Application to Add Midazolam to the Model List of Essential Medicines

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries

Pharmacotherapy in Neonatal and Pediatric Extracorporeal Membrane Oxygenation (ECMO)

ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research

Feasibility of sedation and analgesia interruption following cannulation in neonates on extracorporeal membrane oxygenation

In most extracorporeal membrane oxygenation (ECMO) centers patients are heavily sedated to prevent accidental decannulation and bleeding complications. In ventilated adults not on ECMO, daily sedation interruption protocols improve short- and long-term outcome. This study aims to evaluate safety and feasibility of sedation interruption following cannulation in neonates on ECMO. Prospective observational study in 20 neonates (0.17-5.8 days of age) admitted for ECMO treatment. Midazolam (n = 20) and morphine (n = 18) infusions were discontinued within 30 min after cannulation. Pain and sedation were regularly assessed using COMFORT-B and visual analog scale (VAS) scores. Midazolam and/or morphine were restarted and titrated according to protocolized treatment algorithms. Median (interquartile range, IQR) time without any sedatives was 10.3 h (5.0-24.1 h). Median interruption duration for midazolam was 16.5 h (6.6-29.6 h), and for morphine was 11.2 h (6.7-39.4 h). During this period no accidental extubations, decannulations or bleeding complications occurred. This is the first study to show that interruption of sedatives and analgesics following cannulation in neonates on ECMO is safe and feasible. Interruption times are 2-3 times longer than reported for adult ICU patients not on ECMO. Further trials are needed to substantiate these findings and evaluate short- and long-term outcomes

Combining Brain Microdialysis and Translational Pharmacokinetic Modeling to Predict Drug Concentrations in Pediatric Severe Traumatic Brain Injury: The Next Step Toward Evidence-Based Pharmacotherapy?

Evidence-based analgosedation in severe pediatric traumatic brain injury (pTBI) management is lacking, and improved pharmacological understanding is needed. This starts with increased knowledge of factors controlling the pharmacokinetics (PK) of unbound drug at the target site (brain) and related drug effect(s). This prospective, descriptive study tested a pediatric physiology-based pharmacokinetic software model by comparing actual plasma and brain extracellular fluid (brainECF) morphine concentrations with predicted concentration-time profiles in severe pTBI patients (Glasgow Coma Scale [GCS], </=8). Plasma and brainECF samples were obtained after legal guardian written consent and were collected from 8 pTBI patients (75% male; median age, 96 months [34.0-155.5]; median weight, 24 kg [14.5-55.0]) with a need for intracranial pressure monitoring (GCS, </=8) and receiving continuous morphine infusion (10-40 mug/kg/h). BrainECF samples were obtained by microdialysis. BrainECF samples were taken from "injured" and "uninjured" regions as determined by microdialysis catheter location on computed head tomography. A previously developed physiology-based software model to predict morphine concentrations in the brain was adapted to children using pediatric physiological properties. The model predicted plasma morphine concentrations well for individual patients (97% of data points within the 90% prediction interval). In addition, predicted brainECF concentration-time profiles fell within a 90% prediction interval of microdialysis brainECF drug concentrations when sampled from an uninjured area. Prediction was less accurate in injured areas. This approach of translational physiology-based PK modeling allows prediction of morphine concentration-time profiles in uninjured brain of individual patients and opens promising avenues towards evidence-based pharmacotherapies in pTBI