Morphine and midazolam levels in plasma during sedation of critically ill patients

AbstractSedation regimens of midazolam and morphine in nine intensive care patients were evaluated clinically by using the Ramsay scoring system and pharmacokinetically by measuring plasma concentrations of midazolam, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Measurements were made in steady state and in the decay phase after the infusion was stopped. The infusion rates of midazolam and morphine varied by a factor of 10 and 18 respectively to achieve a target state of sedation. Clearance of midazolam in seven of nine patients was similar to known values in healthy controls, whereas the elimination half-lives were increased due to an elevated volume of distribution. In two patients clearance of midazolam was constantly low. Temporary cardiovascular instability led to a temporary failure in the clearance of midazolam, while the development of acute renal and/or liver failure were without notable effect. Morphine was effectively cleared from the plasma in all patients. Morphine glucuronides accumulated extensively in patients with renal failure despite apparently successful peritoneal dialysis in one of them. The M3G:M6G ratio was independent of both the duration of infusion and plasma levels. In conclusion, plasma levels of morphine and midazolam do not predict the intensity of sedation in intensive care patients. Measurements of the plasma concentration of midazolam are of value in patients with cardiovascular instability; morphine, morphine glucuronides and, preferably, also a aa aa-hydroxymidazolam glucuronide should be measured in patients who develop acute renal failure in the intensive care unit (ICU) and/or have delayed awakening.