title: Unrepaired Tetralogy of Fallot-related Pathophysiologic Changes Reduce Systemic Clearance of Etomidate in Children.
abstract: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF.
  
  
  
  Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 μg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model.
  
  
  
  Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min.
  
  
  
  A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.
authors.affiliation: From the *Pediatric Clinical Pharmacology Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and †Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Cai
authors.forename: Wei
authors.initials: W
authors.lastname: Ji
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Jing
authors.initials: J
authors.lastname: Niu
authors.forename: Ma-Zhong
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D005045:Etomidate / Q000008:administration & dosage / Q000097:blood*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood*; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D013771:Tetralogy of Fallot / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D006993:Hypnotics and Sedatives; D005045:Etomidate