A hemodynamic model to guide blood pressure control during deliberate hypotension with sodium nitroprusside in children.

Jeffrey S Barrett,Tammy Reece,David R Drover,Nick Holford,Anne Zajicek,Gregory B Hammer,Brian Anderson,Sarapee Hirankarn,Erin Dombrowski,Scott R Schulman,Carol A Cohane

doi:10.3389/fphar.2015.00151

Abstract

Sodium nitroprusside (SNP) has been widely used to control blood pressure in infants and children. The goals of this analysis were to develop models that describe the hemodynamic response to SNP dosing in pediatric patients; examine sources of variation in dose-response, defining age, and size dependencies; and determine vulnerable populations or patient subtypes that may elicit dosing modifications. A multi-center, randomized, double-blinded, parallel-group, dose-ranging, effect-controlled study, followed by an open-label dose titration of an intravenous infusion of SNP was undertaken in 203 pediatric subjects, who required deliberate hypotension or controlled normotension during anesthesia. A total of 3464 MAP measurements collected from 202 patients during the study's blinded phase, including baseline measurements up to 6 min prior to the blinded were available for analysis. A population K-PD model was developed with a one-compartment model assumed for SNP. Size differences in CL and V of the effect compartment were described using theory-based allometry. An inhibitory sigmoidal Emax model was used to describe the effect of SNP. A power function of age was used to describe age-related differences in baseline MAP. A mixture model of two groups with low and high EC50 was used to explain variability in MAP response. Change in MAP was characterized by a linear disease progression slope during the blinded phase. In the final population model, CL and V increased with weight, and baseline MAP increased with age. The effect compartment half-life of SNP was 13.4 min. The infusion rate producing 50% of Emax (ER50) at steady state for high EC50, was 0.34 μg/kg/min and for low EC50 0.103 μg/kg/min. The K-PD model well-describes initial dosing of SNP under controlled circumstances; model-based dosing guidance agrees with current practice. An initial titration strategy supported via algorithm-based feedback should improve maintenance of target MAP.

Highlights

Controlled hypotension, referred to as deliberate hypotension, is a technique in general anesthesia in which a short-acting hypotensive agent is administered to reduce blood pressure and bleeding during surgery
We present the details of the hemodynamic K-PD analysis along with simulations based on the model that assess dosing considerations in children
Analysis Dataset A total of 203 patients enrolled in the study and total of 3038 mean arterial pressure (MAP) measurements obtained from 202 patients were available for the model-building analysis

Summary

Introduction

Controlled hypotension, referred to as deliberate hypotension, is a technique in general anesthesia in which a short-acting hypotensive agent is administered to reduce blood pressure and bleeding during surgery. While the use of general anesthetic agents or regional anesthesia is an alternative, management of controlled hypotension with sodium nitroprusside (SNP) (Degoute, 2007) has been common strategy in pediatrics for many years. Despite the usage, dosing guidance has been empirically-based and varies across institutions and practices. Due to rapid metabolism and chemical instability and a short half-life, the measurement of SNP plasma concentration for pharmacokinetic (PK) analysis has not been possible, despite numerous attempts to quantify the parent compound and metabolites (Pérez-Ruiz et al, 1991; Vesey et al, 1999). Initial dosing is based on patient weight with subsequent empirical adjustment of dose (infusion rate and duration) largely guided by the individual mean arterial pressure (MAP) response over time

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