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

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.

Keywords: biological; controlled; hemodynamics; hypotension; models; pediatrics; sodium nitroprusside.

Figure 1

(A–D) Diagnostic plots from final SNP K-PD hemodynamic model constructed from blinded phase data for low and high MAP response groups: (A) Low EC₅₀ population-predicted vs. observed, (B) High EC₅₀ population-predicted vs. observed, (C) Low EC₅₀ individual-predicted vs. observed, and (D) High EC₅₀ individual-predicted vs. observed.

Figure 2

(A–C) Visual predictive check plots based on the final SNP K-PD hemodynamic model: (A) observed MAP response with 5th, 50th, and 95th percentiles, (B) predictions and prediction intervals for low EC₅₀ group, and (C) predictions and prediction intervals for high EC₅₀ group.

Figure 3

Scatterplot of observed MAP with 5th, 50th, and 95th percentiles (A) and visual predictive check based on applying the final SNP K-PD hemodynamic model to the open (unblinded) phase MAP response (B).

Figure 4

Simulation-based (deterministic) dose^* prediction for Low (A) and High (B) EC₅₀ response groups to achieve target MAP across age strata (targeted reduction of 10 mm Hg within 5 min).

Figure 5

Simulation-based (deterministic) two-stage infusion dose^* prediction for Low (A) and High (B) EC₅₀ response to achieve a target MAP of 60 mm Hg within 3 min and maintaining this level for 30 min. The simulation is based on the response in a representative (virtual) patient of 7 months weighing 8 kg. Shaded areas refer to infusion durations.