Continuing Education Activity

Intravenous midazolam is used for the induction of anesthesia and also in the management of acute seizures. Because of its water-soluble nature, midazolam has a rapid onset of action and can be used to manage status epilepticus when intravenous administration of other medications is not feasible. Midazolam can be used for anxiolysis and hypnosis during the maintenance phase of general anesthesia. Midazolam is an adjunct medication to regional and local anesthesia for a wide range of diagnostic and therapeutic procedures and has greater patient and clinician acceptance. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of midazolam, pertinent for members of the interprofessional team in the treatment of patients where it is of clinical value.

Objectives:

• Summarize the mechanism of action of midazolam.
• Describe the various indications where midazolam can be effective.
• Review the adverse event profile of midazolam.
• Summarize interprofessional team strategies for improving care coordination and communication to properly use midazolam to improve patient outcomes in the varied scenarios where it can be effective.

Indications

Intravenous midazolam is used for the induction of anesthesia and also in the management of acute seizures. Because of its water-soluble nature, midazolam has a rapid onset of action and can be used to manage status epilepticus when intravenous administration of other medications is not feasible. Midazolam has a high rate of tolerance, and the dose can be increased to maintain the therapeutic effect. Because of its easy mode of administration through the buccal and intranasal routes, it is a viable option in children to manage seizures. For its use in anesthesia, the response to the induction dose is more variable compared to thiopental. Midazolam can be used for anxiolysis and hypnosis during the maintenance phase of general anesthesia and is also superior to thiopental in the maintenance of anesthesia because of the less need for adjunct medications. Midazolam is an adjunct medication to regional and local anesthesia for a wide range of diagnostic and therapeutic procedures and has greater patient and physician acceptance.[1][2][3]

Mechanism of Action

Midazolam has poor oral absorption and has an elimination half-life of 1.5 to 2.5 hours. Midazolam converts into its active metabolite alpha-1 hydroxy midazolam, which contributes to 10% of drug action. Midazolam metabolism occurs via hepatic CYP450 enzymes and glucuronide conjugation. The mechanism of action of midazolam indirect and is related to GABA accumulation and its affinity to the benzodiazepine receptors. Two separate receptors for GABA and benzodiazepine couple to a common chloride channel. It increases the frequency of chloride channel opening. Occupation of both the receptors cause membrane hyperpolarization and neuronal inhibition. The anticonvulsant activity of midazolam is related to the excess GABA action on motor circuits in the brain. Midazolam acts on glycine receptors and produces a muscle-relaxing effect. Almost all the pharmacologic effects, including sedation, anxiolysis, anterograde amnesia, and anticonvulsant effect, can are explainable through its action on GABA receptors. Age-related deficits, hepatic, and renal insufficiency, also affect the pharmacokinetics of midazolam.[4][5][6][7] Midazolam has both hydrophilic and lipophilic properties, depending upon the pH.

Administration

Midazolam administration can be through oral, intranasal, buccal, intravenous, and intramuscular routes. For the perioperative use of midazolam, the induction dose is 0.15 to 0.40 mg/kg via the intravenous route. For the premedication, the dose is 0.07 to 0.10 mg/kg with the intramuscular route. For intravenous sedation, the dose is titrated at 0.05 to 0.15 mg/kg. For children 1 to 5 months old, the recommended intranasal dose is 0.2mg/kg. For children six months and older, 0.2 to 0.3 mg/kg intranasal dose is the recommendation.[1] Since elderly patients metabolize benzodiazepines more slowly and are more prone to adverse effects, caution is advised when administering the drug in that patient population.

Adverse Effects

The common adverse effects associated with midazolam use are hiccoughs, cough, nausea, and vomiting. Thrombophlebitis, thrombosis, and pain on injection are other adverse effects. The incidence of thrombophlebitis is less than with diazepam but similar to that of thiopental. Midazolam causes anterograde amnesia, drowsiness, ataxia, falls, and confusion in the elderly. Residual hangover effect can happen with nighttime administration of midazolam, which can impair the cognitive and psychomotor abilities, which can result in falls in elderly and impaired coordination during driving. Hypotension and tachycardia can occur with rapid intravenous administration. A higher dose can result in midazolam infusion syndrome and respiratory depression. Instances of midazolam infusion syndrome require continuous ventilator support. Paradoxical effects of midazolam are possible in individuals with a history of alcohol abuse and aggressive behavior, potentially leading to involuntary movements, verbalization, uncontrollable crying, and aggressive behavior. Respiratory depression can happen with a dose of 0.15 mg/kg, and the risk increases when used along with fentanyl. Concomitant use of midazolam with other CNS depressants can result in severe respiratory depression and death even at therapeutic doses.

Long-term use of midazolam is associated with lasting memory deficits, which are only partially reversible after discontinuing the drug. For pregnant women, the administration of the drug in the third trimester causes benzodiazepine withdrawal syndrome in the neonate resulting in hypotonia, cyanosis, and apnoeic spells. Neonates may suffer from diarrhea, tremors, and hyperexcitability. About one-third of individuals receiving midazolam can suffer from tolerance after using the drug for four weeks. Withdrawal syndrome can occur if the dose tapers too rapidly. Symptoms due to the withdrawal of benzodiazepine include irritability, clonus, hypertonicity, nausea, vomiting, diarrhea, tachycardia, and hypertension. Sudden discontinuation of midazolam can result in status epilepticus.[8][9][10][11]

Contraindications

Contraindications for the use of midazolam include acute angle-closure glaucoma, hypotension, and shock. Careful dose adjustment is necessary in cases of kidney and liver diseases, alcohol, and drug-dependent individuals. Caution is necessary for pregnant individuals, children, and individuals with comorbid psychiatric conditions. Administration in elderly individuals and acutely ill patients requires caution to prevent the accumulation of active metabolites. Extra precautions should be taken in critically ill individuals as dose accumulation can occur.[12][13]

Monitoring

Frequent monitoring of blood levels of midazolam and its metabolites is a requirement during the treatment of midazolam overdose. Levels of midazolam and its metabolites can are measurable in blood, plasma, and serum. Monitoring is essential for elderly individuals and individuals with liver and kidney disease. The elimination of both the drug and its metabolite decreases with renal insufficiency. Monitoring is also necessary for drug interactions with erythromycin, clarithromycin, diltiazem, sertraline, protease inhibitors, rifampin, phenytoin, phenobarbital, carbamazepine, opioids, antipsychotics, and alcohol. Induction and inhibition of CYP450 3A4 play a role in decreased and increased drug levels in the circulation. Grapefruit juice reduces the activity of the CYP 450 enzyme and increases the level of the drug. St. John's wort induces the enzyme and reduces the blood level of midazolam.[1][14][7]

Toxicity

Toxicity with midazolam is rare but can happen when combined with other CNS depressants like alcohol, opioids, and other tricyclic antidepressants. The risk increases with intravenous administration and in elderly individuals with COPD. Symptoms of overdose include ataxia, nystagmus, hypotension, slurred speech, slurred speech, impaired motor coordination, coma, and death. Impaired reflexes, impaired balance and dizziness, dysarthria, and vasomotor collapse can also occur. Flumazenil is the antidote for midazolam toxicity.[15] Supportive treatment is the initial therapy course. Activated charcoal is an option within 1 hour of intoxication. In many instances, flumazenil is not prudent, as it can precipitate seizures when used in a mixed overdose of CNS depressants. Rapid intravenous infusion in elderly individuals having COPD can also result in an overdose.[15][6]

Enhancing Healthcare Team Outcomes

All healthcare workers who use midazolam should know what to do in the event of an overdose. Resuscitative equipment and flumazenil must be available in the room when using this agent. The drug is relatively safe but is known to cause respiratory depression, especially when combined with fentanyl. Interprofessional teamwork that includes clinicians, mid-level practitioners, nurses, and pharmacists will yield better results and minimize adverse reactions with midazolam through coordinated monitoring and supportive patient counseling, leading to improved patient outcomes. [Level 5]

Review Questions

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References

1.

Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology. 1985 Mar;62(3):310-24. [PubMed: 3156545]

2.

Appleton R, Macleod S, Martland T. Drug management for acute tonic-clonic convulsions including convulsive status epilepticus in children. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD001905. [PubMed: 18646081]

3.

Walker M. Status epilepticus: an evidence based guide. BMJ. 2005 Sep 24;331(7518):673-7. [PMC free article: PMC1226249] [PubMed: 16179702]

4.

Richter JJ. Current theories about the mechanisms of benzodiazepines and neuroleptic drugs. Anesthesiology. 1981 Jan;54(1):66-72. [PubMed: 6109471]

5.

Spina SP, Ensom MH. Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. 2007 Mar;27(3):389-98. [PubMed: 17316150]

6.

Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;(182):335-60. [PubMed: 18175099]

7.

Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008 Aug;118(2):69-86. [PubMed: 18384456]

8.

Korttila K, Aromaa U. Venous complications after intravenous injection of diazepam, flunitrazepam, thiopentone and etomidate. Acta Anaesthesiol Scand. 1980 Jun;24(3):227-30. [PubMed: 6108669]

9.

Vermeeren A. Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18(5):297-328. [PubMed: 15089115]

10.

Mencía SB, López-Herce JC, Freddi N. Analgesia and sedation in children: practical approach for the most frequent situations. J Pediatr (Rio J). 2007 May;83(2 Suppl):S71-82. [PubMed: 17530139]

11.

McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol. 1994 Nov-Dec;8(6):461-75. [PubMed: 7881198]

12.

Suri Y. EVALUATION OF MIDAZOLAM AND DIAZEPAM FOR PRE-OPERATIVE SEDATION. Med J Armed Forces India. 2000 Oct;56(4):287-292. [PMC free article: PMC5532121] [PubMed: 28790742]

13.

Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008 Dec;64(12):1147-61. [PubMed: 18762933]

14.

Bushra R, Aslam N, Khan AY. Food-drug interactions. Oman Med J. 2011 Mar;26(2):77-83. [PMC free article: PMC3191675] [PubMed: 22043389]

15.

Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med. 1997 May-Jun;15(3):357-65. [PubMed: 9258787]

Disclosure: Thejasvi Lingamchetty declares no relevant financial relationships with ineligible companies.

Disclosure: Seyed Alireza Hosseini declares no relevant financial relationships with ineligible companies.

Disclosure: Abdolreza Saadabadi declares no relevant financial relationships with ineligible companies.