Poster presented at: SPA/AAP PEDIATRIC ANESTHESIOLOGY 2010 - Winter Meeting; April 2010; San Antonio, TX

Healy, Daniel P.

Knoderer, Chad A.

Saft, Sarah A.

Sowinski, Kevin M.

Walker, Scott G.

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Butler UniversityDigital Commons @ Butler UniversityScholarship and Professional Work – COPHS College of Pharmacy & Health Sciences2010Pharmacokinetics of Cefuroxime are notSignificantly Altered by Cardiopulmonary Bypassin ChildrenChad A. KnodererButler University, cknodere@butler.eduSarah A. SaftScott G. WalkerDaniel P. HealyKevin M. SowinskiFollow this and additional works at: http://digitalcommons.butler.edu/cophs_papersPart of the Pediatrics Commons, and the Pharmacy and Pharmaceutical Sciences CommonsThis Presentation is brought to you for free and open access by the College of Pharmacy & Health Sciences at Digital Commons @ Butler University. Ithas been accepted for inclusion in Scholarship and Professional Work – COPHS by an authorized administrator of Digital Commons @ ButlerUniversity. For more information, please contact fgaede@butler.edu.Recommended CitationKnoderer, Chad A.; Saft, Sarah A.; Walker, Scott G.; Healy, Daniel P.; and Sowinski, Kevin M., "Pharmacokinetics of Cefuroxime arenot Significantly Altered by Cardiopulmonary Bypass in Children" (2010). Scholarship and Professional Work – COPHS. Paper 44.http://digitalcommons.butler.edu/cophs_papers/44Chad A. Knoderer, PharmD • Sarah A. Saft, PharmD, BCPS • Scott G. Walker, MD •Daniel P. Healy, PharmD, FCCP, FIDSA • and Kevin M. Sowinski PharmD, BCPS, FCCPButler University College of Pharmacy and Health Sciences, Indiana University School of Medicine, Purdue University, School of Pharmacy and Pharmaceutical Sciences and University of Cincinnati, Winkle College of Pharmacy • Indianapolis and West Lafayette, Indiana and Cincinnati, OhioPHARMACOKINETICS OF CEFUROXIME ARE NOT SIGNIFICANTLY ALTERED BY CARDIOPULMONARY BYPASS IN CHILDRENBACKGROUNDSTUDY DESIGN•Sternal wound infections occur in 5% of all children after median sternotomy.1 Associated mortality is as high as 60% in adults.2•Surgical Infection Prevention (SIP) Project recommends cefuroxime as a preferred antibiotic during cardiac surgery.3•There are no published recommendations for the redosing of cefuroxime during pediatric cardiac surgeries requiring CPB. Cephalosporins display time-dependent PD, thus maintaining adequate concentrations throughout the entire surgery is essential.3• CPB related hemodilution alters the volume of distribution of drugs, including cephalosporins in one study. CPB may also sequester drug.4,5• Hypothermia during CPB may affect drug clearance via several mechanisms: decreasing hepatic and renal clearance and altered hepatic and renal blood flow.6• There are limited data describing CPB effects on pediatric prophylactic antibiotic therapy, and none of which describe cefuroxime.7Patients•Patients (n=15) scheduled to undergo a surgical procedure requiring cardiopulmonary bypass at Riley Hospital for Children, Indianapolis, IN •Study was approved by the Investigational Review Board at Indiana University-Purdue University-Indianapolis•All parents/guardians provided written informed consent•Exclusion Criteria:• Allergy to beta-lactam antibiotics•Age less than 36 weeks gestational age or greater than 3 years•Anticipated CPB time less than 30 minutes•History of culture positive for Methicillin-resistant Staphylococcus aureus•Ventricular assist device therapy•Cardiac transplantationExperimental Protocol•Patients received two doses of cefuroxime as an IV bolus. The first dose of cefuroxime (target: 25 mg/Kg) was administered prior to surgical incision and a second dose (target: 12.5 mg/Kg) was administered in the CPB prime solution.•Serial blood samples were obtained, before, during, and after CPB•Blood samples were collected into heparinized blood collection tubes and the plasma was collected and stored frozen at -70 deg C until analysis. Samples were shipped on dry ice to the analytical laboratory.Determination of Plasma Cefuroxime Concentrations•Cefuroxime concentrations were determined at the University of Cincinnati using reverse-phase HPLC assay with UV detection. •The standard curves were linear, and the intra-run and inter-run coefficients of variation were ≤ 10%.Pharmacokinetic Analysis•Candidate pharmacokinetic models were fit to the cefuroxime concentration-time date with ADAPT II using MAP Bayesian estimation.•Model discrimination was accomplished by visual inspection of the predicted versus measured data, the distribution of the residuals, and the AIC.•Two compartment model was chosen as the model of best fit.•PK parameters: Vc and Vp (apparent volume of distribution in the central compartment and peripheral compartments respectively), and Cld and Cls (distribution clearance and systemic clearance, respectively).•Secondary parameters: apparent steady-state volume of distribution (Vss), elimination rate constant and elimination half-life (t1/2) were calculated by standard equations.•Simulations of a single-dose (25 mg/Kg pre-CBG) approach and a two-dose (25 mg/Kg pre and 12.5 mg/Kg prime solution dose) were performed.RESULTSSUMMARYREFERENCESCONCLUSIONS1. Mehta PA, Cunningham CK, Colella CB, et al. Risk factors for sternal wound and other infections in pediatric cardiac surgery patients. Pediatr Infect Dis J. Oct 2000; 19(10):1000-1004.2. Combes A, Trouillet JL, Baudot J, et al. Is it possible to cure mediastinitis in patients with major postcardiac surgery complications? Ann Thorac Surg. Nov 2001;72(5):1592-1597.3. Bratzler DW. The Surgical Infection Prevention and Surgical Care Improvement Projects: promises and pitfalls. AmSurg. Nov 2006;72(11):1010-1016.4. Buylaert WA, Herregods LL, Mortier EP, Bogaert MG. Cardiopulmonary bypass and the pharmacokinetics of drugs. An update. Clin Pharmacokinet. Jul 1989;17(1):10-26.5. Fellinger EK, Leavitt BJ, Hebert JC. Serum levels of prophylactic cefazolin during cardiopulmonary bypass surgery. Ann Thorac Surg. Oct 2002;74(4):1187-1190.6. Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass. Acta Anaesthesiol Scand. Mar 2000;44(3):261- 273.7. Haessler D, Reverdy ME, Neidecker J, et al. Antibiotic prophylaxis with cefazolin and gentamicin in cardiac surgery for children less than ten kilograms. J Cardiothorac Vasc Anesth. Apr 2003;17(2):221-225.Based upon the results of this study, the pharmacokinetics of cefuroxime are not altered by CPB.•Currently recommended pediatric doses of cefuroxime (25- 50mg/Kg) can be used in infants and children undergoing CPB to maintain adequate concentrations for surgical site infection prophylaxis.•No indication of alteration in cefuroxime PK during CPB.STUDY OBJECTIVETo determine the pharmacokinetics of cefuroxime in pediatric patients undergoing open heart surgery with CPB.Table 1, Patient Characteristics, n=15Age (months) 13.2  + 9.2Male (%) 53% Weight (Kg) 9.4 + 2.8kgDuration of CPB (minutes) 145 + 77.5Table 2, Pharmacokinetic Parameters, n=15Dose 1(mg/Kg)Dose 1 Cmax (mg/L)Dose 2(mg/Kg)Cls (L/hr/Kg)Vss(L/Kg)Vc(L/Kg)t1/2 (hrs)Median 24.2 344 12.5 0.050 0.213 0.072 3.76Range 20.9- 26.7150-5120-29.10.041- 0.0580.081- 0.4230.046- 0.1621.03- 6.810 2 4 6 80100200300400 25 mg/Kg25  + 12.5 mg/KgTime (Hours)CefuroximeConcentrations (mg/L)Figure.  Simulation of cefuroxime concentrations based on median PK parameters in Table 2.Table 3.  Simulated Cefuroxime Concentrations (mg/L)Cmax C6 hour C8 hourSingle Dose 340.3 23.2 16.0Two Dose 340.3 38.5 26.5

Pharmacokinetics of Cefuroxime are not Significantly Altered by Cardiopulmonary Bypass in Children

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Pharmacokinetics of Cefuroxime are not Significantly Altered by Cardiopulmonary Bypass in Children

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