Midazolam Therapeutic Drug Monitoring in Intensive Care Sedation

Abstract

During a 5-year period, 1997 to 2002, therapeutic drug monitoring of midazolam plasma concentrations in combination with the level of sedation as assessed by the Ramsay sedation scale was performed in 648 critically ill patients requiring artificial ventilation. In a subgroup of 189 patients sepsis-related organ failure assessment procedure was additionally performed. A total number of 3354 samples were analyzed. Significantly reduced clearance of midazolam was observed within the first 4 days of midazolam treatment of critically ill patients. As a result, accumulation of midazolam and its metabolites occurred within the first week of treatment. In contrast, parameters such as serum bilirubin or creatinine, which are commonly used to adapt drug therapy to organ dysfunction, showed significant changes with a delay of more than 10 days as compared with the findings of midazolam monitoring. Midazolam plasma concentrations showed a good correlation with the sedative capacity of the drug (r2 = 0.906). However, a great variability of the drug effect between patients could be demonstrated, which, as a consequence, may complicate the development of dosing strategies based on midazolam plasma concentrations to better control sedation in critically ill patients. Furthermore, patient age seems to be an important factor for the considerable variability of the sedative effect of midazolam. To achieve a certain levels of sedation, significantly lower midazolam infusion rates as well as plasma concentrations were required as the patients age increased. No significant sex-related differences could be observed for any pharmacologic parameter obtained in this study. Our findings suggest that midazolam therapeutic drug monitoring might be a useful tool to individualize midazolam therapy, especially in critically ill patients developing organ dysfunction and requiring long-term sedation to minimize the risk of drug accumulation and excessive sedation.

Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

“…demonstrated in critically ill patients plasma concentrations ranging from 60 to 136 ng/ml for midazolam and from 11 to 62.5 ng/ml for 1-hydroxymidazolam for lightly sedated patients as well as plasma concentrations ranging from 307 to 1106 ng/ml for midazolam and from 41 to 119 ng/ml for 1-hydroxymidazolam for deeply sedated patients 3 . Taking into account the molecular weights of the two compounds, midazolam’s free unbound fraction of approximately 3% 1 and the brain-to-unbound-serum concentration ratio of almost 34 43 , this would correspond to a midazolam concentration of about 130 to 2,400 nM in the central nervous system.…”

“…To compare the actions of midazolam with those of 1-hydroxymidazolam we tested a concentration range of 1-hydroxymidazolam from 5 nM to 1 µM, because the in vivo concentration range of 1-hydroxymidazolam is lower than that of midazolam itself  3 .…”

“…Inhibitory actions of 1-hydroxymidazolam could be observed starting at a concentration of 100 nM, corresponding to a plasma concentration of nearly 40 ng/ml. Considering the plasma concentration measured in a previous study 3 , 1-hydroxymidazolam may, therefore, contribute to the effects of midazolam, above all, in cases of deep sedation or in patients with severe renal dysfunction 22 . A summary of clinical and experimental findings concerning effects of midazolam and 1-hydroxymidazolam at different concentrations can be found in Table 1.…”

Treatment with midazolam for nocturnal sedation of terminal cancer patients in a hospice setting

“…Age was not a covariate. It has been reported that in the ICU the dose [15] and infusion rate [9] decrease with age when the sedation level is kept at the same level for all patients, and it has also been reported that pharmacological reactivity to hypnotics increases in aged people [9,16]. However, an age-dependent decrease in the maintenance dose was not observed in this study, probably because the subjects were relatively old and relatively less varied in age (46 -94 years of age), or because the pharmacokinetic capacity varied widely among the subjects due to their varied disease conditions.…”

“…Midazolam produces a hypnotic and sedative effect and is commonly used as an anesthetic induction agent and as an intravenous agent for sedation in the ICU [3][4][5][6][7][8][9]. In the field of palliative medicine, midazolam has been administered by continuous infusion intravenously or subcutaneously to ease terminal uncontrollable symptoms such as delirium, nausea and vomiting, dyspnea, and fatigue [10][11][12].…”