Serum Concentrations Of Midazolam Research Articles

Time-course relationship between cerebrospinal fluid and serum concentrations of midazolam and albumin in patients with cardiac arrest undergoing targeted temperature management

AimTo understand the serum and cerebrospinal fluid (CSF) distribution of midazolam is important for proper timing of neurological prognostication of targeted temperature management(TTM) patients. Midazolam binds extensively to albumin in serum although non protein bound form exist in CSF. We investigated the time-course of CSF, serum concentrations of midazolam and albumin in patients with cardiac arrest who underwent TTM. MethodsThis prospective, single-center, observational study was conducted between May 2020 and April 2022. Midazolam and albumin concentrations in CSF and serum were quantified 0, 24, 48, and 72 h after the return of spontaneous circulation for comparison between the good (Cerebral Performance Category (CPC) 1 and 2) and poor (CPC 3, 4, and 5) neurologic outcome groups. The CSF/serum (C/S) ratios of midazolam and albumin concentrations were determined, along with their correlation coefficients. ResultsOf the 19 enrolled patients, 13 experienced poor outcomes. At 0 h, serum midazolam concentrations were the lowest, whereas serum albumin levels were the highest; in the CSF, the concentrations of both peaked at 24 h. There were no significant inter-group differences in midazolam concentrations in CSF or serum. The C/S ratios of midazolam and albumin significantly differed between the groups. Moderate to strong positive correlations were observed between the midazolam and albumin C/S ratios. ConclusionIn CSF, midazolam and albumin concentrations peaked 24 h post-cardiac arrest. Midazolam and albumin C/S ratios were significantly higher in the poor outcome group and positively correlated with each other, suggesting blood–brain barrier disruption 24 h post-cardiac arrest.

Monitoring of sedation depth in intensive care unit by therapeutic drug monitoring? A prospective observation study of medical intensive care patients

BackgroundAnalgosedation is a cornerstone therapy for mechanically ventilated patients in intensive care units (ICU). To avoid inadequate sedation and its complications, monitoring of analgosedation is of great importance. The aim of this study was to investigate whether monitoring of analgosedative drug concentrations (midazolam and sufentanil) might be beneficial to optimize analgosedation and whether drug serum concentrations correlate with the results of subjective (Richmond Agitation-Sedation Scale [RASS]/Ramsay Sedation Scale) and objective (bispectral (BIS) index) monitoring procedures.MethodsForty-nine intubated, ventilated, and analgosedated critically ill patients treated in ICU were clinically evaluated concerning the depth of sedation using RASS Score, Ramsay Score, and BIS index twice a day. Serum concentrations of midazolam and sufentanil were determined in blood samples drawn at the same time. Clinical and laboratory data were statistically analyzed for correlations using the Spearman’s rank correlation coefficient rho (ρ).ResultsAverage age of the population was 57.8 ± 16.0 years, 61% of the patients were males. Most frequent causes for ICU treatments were sepsis (22%), pneumonia (22%), or a combination of both (25%). Serum concentrations of midazolam correlated weakly with RASS (ρ = − 0.467) and Ramsay Scores (ρ = 0.476). Serum concentrations of sufentanil correlated weakly with RASS (ρ = − 0.312) and Ramsay Scores (ρ = 0.295). Correlations between BIS index and serum concentrations of midazolam (ρ = − 0.252) and sufentanil (ρ = − 0.166) were low.ConclusionCorrelations between drug serum concentrations and clinical or neurophysiological monitoring procedures were weak. This might be due to intersubject variability, polypharmacy with drug-drug interactions, and complex metabolism, which can be altered in critically ill patients. Therapeutic drug monitoring is not beneficial to determine depth of sedation in ICU patients.

Inhibitory Effect of Oxethazaine on Midazolam Metabolism in Rats.

There have been few reports concerning to the drug-drug interactions (DDIs) with OTC drugs although an increase in the use of OTC drugs in recent years. This current study was conducted to clarify the DDIs through CYP3A inhibition by oxethazaine (OXZ), an antacid available as an OTC drug. Midazolam (MDZ) was used as a probe drug for CYP3A activity. In an in vivo study, a single oral dose of OXZ (50 mg/kg) was administered to rats 30, 60, or 120 min before oral MDZ administration (15 mg/kg). Serum concentrations of MDZ were analyzed by HPLC, and its pharmacokinetic parameters were compared with a water-treated control group. The inhibitory effect of OXZ on MDZ 1'-hydroxylation (MDZ 1'-OH) activity was investigated in vitro using rat liver and intestinal microsomes. Pretreatment of OXZ 120 min before MDZ administration significantly increased the area under the serum concentration-time curve (AUC0-∞) of MDZ six-fold compared to the control group without a change in elimination half-life (t1/2). In contrast, OXZ pretreatment 30 or 60 min before MDZ administration did not show any remarkable change in MDZ pharmacokinetic parameters. The in vitro study showed that OXZ inhibited MDZ 1'-OH activity in a concentration-dependent manner both in liver and intestinal microsomes. These results suggested that OXZ increases serum MDZ concentration presumably by the inhibition of liver and/or intestinal CYP3A activity. OXZ was predicted to cause the DDIs mediated by CYP3A inhibition, although this effect depended on the dose interval.

Disposition of Midazolam in Asphyxiated Neonates Receiving Therapeutic Hypothermia – A Pilot Study

Moderate hypothermia has become an established therapy for asphyxiated neonates. Midazolam is a frequently used sedative for this indication, although it has never been investigated how therapeutic hypothermia and asphyxia influence midazolam metabolism in neonates.9 asphyxiated newborns were treated with whole body hypothermia of 32-34°C for 72 h and all of them received continuous midazolam infusion for sedation. Serum concentrations of midazolam and its metabolites 1-hydroxy-midazolam and 4-hydroxy-midazolam were measured during hypothermia and the rewarming period. Renal and hepatic parameters were assessed to take into account the influence of asphyxia related renal or hepatic impairment.We found a high interindividual variability of serum midazolam concentrations in asphyxiated neonates with therapeutic hypothermia; median midazolam concentration was 369.3 ng/ml (minimum 36.6; maximum 3 218.6 ng/ml). The population pharmacokinetic model revealed a midazolam clearance of 2.57 ml/kg/min, comparable to midazolam clearances observed in normothermic critically ill neonates. However, midazolam clearance was significantly decreased in patients with asphyxia related renal and hepatic impairment.It seems that isolated hypothermia does not significantly influence midazolam metabolism. However, neonates with asphyxia related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations. In addition pronounced interindividual variability of midazolam metabolism may contribute to dangerously high midazolam concentrations.

Pharmacokinetics and pharmacodynamics of nasally delivered midazolam

To investigate the pharmacokinetics and pharmacodynamics of nasal formulations containing midazolam (5-30 mg ml(-1)) complexed with cyclodextrin. An open-label sequential trial was conducted in eight healthy subjects receiving single doses of 1 mg and 3 mg intranasally and 1 mg midazolam intravenously. Pharmacokinetic parameters were obtained by non-compartmental and two-compartmental models. Pharmacodynamic effects of midazolam were assessed using VAS and a reaction time test. Mean bioavailability of midazolam after nasal administration ranged from 76 +/- 12% to 92 +/- 15%. With formulations delivering 1 mg midazolam, mean C(max) values between 28.1 +/- 9.1 and 30.1 +/- 6.6 ng ml(-1) were reached after 9.4 +/- 3.2-11.3 +/- 4.4 min. With formulations delivering 3 mg midazolam, mean C(max) values were between 68.9 +/- 19.8 and 80.6 +/- 15.2 ng ml(-1) after 7.2 +/- 0.7-13.0 +/- 4.3 min. Chitosan significantly increased C(max) and reduced t(max) of midazolam in the high-dose formulation. Mean ratios of dose-adjusted AUC after intranasal and intravenous application for 1'-hydroxymidazolam were between 0.97 +/- 0.15 and 1.06 +/- 0.24, excluding relevant gastrointestinal absorption of intranasal midazolam. The pharmacodynamic effects after the low-dose nasal formulations were comparable with those after 1 mg intravenous midazolam. The maximum increase in reaction time by the chitosan-containing formulation delivering 3 mg midazolam was greater compared with 1 mg midazolam i.v. (95 +/- 78 ms and 19 +/- 22 ms, mean difference 75.5 ms, 95% CI 15.5, 135.5, P < 0.01). Intranasal midazolam was well tolerated but caused reversible irritation of the nasal mucosa. Effective midazolam serum concentrations were reached within less than 10 min after nasal application of a highly concentrated midazolam formulation containing an equimolar amount of the solubilizer RMbetaCD combined with the absorption enhancer chitosan.

Reversal of Midazolam Sedation with Flumazenil

Objective To demonstrate the efficacy of flumazenil in reversing the sedative action of midazolam in ventilated intensive care patients. Design Prospective, double-blind randomized study. Setting ICU of a tertiary, university-affiliated teaching hospital. Patients Thirty ICU patients requiring artificial ventilation for greater than 12 hrs were studied. Interventions All patients received a midazolam infusion for sedation. Twenty-nine patients received supplementary narcotics. At the end of the sedation period, either flumazenil or placebo was administered to all the patients in a double-blind, randomized fashion, and the effects were observed. Measurements and main results Sedation levels were measured hourly during the infusion; at the end of the infusion; and at 5, 15, 30, 60, and 120 mins after cessation of the midazolam infusion. Midazolam concentrations in serum were measured at the time of cessation of the midazolam infusion and at 30, 60, and 120 mins later. Reversal of sedation was observed in 14 of 15 patients who received flumazenil, and resedation occurred in seven of these patients. Reversal was not seen in any of the patients who received placebo. Midazolam serum concentrations were similar in both groups. Conclusion Flumazenil in a dose of 0.15 mg is a safe drug that reverses the sedative effect of midazolam.

Importance of the interaction of midazolam and cimetidine.

Six healthy volunteers were given in an open study 15 mg of midazolam orally, and a couple of weeks later the same treatment preceded by 400 mg of cimetidine orally. We followed midazolam serum concentrations and the following pharmacodynamic parameters for five hours: subjective sedation, Maddox wing readings, critical flicker fusion frequency and peak velocity of saccadic eye movements. A statistically significant change was found in Cmax and total AUC between the two sessions. The pharmacodynamic responses differed also clearly from each other suggesting a significant change in midazolam effect even after a single oral dose of cimetidine.