Correlation of Serum and Urine Midazolam Levels with Consciousness Tests after Discontinuation of Sedation in the Intensive Care Unit

bAckround: Continuous infusion of midazolam is related to prolonged activity and delayed awakening in the critically ill. Serum midazolam levels can be helpful in differentiating residual benzodiazepine activity from other causes of impaired level of consciousness (LOC). Although drug levels can also be measured in the urine, the relationship between serum and urine levels with the observed LOC has not been studied in clinical practice. objectives: To investigate the correlation between serum and urine midazolam levels in the critically ill and their correlation with the observed level of consciousness estimated with the Glasgow Coma Scale (GCS) and the Full Outline of UnResponsiveness Score (FOUR score). PAtients And Methods:This is a prospective observational study involving patients admitted to a 30 bed General Intensive Care Unit (ICU), who were intubated and mechanically ventilated, with GCS prior to intubation >8. Midazolam infusion was discontinued for at least 12 hours before sampling. Serum and urine sampling to measure midazolam levels and clinical evaluation to calculate the GCS and FOUR score were done simultaneously results: Twenty patients fulfilled the inclusion criteria and participated in the study. Serum midazolam levels correlated moderately with the GCS (R =-0.496, p=0.026) and better with the FOUR score (R =-0.685, p=0.001), but did not correlate with measured levels in the urine (R =-0.029 p=0.904). conclusions: After discontinuation of midazolam sedation, the LOC correlate significantly with the drug levels in the serum. Urine midazolam levels do not correlate with those measured in the serum or with the observed LOC. originAl Article 1st Department of Intensive Care, Evangelismos Hospital, University of Athens Medical School, 45-47 Ipsilantou Str. , 106 76 Athens, Greece Department of Clinical Biochemistry, Evangelismos Hospital, Athens, Greece HOSPITAL CHRONICLES 2019, 14(2): 48–53 Correspondence to: Marielena Papadaki, MD Nephrologist, ICU Fellow Evangelismos Hospital Tel: 00306974812848 E-mail: merielen_emm@hotmail.com Manuscript received March 14, 2019; revised manuscript received December 3, 2019; Accepted December 19, 2019 key words: Sedation, midazolam, level of consciousness, critical illness AbbreviAtion List: LOC: level of consciousness GCS: Glasgow Coma Scale FOUR score: Full Outline of UnResponsiveness Score SOFA: Sequential Organ Failure Assessment RASS: RichmondAgitation-Sedation Scale CVVHDF: Continuous Veno-Venous Haemodiafiltration No financial support was provided for this study CORRELATION OF SERUM AND URINE MIDAzOLAM LEVELS wITH CONSCIOUSNESS TESTS 49 i n t r o d u c t i o n Midazolam Hydrochloride was first synthesised by Fryer and walser in 1976. It is a short-acting water-soluble benzodiazepine drug with an elimination half life of 2.3 2.5 hours that acts on GABA(γ-amino butyric acid) associated benzodiazepine receptors. It has hypnotic, anticonvulsant, muscle-relaxant and anxiolytic properties and anterograde amnesic effects. In clinical practice, it is used for the induction of anesthesia, sedation and the treatment of generalised seizures or status epilepticus. Due to its chemical structure it has rapid absorption, distribution rate and metabolism. Following intravenous injection the plasma concentration of the drug decreases to 10% within 2 hours. Midazolam is bound extensively to plasma proteins and only the unbound drug is pharmacologically active. Once administered, it becomes highly lipophilic and has enhanced penetration into the central nervous system (CNS). It is oxidised by the liver faster than other benzodiazepines and, consequently, has a shorter duration of action. Its hepatic metabolites, 1′-hydroxymidazolam (1′-OHMDz) and, to a smaller extent, 4-hydroxymidazolam (4-OHMDz) and 1,4-dihydroxymidazolam, are pharmacologically active and are conjugated and then excreted as glucuronides in the urine. Midazolam is the benzodiazepine of choice for sedation in the critically ill because of its fast onset and short duration of action, its minimal cardiovascular and respiratory effects and the induction of retrograde amnesia. Nevertheless, it has significant side effects, the most notable of which is residual sedation after cessation of the drug following prolonged continuous infusion. Residual sedation mechanisms include fat absorption and redistribution of the drug from the fat tissue to the circulation, delayed metabolism and excretion in case of renal and hepatic failure and P450 inhibition by other co-administered drugs. In the critically ill, residual sedation may be difficult to differentiate clinically from other causes of decreased level of consciousness (LOC) such as non-convulsive status epilepticus, encephalopathy, CNS infections, cerebrovascular disease and post anoxic injury. The need to rule out these entities may result in overuse of imaging and neurophysiological studies. Serum benzodiazepine levels can be helpful in differentiating residual drug activity from other causes of impaired LOC. Urine samples have also been used mainly in the emergency and in the palliative care setting. This study aims at identifying if urine midazolam levels are correlated with serum midazolam levels and with the level of consciousness in critically ill patients. Based on the drug’s complex pharmacokinetics we hypothesize that serum levels have a better correlation with the LOC as measured by the GCS and the FOUR score than the urine levels, and that there is a weak or no correlation between the serum and the urine levels of the drug. M e t h o d s