD, MPH

Submitted by Petra M. Meier, MD, DEAA

Intraperitoneal (IP) administration of local anesthetics (LA) is used in adults and children for postoperative analgesia after elective laparoscopic surgery. However in comparison to adult laparoscopic surgery, the use of IP LA in children is understudied.1 The high absorptive capacity of the peritoneum and high peritoneal surface area to volume ratio in children presents a challenge. Even though IP LAs have been shown to be effective for perioperative analgesia in adults2 and children3, the pharmacokinetics (PK) in children are not known. The objectives of this prospective study were (1) to develop a population PK model to compare the PK of bupivacaine and (2) assess opioid requirements following IP manual bolus atomization versus micropump nebulization. The following two hypothesis were tested: First, the micropump nebulization device is associated with lower plasma concentrations and less variability after IP bupivacaine administration than the manual bolus atomization device. A second hypothesis was to determine whether the micropump nebulizer technique is associated with lower postoperative opioid requirements compared to the manual bolus atomization.

After IRB approval and written informed parental consent, 67 children (44 males, 23 females) ages six months to six years (median 30 months), undergoing robot-assisted laparoscopic urologic surgery received IP bupivacaine after creation of the pressurized pneumoperitoneum. All children received 1.25 mg/kg bupivacaine after creation of the pressurized pneumoperitoneum either diluted in 30 mL normal saline via mucosal atomization device (droplet size 30 microns) as a bolus over 15 sec or undiluted bupivacaine 0.5% via a micropump nebulizer (droplet size five microns) with a fixed nebulization rate into the CO2 insufflation tubing. So the time required for micropump nebulization depends on the amount of volume in the nebulizer chamber. Venous blood samples were obtained at 4 time intervals between 1-120 min during the procedure. Bupivacaine plasma concentrations were determined using high pressure liquid chromatography. Nonlinear regression modeling was used to estimate PK parameters for each technique with 95% confidence intervals.

Patient baseline characteristics between the delivery methods were comparable. Both administration techniques were characterized by a rapid onset of absorption followed by an exponential decrease of bupivacaine plasma concentrations. For the manual bolus atomization the highest measured bupivacaine plasma concentration was 2.44 μg/mL whereas for the micropump nebulization it was 0.97 μg/mL, which is approximately two and a half times lower. The micropump nebulization group  showed  much less interpatient variability /dispersion in the measured plasma concentrations compared to the manual bolus group (20-30% vs 25 -50% through the first 60 minutes). In neither group were any clinical signs of cardiac or neurotoxicity observed.

IP bupivacaine data was described as a one compartmental model with significant differences in all PK parameters except half-life and residence time between the two delivery devices. The micropump nebulizer had a 40% lower Cmax and a 60 % lower Tmax than the manual bolus atomizer. The PK model allows these findings to be extrapolated to the underlying population. The model showed an excellent agreement of the observed plasma concentration versus the individually predicted concentration for the micropump nebulizer with very little interpatient variability.  

Regardless of the delivery method IV morphine requirements were low at all time points up to 24 hours postoperatively. In the PACU three quarters of children in the manual bolus group and two thirds of the children in the micropump nebulization group required opioids in the PACU. After transfer from the PACU to the ward most children (approx. 85%) did not require further IV morphine and were converted to oral pain medication. The cumulative IV/oral requirements for morphine equivalents showed no difference between manual bolus atomization versus micropump nebulization groups (0.16 vs 0.19 mg/kg).

In summary this is the first population PK study of IP bupivacaine administration in children. The delivery of IP bupivacaine by micropump nebulization confers lower plasma concentrations, less interpatient variability, may reduce the potential for systemic toxicity, and equal clinical efficacy in regard to postoperative opioid requirements compared to manual bolus atomization. We recommend for multimodal pain management using the micropump nebulizer for IP bupivacaine administration due to more desirable PK characteristics with equal opioid requirements for manual bolus atomization. Future technical developments should aim at developing a micropump nebulization device with faster drug delivery to reduce the delivery time of the local anesthetic and ideally minimize the time of fog development that can delay surgery because of reduced visibility.

References

1. Hamill JK, Rahiri JL, Liley A, Hill AG. Intraperitoneal Local Anesthetic in Pediatric Surgery: A Systematic Review. Eur J Pediatr Surg 2016;26:469-75.
2. Ingelmo PM, Bucciero M, Somaini M, Sahillioglu E, Garbagnati A, Charton A, Rossini V, Sacchi V, Scardilli M, Lometti A, Joshi GP, Fumagalli R, Diemunsch P. Intraperitoneal nebulization of ropivacaine for pain control after laparoscopic cholecystectomy: a double-blind, randomized, placebo-controlled trial. British Journal of Anaesthesia 2013;110:800-6.
3. Tian X, Yang P, Su T, Yu J, Zhao S, Xiang G, Yu D, Zhang W, Manyande A, Gao F, Tian Y, Yang H. Intraperitoneal ropivacaine and early postoperative pain and postsurgical outcomes after laparoscopic herniorrhaphy in toddlers: a randomized clinical trial. Paediatric Anaesthesia 2016;26:891-8.