Clinical Pharmacokinetic Monitoring of Midazolam in Critically Ill Patients

Sean P. Spina, B.Sc.Pharm.; Mary H. H. Ensom, Pharm.D., FASHP, FCCP, FCSHP


Pharmacotherapy. 2007;27(3):389-398. 

In This Article

Abstract and Introduction

Midazolam is a commonly used sedative in critically ill, mechanically ventilated patients in intensive care unit (ICU) settings worldwide. We used a nine-step decision-making algorithm to determine whether therapeutic monitoring of midazolam in the ICU is warranted. Midazolam has a higher clearance and shorter half-life than other benzodiazepines, and prolonged sedation is achieved with continuous infusion. There appears to be very good correlation between plasma concentrations of both midazolam and its active metabolite, α1-hydroxymidazolam, and the degree of sedation. However, due to high interpatient variability, it is not possible to predict the level of sedation in any given individual based on plasma concentration of midazolam or its metabolites. Moreover, no simple and practical assay is available to quantitate midazolam plasma concentrations in the acute ICU setting. Many scales are available to assess the sedative effects of midazolam. Because the plasma concentration of midazolam required to achieve a constant level of sedation is highly variable, it is usually more prudent for the clinician to monitor for sedation with a validated clinical scale than by plasma concentrations alone. Various physiologic parameters, including age-related effects, compromised renal function, and liver dysfunction affect the pharmacokinetics of midazolam and α1-hydroxymidazolam. Although routine drug monitoring for all critically ill patients receiving midazolam is not recommended, this practice is likely beneficial in patients with neurologic damage in whom sedation cannot be assessed and in patients who have renal failure with a prolonged time to awakening.

Patients worldwide have been sedated in intensive care units (ICUs) for decades; however, many controversies still surround the issue of how to monitor for sedation in the ICU setting.[1,2] The main aim of sedation in the critically ill patient is to make the patient calm, cooperative, and able to communicate by providing relief from agitation, anxiety, and pain.[3,4] Benzodiazepines have a high affinity for γ- aminobutyric acid (GABA) receptors. By agonizing GABA receptor complexes, midazolam produces anxiolysis, hypnosis, amnesia, muscular relaxation, and anticonvulsant activity.[5] Midazolam is a short-acting benzodiazepine with a rapid onset of action; it has been widely used as a sedative in mechanically ventilated patients since its introduction to United States and Canadian markets in 1986 and 1988, respectively.[2–7] The half-life of midazolam is approximately 3 hours; however, there is wide interindividual variability in both healthy individuals and critically ill patients.[7,8]

Midazolam undergoes hydroxylation by hepatic cytochrome P450 (CYP) isoenzyme 3A4 to form three metabolites, which are cleared renally. The active metabolite, α1-hydroxymida-zolam, is 20% less potent than the parent compound, with a half-life of approximately 0.8–1 hour in patients with normal renal function.[9,10] The other two metabolites, α4-hydroxymidazolam and 1,4-di-hydroxymida-zolam, are pharmacologically insignificant.[7,10] Once midazolam has been conjugated to a glucuronide in the liver, its metabolites are eliminated from the body through the kidneys by glomerular filtration and tubular secretion.[11]

Midazolam has become a frequently used sedative for acutely agitated patients in ICUs due to its favorable pharmacokinetic properties.[4] These include rapid awakening once the infusion is terminated, which aids in extubation. Clinicians should strive to provide sedation to critically ill patients with intermittent sedative administration and daily awakenings; however, maintenance of sedation can be accomplished with both intermittent and continuously infused sedatives.[12] Unfortunately, the pharmacokinetics of midazolam change significantly during long periods of continuous infusions.[5,6] These changes include depot formation in peripheral tissues and prolonged duration of action. Obese patients, by nature of their excess adipose tissue and thus accumulation of drug and metabolite, appear to be at heightened risk for prolonged sedation; clinical recovery in these patients may be delayed for hours or even days.[5] Critical care patients usually have numerous factors that alter the pharmacokinetics of midazolam. Among these is an increased volume of distribution, which results in a prolonged half-life.[13–15] Midazolam is an intermediate-to-high–extraction drug; therefore, clearance is largely dependent on hepatic blood flow.[4] Any factor affecting blood flow, including multiorgan failure, shock, or circulatory collapse, as well as the plethora of drugs administered to critical care patients, can affect the pharmacokinetics of midazolam.[4,6,14] Diltiazem, macrolide antibiotics, cimetidine, and ranitidine can all interfere with the metabolism of midazolam by inhibiting the CYP3A4 isoenzyme.[5]

Both over- and undersedation are common problems in the ICU setting. Up to 70% of patients experience anxiety and agitation during their ICU stay, presumably secondary to undersedation; almost half recall unpleasant, painful, or stressful events.[16] The Ramsay sedation scale and the Richmond Agitation Sedation Scale (RASS) are two of many validated sedation scales that allow clinicians to minimize inadequate sedation; however, quantification of oversedation remains problematic.[6,17–19] In an attempt to clear the body of excessive sedative drug, which would delay awakening, clinical practice guidelines recommend drug holidays.[12] Discontinuing the sedative infusion on a daily basis allows the nursing staff to let the patient wake up and requires daily retitration to a sedative scale end point. This procedure reduces total midazolam requirements, leading to a shorter duration of mechanical ventilation and ICU stay.[20] During daily awakening, patients need to be monitored closely to minimize self-extubation or removal of other devices.[12]

Therapeutic drug monitoring may be a useful adjunct to clinical scale assessments for providing adequate clinical sedation with midazolam. To our knowledge, few published reports have addressed the possibility of performing therapeutic drug monitoring in addition to bedside clinical assessment for sedation of mechanically ventilated patients. Often, therapeutic drug monitoring is not considered for drugs that lack commercially available assays or defined therapeutic ranges.[21] Therefore, we employed a previously published nine-step decision-making algorithm[22] to evaluate the best available evidence and determine whether clinical therapeutic drug monitoring of midazolam and its active metabolites is warranted.


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