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Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple‐Trauma Patients at the Usual Dosage and a New Proposal for Administration

The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple‐trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6‐hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half‐life, area under serum concentration‐time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady‐state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty‐two patients were studied, mostly young (age 44 [34‐64] years) males (68%), not obese (weight 78 [70‐84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7‐38.7] μg/mL and minimum concentration 0.5 [0.2‐2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half‐life 1.2 [1.0‐1.9] hours; area under the curve for 6 hours 34.7 [29.7‐52.7] μg·h/mL; mean residence time 1.8 [1.3‐2.6] hours; steady‐state volume of distribution 50.8 [42.5‐66.5] L; and serum and renal clearance 28.8 [18.9‐33.7] L/h and 15 [11‐19] mL/min, respectively. Theoretically, daily doses for a steady‐state minimum concentration of 10 μg/mL would be 12.2 [7.8‐16.4] g/day (166 [112‐202] mg/[kg·day]); for an average steady‐state concentration of 10 μg/mL, they would be 6.9 [4.5‐8.1] g/day (91 [59‐111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple‐trauma patients yields serum concentrations below 10 μg/mL due to increased elimination. To reach the 10 μg/mL target, and from a strictly pharmacokinetic point of view, continuous infusion may be more feasible than bolus dosing. Such a change in dosing strategy requires appropriate, pharmacokinetic‐pharmacodynamic and specific safety study.