A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of propofol sedation of critically ill, mechanically ventilated infants and children.
DESIGN: A prospective clinical study.
SETTING: A pediatric intensive care unit (ICU) in a university hospital. PATIENTS: Clinically stable, mechanically ventilated pediatric patients were enrolled into our study after residual sedative effects from previous sedative therapy dissipated and the need for continued sedation therapy was defined. Patients were generally enrolled just before extubation.
INTERVENTIONS: A stepwise propofol dose escalation scheme was used to determine the steady-state propofol dose necessary to achieve optimal sedation, as defined by the COMFORT scale, a validated scoring system which reliably and reproducibly quantifies a pediatric patient's level of distress. When in need of continued sedation, study patients received an initial propofol loading dose of 2.5 mg/kg and were immediately started on a continuous propofol infusion of 2.5 mg/kg/hr. The propofol infusion rate was adjusted and repeat loading doses were administered, if needed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the propofol infusion was discontinued and simultaneous blood sampling and COMFORT scores were obtained until the patient recovered. Additional blood samples were obtained up to 24 hrs after stopping the infusion and analyzed for propofol concentration by high-performance liquid chromatography.
MEASUREMENTS AND MAIN RESULTS: Twenty-nine patients were enrolled into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propofol loading dose; 28 patients completed the study. All patients were sedated immediately after the first 2.5-mg/kg propofol loading dose. Eight patients were adequately sedated with the starting propofol dose regimen, whereas five patients required downward dose adjustment and 11 patients required dosage increases to achieve optimal sedation. Four patients failed to achieve adequate sedation after five dose escalations and the drug was stopped. Recovery from sedation (COMFORT score of > or = 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patients who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of the blood propofol concentration at the time of recovery from propofol sedation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but < or = 1 mg/L in 13 of 15 patients. Similarly, tremendous variation was observed in propofol pharmacokinetics. Propofol disposition was best characterized by a three-compartment model with initial rapid distribution into a small central compartment, V1, and two larger compartments, V2 and V3, which are two-and 20-fold greater in volume, respectively, than V1. Redistribution from V2 and V3 into V1 was much slower than ingress, underscoring the importance of the propofol concentration in V1 as reflective of the drug's sedative effect. Propofol was well tolerated. Two patients experienced an acute decrease in blood pressure which resolved without treatment.
CONCLUSIONS: We conclude that a descending propofol dosing strategy, which maintains the propofol concentration constant in the central compartment (V1) while drug accumulates in V2 and V3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed dosing scheme to achieve and maintain the blood propofol concentration of 1 mg/L would appear effective for sedation of most clinically stable, mechanically ventilated pediatric patients.