Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia.

Objectives To determine the extent of inter-individual variation in clearance of midazolam in children and establish which factors are responsible for this variation. Methods A systematic literature review was performed to identify papers describing the clearance of midazolam in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL and Cochrane Library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined. Results 25 articles were identified. Only 13 studies gave the full range of clearance values for individual patients. The CV was greater in critically ill patients (18%–170%) than non-critically ill patients (13%–54%). Inter-individual variation was a major problem in all age groups of critically ill patients. The CV was 72%–106% in preterm neonates, 18%–73% in term neonates, 31%–130% in infants, 21%–170% in children and 47%–150% in adolescents. The mean clearance was higher in children (1.1–16.7 mL/min/kg) than in neonates (0.78–2.5 mL/min/kg). Conclusions Large inter-individual variation was seen in midazolam clearance values in critically ill neonates, infants, children and adolescents.

https://adc.bmj.com/content/archdischild/early/2014/10/03/archdischild-2013-305720.full.pdf

Inter-individual variation in midazolam clearance in children

Background: γ-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter, activates persistent low amplitude tonic currents in several brain regions, in addition to conventional synaptic currents. Tonic conductance is highly sensitive to low concentrations of volatile anesthetics and therefore might contribute to amnestic properties. We compared the properties of GABAergic tonic currents mediated by sedative-amnestic midazolam and anesthetic propofol in rat hippocampal neurons. Methods: Patch clamp techniques were used to characterize the GABAergic currents recorded in CA1 pyramidal neurons in rat hippocampal slices. The amplitude of the tonic currents and the decay of miniature inhibitory postsynaptic currents (mIPSCs) were measured after administration of midazolam or propofol. Results: Both midazolam and propofol caused concentration dependent increases in the tonic currents. The enhancement of the tonic currents by midazolam concentrations of greater than 0.5 μM caused no further increase in current amplitude. Propofol continued to increase with concentrations over the range tested (0.1−10 μM). Low concentrations of midazolam 0.01 μM and propofol 0.5 μM selectively enhanced the tonic currents but failed to alter mIPSCs. Conclusions: Low concentrations of midazolam and propofol selectively enhanced the tonic currents but not synaptic currents of rat hippocampal pyramidal neurons. Unlike midazolam, the response to propofol did not become saturated and had a greater effect on the tonic currents. (Korean J Anesthesiol 2009; 56: 675～80)

pdf/comparison-of-the-gabaergic-currents-associated-with-go0f74d99p.pdf

Comparison of the GABAergic currents associated with midazolam and propofol in rat hippocampal neurons

This prospective study was undertaken to evaluate the efficacy and safety of midazolam as a sedative agent in 14 critically ill patients without coma admitted to the intensive care unit at Nihon University Itabashi Hospital, Japan. Adequate sedation (sedation score [SS] 4–6) was induced with 0.058–0.372 mg/kg midazolam and maintained with a dose range of 0.03–0.4 mg/kg per h. Most burn or trauma patients required higher midazolam doses than patients with cardiovascular disease. The most frequent adverse events observed were hypotension, heart-rate fluctuation and electrocardiogram abnormalities. Pharmacokinetic analysis of the population suggested that lower drug clearance rates correlated with presence of complications. Plasma concentrations (EC50) of SS 5, estimated by logistic regression analysis, varied among patients (mean 194 ng/ml). Midazolam infusion achieved successful sedation in this critical care setting, but the optimum dose differed by patient and was influenced by the presence of complications.

https://journals.sagepub.com/doi/pdf/10.1177/147323000102900411

Midazolam for continuous sedation in Japanese critical care patients: phase II study.

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Midazolam for continuous sedation in Japanese critical care patients: phase II study.