Midazolam

Brand Names Reversal Agents Warnings
Description Special Circumstances Alternative Medications
Dosing Side Effects and Risks Contraindications
Over Sedation Common Issues  

Brand Names

Versed 

Description
  • Midazolam is a water-soluble, short-acting benzodiazepine central nervous system (CNS) depressant. Midazolam is water-soluble in an acidic solution (pH<3). After intravenous administration, midazolam undergoes an intramolecular reconfiguration at physiologic pH (7.4), increasing its lipid solubility. Midazolam is 1.5-3.5 times more potent than diazepam.
  • Midazolam is distinguished from the other benzodiazepines by its more rapid onset action and shorter duration effect.
  • The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.
  • Endoscopists prefer the use of midazolam instead of diazepam because of midazolam’s more rapid onset action and shorter duration effect.

How supplied

  • Package configurations containing midazolam hydrochloride equivalent to 5mg midazolam/mL:
    • 1-mL vials (5mg)—boxes of 25
    • 2-mL vials (10 mg)—boxes of 25
    • 5-mL vials (25 mg)—boxes of 10
    • 10-mL vials (50 mg)—boxes of 10
  • Package configurations containing midazolam hydrochloride equivalent to 1mg midazolam/mL:
    • 2-mL vials (2 mg)—boxes of 10
    • 2-mL vials (2 mg)—boxes of 25
    • 5-mL vials (5 mg)—boxes of 10
    • 10-mL vials (10 mg)—boxes of 10
Dosing

 

Midazolam Dosing for Endoscopic Sedation

Adult  

  • Initial dose:  1-2 mg
  • Additional doses: 1 mg administered at 2-minute intervals
  • Onset of action:  1-2 minutes
  • Peak effect: 3-4 minutes
  • Duration of effect:  15-80 minutes

Pediatric

  • Infants less than 6months*: limited information available for this age group; recommendations unclear
  • Infants and children ages 6 months to 12 years:
    • Initial dose: 0.05 mg/kg (maximum dose 2.5 mg)
    • Additional doses:  0.05 mg/kg (maximum dose 2.5mg) at 3 minute intervals until maximum dose is reached
    • Maximum dose: 0.3 mg/kg or 15mg, whichever is less

*Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl.

Notes:

  • Dose needs to be individualized based on age, underlying diseases, and concurrent medications. Individual response will vary with age, physical status and concomitant medications, but may also vary independent of these factors.
  • Midazolam should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect.
  • Decrease dose by approximately 30% if narcotics or other CNS depressants are administered concomitantly.
  • Personnel and equipment needed for standard respiratory resuscitation should be immediately available during midazolam administration.
Over Sedation

Symptoms

  • The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and untoward effects on vital signs. No evidence of specific organ toxicity from midazolam overdosage has been reported.

Treatment

  • Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines.
  • Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen.
  • Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures.
  • There is no information as to whether peritoneal dialysis, forced diuresis or hemodialysis are of any value in the treatment of midazolam overdosage.
  • Flumazenil is a specific benzodiazepine-receptor antagonist that is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected.
Reversal Agents
Special Circumstances
  • Withdrawal symptoms:
    • Withdrawal symptoms of the barbiturate type (e.g. dizziness, lightheadedness or faintness, anxiety or restlessness, hallucinations, vision problems, nausea and vomiting, seizures, weakness) have occurred after the discontinuation of benzodiazepines.
  • Use in pediatric patients:
    • The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients.
    • UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS.
    • As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults.
    • Younger (less than 6 years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.
    • In obese pediatric patients, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.
    • The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.
  • Use in patients age 60 or older, and debilitated or chronically ill patients:
    • Because the danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve, and because the peak effect may take longer in these patients, initial dosing should be half the recommended adult dose with additional doses of half the recommended adult dose administered at 2 minute intervals.
    • Patients over age 70 may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia.
    • Titrate slowly to the desired effect (e.g., the initiation of slurred speech). Some patients may respond to as little as 1 mg. No more than 1.5 mg should be given over a period of no less than 2 minutes. Wait an additional 2 or more minutes to fully evaluate the sedative effect.
    • If additional titration is necessary, it should be given at a rate of no more than 1 mg, waiting an additional 2 or more minutes each time to fully evaluate the sedative effect.
    • Additional doses to maintain the desired level of sedation may be given in increments 1 mg administered with 2 minute intervals between doses , but again only by slow titration, especially in the elderly and chronically ill or debilitated patient.
    • These additional doses should be given only after a thorough clinical evaluation clearly indicates the need for additional sedation.
    • Administration of IM and IV midazolam to elderly and/or high risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics.
  • Use in pregnancy:
    • An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies.
    • If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.
  • Use in labor and delivery:
    • In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug.
  • Use in nursing mothers:
    • Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman.
  • Disease-related concerns:
    • Heart failure: use with caution.
    • Impaired gag reflux: use with caution.
    • Renal impairment: use with caution.
    • Respiratory disease: use with caution.
Side Effects and Risks
  • Drug Interactions:
    • Anesthetics, inhalation: Inhalation anesthetics may need to be reduced if midazolam is used as an induction agent. IV administration decreases minimum alveolar concentration of halothane required for general anesthesia.
    • Azole antifungal agents: Serum concentration of certain benzodiazepines may be increased and prolonged, producing enhanced CNS depression and prolonged effects.
    • Barbiturates, alcohol, other CNS depressants: May prolong effect and increase risk of underventilation or apnea.
    • Cimetidine: May increase midazolam levels.
    • Contraceptives, oral: coadministration may result in prolongation of benzodiazepine half-life.
    • Droperidol, narcotics, secobarbital: may accentuate hypnotic effect of midazolam.
    • Alcohol: increased CNS effects with acute ethanol ingestion.
    • Fluvoxamine: reduced clearance, prolonged half-life, and increased serum concentrations of certain benzodiazepines may occur. Sedation or ataxia may be increased.
    • Indinavir: possibly severe sedation and respiratory depression.
    • Propofol: pharmacologic effects of propofol may be increased.
    • Rifamycins: pharmacokinetic parameters of benzodiazepines may be altered.
    • Ritonavir: possibly severe sedation and respiratory depression.
    • Theophyllines: sedative effects of benzodiazepines may be antagonized.
    • Thiopental: moderate reduction in induction dosage requirements has been noted following use of IM midazolam for premedication.
    • Valproic acid: pharmacokinetic parameters of benzodiazepines may be increased. Liver metabolism may be decreased.
    • Verapamil: effects of certain benzodiazepines may be increased, producing increased CNS depression and prolonged effects.
  • Drug Incompatibility: Dimenhydrinate, pentobarbital, perphenazine, prochlorperazine, ranitidine.
  • Drug Abuse and Dependence:
    • Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970.
    • Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
Common Issues
  • Intravenous midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted.
  • Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease and apnea as well as variations in blood pressure and pulse rate.
  • The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures).
  • Other adverse reactions include:
    • Respiratory.  Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea
    • Cardiovascular. Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm
    • Gastrointestinal. Acid taste, excessive salivation, retching
    • CNS/Neuromuscular. Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia
    • Special Senses. Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness
    • Integumentary. Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site
    • Hypersensitivity. Allergic reactions including anaphylactoid reactions, hives, rash, pruritus
    • Miscellaneous. Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma
Warnings

BOXED WARNING

Adult and Pediatrics  

  • Intravenous midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted.
  • Intravenous midazolam should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, ie, pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured.
  • For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.
  • The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation may be considered to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam HCl for sedation/anxiolysis/amnesia is age, procedure and route dependent.

 

  • Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression.
  • Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.
  • Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, ie, pulse oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period.
  • Because intravenous midazolam depresses respiration and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation.
  • When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population.
  • Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic.
  • Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.
  • Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.
  • Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly. Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.
  • Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.
  • There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.
  • The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously.
  • The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.
Alternative Medications
Contraindications
  • Midazolam injection is contraindicated in patients with a known hypersensitivity to the drug or any component of the formulation including benzyl alcohol.
  • Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied.

Sources

Cohen LB et al. AGA Institute Review of Endoscopic Sedation, Gastroenterology. 2007 Aug;133(2):675-701

Midazolam Hydrochloride Injection [package insert], Baxter Healthcare Corporation. October 2006. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2147  Accessed April 20, 2008.

Midazolam hydrochloride. Professional Information: A-Z Drug Facts. March 12, 2008.  http://www.drugs.com/ppa/midazolam-hydrochloride.html   Accessed April 28, 2008.

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