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Disclaimer to the On-line Edition
This Manual has been designed for use in the NICU at London Health Sciences Centre (LHSC), London, Ontario, Canada, and represents clinical practice at this institution. The information contained within the Manual may not be applicable to other centres. If users of this Manual are not familiar with a drug, it is recommended that the official monograph be consulted before it is prescribed and administered. Any user of this information is advised that the contributors, Editor and LHSC are not responsible for any errors or omissions, and / or any consequences arising from the use of the information in this Manual.

MIDAZOLAM

Indication

  • midazolam is a benzodiazepine that is used to provide sedation
  • it has also been used, after phenobarbital and phenytoin have failed, as an anticonvulsant

Pharmacology

  • midazolam is a water-soluble benzodiazepine.
  • midazolam, like other benzodiazepine, interacts with gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, to produce a tranquilizing effect (limbic system), muscle relaxant effect (spinal cord) and hypnotic, sedative, and anticonvulsant effects (cerebral cortex).
  • midazolam is almost completely metabolized by the liver
  • hepatic metabolism is predominately by the CYP3A enzyme; erythromycin, for example can significantly inhibit the metabolism of midazolam, resulting in increased serum midazolam concentrations
  • the metabolites are eliminated by the kidney; therefore, patients in hepatic or kidney failure will likely require dosage modification.
  • the sedative effect following IV administration is evident in 3 to 20 minutes; the effectiveness has ranged in length from 2 to 12 hours.
  • a large variation in the plasma concentration (up to 20x difference) has been reported in infants less than 1 year old. Therefore, some infants may not have adequate serum levels to provide adequate sedation.

Side Effects

  • may cause central respiratory depression.
  • midazolam associated apnea is dose related and is also dependent on the rate of adminstration.
  • there are several published (and unpublished) reports of infants who have experienced seizures following an IV bolus of midazolam.

MIDAZOLAM SHOULD BE GIVEN WITH CAUTION, IF AT ALL, TO INFANTS WHO HAVE A HISTORY OF CEREBRAL COMPLICATIONS

Nursing Measures

  • ensure infant is on a cardiac respiratory monitor (midazolam may cause central respiratory depression).
  • regulary evaluate blood pressure.
  • monitor O2 saturation with pulse oximetry.
  • respiratory depression can intensify with concurrent narcotics (eg. morphine, fentanyl) or drugs that may interfere with the metabolism of midazolam (eg. erythromycin).

    REVERSAL OF EFFECTS OF MIDAZOLAM

    FLUMAZENIL, a benzodiazepine antagonist, reverses the effects of benzodiazepines such as midazolam.

    DOSE OF FLUMAZENIL:

    • 5 to 10 mcg/kg IV, every 5 minutes prn, up to 3 doses given by MD or CNS/NP only
    • given IV push over 15 seconds
    • may use undiluted (100 mcg/mL) or diluted
    • may cause pain or local inflammation
  • remember that midazolam provides sedation, NOT analgesia.
  • do NOT abruptly stop regularly scheduled midazolam; to avoid WITHDRAWAL (that could present as vomiting, diarrhea, decreased responsiveness, tachycardia, tongue thrusting, staring, irritability, agitation, facial grimacing and generalized seizures) the infant should be slowly weaned (10 to 20% per day) from the medication.

Dose

  • the conventional route of administration is IV or IM
  • IV (slow infusion):
    • 100 mcg/kg (0.1 mg/kg) IV slow infusion over 30 minutes
    • repeat as needed, usually every 2 to 6 hours
    • (the sedative effect is seen within 3 to 20 minutes.)

  • CONTINUOUS IV INFUSION:
    • 0.1 to 2 ug/kg/min (range suggested by most references)
    • infusion rates up to 6 ug/kg/min have been reported

  • RECTAL
    • 0.3 mg/kg (diluted in NaCl 0.9%) has been used in children to provide pre-operative sedation
    • sedative effect within 20-30 minutes.
    • in 1 study only 36% of children were adequately sedated following 0.3 mg/kg midazolam per rectum; in another study a single dose of midazolam 0.5 mg/kg rectally produced sedation in 97% of children; the onset of action was 15-20 min.

  • INTRANASAL
    • single doses of 0.2 to 0.3 mg/kg have provided sedation in infants and children. (administer approx 1/2 total volume into each nostril)
    • onset of action has been seen within 5 to 15 minutes.

  • IM
    • a single dose of midazolam, 0.05 to 0.1 mg/kg, has been given to children; time to reach sedation was 15-20 min.

Stability

  • midazolam is stable for at least 24 hours at room temperature in saline or dextrose mixtures.
  • physically campatible with morphine, meperidine and atropine
  • visually compatible during simulated Y-site injection with calcium gluconate, cefazolin, cefotaxime, cimetidine, clindamycin, digoxin, dopamine, fentanyl, gentamicin, methylprednisolone, metronidazole, nitroglycerin, sodium nitroprusside, tobramycin and vancomycin.
  • NOT compatible with ampicillin, ceftazidime, cefuroxime, dexamethasone, dobutamine, furosemide or sodium bicarbonate.

References

  1. Ellis LJ: The use of midazolam in the NICU, Neonatal Pharmacology Quarterly 1993:2:31-35
  2. Mantong ML and Marquardt ED: Visual compatibility of midazolam hydrochloride with selected drugs during simulated Y-site injection; Am J Health Sys Pharm 1995;52:2567-8
  3. Fraser, Gil: Intranasal midazolam, Hospital Pharmacy 1992;27:73-74
  4. Berman I, Steeves M, Burchart G and Thompson, MD: Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration, J Pediatr 1991;119:644-9
  5. Hughes J, Gill AM, Mulhearn H et al: Steady-state plasma concentrations of midazolam in critically ill infants and children, The Annals of Pharmacotherapy 1996;30:27-30
  6. Turner S, Walsh K and Choonara I: Midazolam infusion in a pediatric intensive care unit (letter), The Annals of Pharmacotherapy 1993;27:791
  7. Wong L and McQueen KD: Midazolam routes of administration, The Annals of Pharmacotherapy 1991;25:475-6
  8. Yaster M, Kost-Byerly S, Berde C and Billet C: The management of opioid and benzodiazepine dependence in infants, children and adolescents, Pediatrics 1996;98:135-40
  9. TaKetomo CK, Hodding JH and Kraus DM: Pediatric Dosage Handbook, 4th Edition (1997-98) Levi-Comp Inc, Cleveland
  10. Phelps SJ : Pediatric Injectable Drugs, 6th Edition, 2002, American Society of Health System Pharmacists.
  11. "Anexate " Product Monograph, Compendium of Pharmaceuticals and Specialties, Canadian Pharmacists Association, 2002

    Updated: 12 April 2002




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