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Drug dosage identifier

Midazolam

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Dose and administration

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  • Slow IV push
    50 to 150 micrograms/kg as a slow push over 5 minutes. Can be repeated Q2-4H as required.
    Give lower dose if opiates being administered simultaneously.
  • Continuous intravenous infusion
    10-60 micrograms/kg/hour. Dosage can be increased if necessary.
        
    Midazolam (micrograms) in 50ml IV solution = 50 x weight (kg) x dose (micrograms/kg/hour)
                                                                                       IV rate ml/hour

Indications

  • Sedation/anaesthesia.
  • Anticonvulsant (3rd or 4th line).

Contraindications and precautions

  • Known hypersensitivity to midazolam.
  • Shock.
  • Caution in preterm infants, especially extreme immaturity.
  • Caution in neonates with hepatic or renal impairment.
  • Caution when concurrent use with opiates, particularly fentanyl.
  • Caution when concurrent use with other anticonvulsants.

Interactions

  • Concurrent administration with erythromycin promotes accumulation.
  • May alter the depth of and prolong the recovery from concurrent neuromuscular blockade.
  • Xanthines may decrease the anaesthetic/sedative effect of benzodiazepines. Care needs to be taken with adding or withdrawing caffeine or aminophylline.

Clinical pharmacology

Midazolam, an imidazobenzodiazepine, has anxiolytic, sedative, muscle relaxant and anticonvulsant actions. Facilitates the action in the brain of gamma aminobutyric acid, a naturally occurring neurotransmitter. Absorption 30% with oral and 50% with nasal administration. Rapid and extensive distribution. Highly protein bound. Hepatic metabolism to active and inactive derivatives, impaired by poor hepatic perfusion . Very slow elimination via the kidneys. Elimination half-life variable (6-7 hours in infants close to term, longer in less mature infants), with the major metabolite (1-hydroxymidazolam) having an even shorter half-life. Rapid onset of action (<3 minutes) and peak sedative action <20 minutes after IV administration. Anticonvulsant action may be more rapid. The IV preparation has a pH of 3.

Possible adverse effects

  • Hypotension and reduced cardiac output, particularly when used in combination with fentanyl.
  • Respiratory depression and apnoea.
  • Hypotonia.
  • Seizures or seizure-like activity may be seen following rapid bolus administration and in patients with underlying CNS disorders.
  • Cerebral blood flow velocities are reported to decrease transiently in preterm infants receiving midazolam boluses, possibly reflecting the reduction in blood pressure.
  • Nasal administration in children and adults has been reported to produce a burning sensation.

Special considerations

  • Lower doses of midazolam should be considered in neonates with reduced cardiac output.
  • Development of tolerance and a requirement for higher doses may occur with prolonged use.
  • Prolonged use may result in neonatal abstinence syndrome.
  • Recent systematic review has suggested that routine use of midazolam for sedation in ventilated infants is associated with an increased incidence of adverse neurological outcomes. 9
  • Management of midazolam overdose and/or toxicity: stop midazolam, supportive therapy (ventilation, volume expansion etc.), consider use of specific antagonist flumazenil (very limited experience in the neonate).

Management of Midazolam administration

Description

  • Hypnovel is a clear colourless to light yellow solution, 1mg/ml (=1000 micrograms/ml) in 5ml ampoules (for IV use).
  • A more concentrated preparation (15mg/3ml) is also available, but the drug calculator does not use this concentration.

Administration

Slow IV Injection

  1. The first dose of midazolam in the non-ventilated baby is to be administered by the doctor/NS-ANP. If no adverse effects, nursing staff may administer subsequent doses.
  2. Further dilution is not necessary.
  3. Filter prior to administration through a Pall 0.22 micron filter.
  4. Administer by slow IV injection over 3-5 minutes.
  5. Is compatible with D5W, D10W and NS. Incompatible with IVN, phenobarbitone and ranitidine.
  6. Do NOT mix with other drugs, IV solutions, blood or blood products.

Continuous IV Infusion

Administered by a nurse with neonatal IV drug certification.

  1. Dilute midazolam immediately prior to use to required strength in D5W, NS.
  2. Administer via a syringe pump.
  3. Change fluid and tubing every 24 hours.
  4. Do NOT administer intra-arterially.

Nursing considerations

  • Before administering, have oxygen and resuscitation equipment available in case of severe respiratory depression.
  • Monitor and record patient response to medication.
  • Observe site closely for extravasation.
  • Monitor for adverse reactions.
  • Continuous cardiorespiratory monitoring.
  • Monitor BP and oxygen saturation.
  • Assess sedated infant for signs of pain (midazolam does not possess analgesic properties).

Storage

  • Store <25°C in narcotic cupboard.
  • Discard ampoules after use.
  • Diluted solution may be kept up 24 hours at room temperature in concentrations from 15 to 150 mcg/ml.

Selected references

  1. Burtin P, Jacqz-Aigrain E, Girard P, et al. Population pharmacokinetics of midazolam in neonates. Clin Pharmacol Ther 1994;56:615-25
  2. Jacqz-Aigrain E, Daoud P, Burtin P, Maherzi S, Beaufils F. Pharmacokinetics of midazolam during continuous infusion in critically ill neonates. Eur J Clin Pharmacol 1992;42(3):329-332
  3. Harte GJ, Gray PH, Lee TC, Steer PA, Charles BG. Haemodynamic reponses and population pharmacokinetics of midazolam following administration to ventilated, preterm neonates. J Paediatr Child Health 1997;33(4):335-338
  4. van Straarten HLM, Rademaker CMA, de Vries LS. Comparison of the effect of midazolam or vecuronium on blood pressure and cerebral blood flow velocity in the premature newborn. Dev Pharmacol Ther 1992;19:191-195.
  5. Jacqz-Aigrain E, Daoud P, Burtin P, Desplanques L, Beaufils F. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet 1994;344:646-650
  6. Young TE, Magnum OB (eds). Neofax '95. A manual of drugs used in neonatal care, ed 8. Columbus, Ohio: Ross Products Division, Abbott Laboratories, USA, 1995, p136-7
  7. Stockley I. Drug Interactions (4th ed). 1996.The Pharmaceutical Press. London.
  8. Young TE, Mangum OB. Neofax : A manual of drugs used in neonatal care (ed 10). Raleigh, North Carolina: Acorn Publishing, USA, 1997, pp166-7.
  9. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in the neonatal intensive care unit. Cochrane Systematic Review 2000 Issue 2. Update Software.

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Document Control

  • Date last published: 30 December 2004
  • Document type: Drug Dosage Guideline
  • Services responsible: ADHB Pharmacy, Neonatology
  • Editor: Sarah Bellhouse
  • Review frequency: 2 years