- midazolam is a benzodiazepine that is used to provide sedation
- it has also been used, after phenobarbital and phenytoin have failed, as an anticonvulsant
- 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.
- 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- there are several published (and unpublished) reports of infants who have experienced seizures following an IV bolus of midazolam.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- Ellis LJ: The use of midazolam in the NICU, Neonatal Pharmacology Quarterly 1993:2:31-35
- 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
- Fraser, Gil: Intranasal midazolam, Hospital Pharmacy 1992;27:73-74
- 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
- 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
- Turner S, Walsh K and Choonara I: Midazolam infusion in a pediatric intensive care unit (letter), The Annals of Pharmacotherapy 1993;27:791
- Wong L and McQueen KD: Midazolam routes of administration, The Annals of Pharmacotherapy 1991;25:475-6
- 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
- TaKetomo CK, Hodding JH and Kraus DM: Pediatric Dosage Handbook, 4th Edition (1997-98) Levi-Comp Inc, Cleveland
- Phelps SJ : Pediatric Injectable Drugs, 6th Edition, 2002, American Society of Health System Pharmacists.
- "Anexate © " Product Monograph, Compendium of Pharmaceuticals and Specialties, Canadian Pharmacists Association, 2002
Updated: 12 April 2002