A PHARMACOKINETICALLY BASED PROPOFOL DOSING STRATEGY FOR SEDATION OF THE CRITICALLY ILL, MECHANICALLY VENTILATED PEDIATRIC-PATIENT

Objective: To assess the pharmacokinetics and pharmacodynamics of prop ofol sedation of critically ill, mechanically ventilated infants and c hildren. Design: A prospective clinical study. Setting: A pediatric in tensive 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 ther apy dissipated and the need for continued sedation therapy was defined . Patients were generally enrolled just before extubation. Interventio ns: A stepwise propofol dose escalation scheme was used to determine t he steady state propofol dose necessary to achieve optimal sedation, a s defined by the COMFORT scale, a validated scoring system which relia bly and reproducibly quantifies a pediatric patient's level of distres s. When in need of continued sedation, study patients received an init ial 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, ii need ed, using a coordinated dosing scheme to maintain optimal sedation for a 4-hr steady-state period. After 4 hrs of optimal sedation, the prop ofol infusion was discontinued and simultaneous blood sampling and COM FORT scores were obtained until the patient recovered. Additional bloo d samples were obtained up to 24 hrs after stopping the infusion and a nalyzed for propofol concentration by high-performance liquid chromato graphy. Measurements and Main Results: Twenty-nine patients were enrol led into this study. One patient was withdrawn from this study because of an acute decrease in blood pressure occurring with the first propo fol loading dose; 28 patients completed the study. All patients were s edated immediately after the first 2.5-mg/kg propofol loading dose. Ei ght patients were adequately sedated with the starting propofol dose r egimen, 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 escalatio ns and the drug was stopped. Recovery from sedation (COMFORT score of greater than or equal to 27) after stopping the propofol infusion was rapid, averaging 15.5 mins in 23 of 24 evaluable patients. In 13 patie nts who were extubated after stopping the propofol infusion, the time to extubation was also rapid, averaging 44.5 mins. Determination of th e blood propofol concentration at the time of recovery from propofol s edation was possible in 15 patients. The blood propofol concentration was variable, ranging between 0.262 to 2.638 mg/L but less than or equ al to 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 distribu tion into a small central compartment, V-1, and two larger compartment s, V-2 and V-3, which are two and 20-fold greater in volume, respectiv ely, than V-1. Redistribution from V-2 and V-3 into V-1 was much slowe r than ingress, underscoring the importance of the propofol concentrat ion in V-1 as reflective of the drug's sedative effect. Propofol was w ell tolerated. Two patients experienced an acute decrease in blood pre ssure which resolved without treatment. Conclusions: We conclude that a descending propofol dosing strategy, which maintains the propofol co ncentration constant in the central compartment (V-1) while drug accum ulates in V-2 and V-3 to intercompartmental steady-state, is necessary for effective propofol sedation in the pediatric ICU. Our proposed do sing scheme to achieve and maintain the blood propofol concentration o f 1 mg/L would appear effective for sedation of most clinically stable , mechanically ventilated pediatric patients.