Between benzodiazepine over-sedation and neurological damage

Abstract

In the February issue of Critical Care, Dr McKenzie and colleagues [1] describe a new method to differentiate between midazolam over-sedation and neurological damage in the intensive care unit by measuring 1-hydroxymidazolam glucuronide (1-OHMG), an active metabolite of midazolam in serum. 1-OHMG is known to have sedative properties [2,3]. Although the method described (i.e. high-performance liquid chromatography coupled to mass spectrometric detection) might be highly specific and sensitive to detect and quantify the presence of the 1-OHMG, the presence of an active substance irrespective of its quantity can never be solely indicative of a given (patho-)physiological response. Development of drug tolerance is a basic principle in clinical pharmacology, the benzodiazepines being a paradigmatic example. Making dose–response relationship assessment in vivo is thus very problematic. It is dangerous to rely on parameters (1-OHMG), even if very carefully measured, without considering the physiological component/response, as potentially important decisions could result from a diagnosis such as neurological damage in the setting of critical illness. In this regard, flumazenil, a selective benzodiazepine receptor antagonist, will remain indispensable.