How does midazolam cause aphasia in a patient postoperatively and what is the optimal dose of flumazenil to give to treat the aphasia?

How does midazolam cause aphasia in a patient postoperatively and what is the optimal dose of flumazenil to give to treat the aphasia?

Comment by InpharmD Researcher

It is theorized that midazolam could affect the GABA receptors within the Broca’s area of the anterior brain region which can lead to impairment in language comprehension. Some patients were unaware of the episode, but others recall being panicked as they were unable to speak. Initial flumazenil intravenous doses ranging from 0.2 to 0.5 mg have demonstrated rapid resolution within minutes in most patients.

Background

Drugs with GABAergic mechanisms have the potential to confer a deficit in neurological motor and language function. Expressive aphasia (EA) or Broca’s aphasia is thought to reversibly affect the anterior region of the brain which includes the Broca’s area. Midazolam binds to and potentiates GABAs inhibitory effects on the gamma-aminobutyric acid type A (GABA-A) receptor. GABA-A receptors are found within the neurons of the Broca’s speech region on Brodmann areas 44 and 45. Therefore, it is believed that midazolam could potentiate the GABA-A receptors within Broca’s area and cause impairment in language comprehension. This theory is further supported by the effects of flumazenil, a competitive antagonist of the GABA-A receptor, which has successfully treated postoperative emergence delirium related to midazolam. [1], [2], [3]

Relevant Prescribing Information

Management of Suspected Benzodiazepine Overdose in Adults:

Flumazenil was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received flumazenil responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. [1]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

How does midazolam cause aphasia in a patient postoperatively and what is the optimal dose of flumazenil to give to treat the aphasia?

Please see Tables 1-2 for your response.

Postoperative expressive aphasia associated with intravenous midazolam administration: a 5-year retrospective case-control study
Design	Retrospective, single-center, case-control study N= 6,756
Objective	To investigate the epidemiology of intravenous midazolam-induced postoperative expressive aphasia
Study Groups	Aphasia (n= 12) No aphasia (n= 6,744)
Inclusion Criteria	Patients who underwent anesthesia for elective orthopedic surgery
Exclusion Criteria	Patients who bypassed the recovery room, were unable to communicate in the recovery room
Methods	Patients who underwent elective orthopedic surgery with anesthesia at a single center in South Korea were subdivided into those who received midazolam and those who did not. For preoperative sedation, midazolam (0.5 to 2 mg) was administered intravenously to adults in the holding room. In the no-midazolam group, there were cases of patient refusal, no administration based on the surgeon’s request, documented allergy to midazolam, and history of delirium after sedation. General anesthesia was induced using propofol (1 to 2.5 mg/kg) with rocuronium (0.8 mg/kg) in adult patients. After inducing regional anesthesia, a propofol infusion (100 to 200 mg/hour) was initiated to maintain intraoperative sedation with additional doses of midazolam (2 to 3 mg) if needed. Patients and controls were also divided based on the occurrence of expressive aphasia. Expressive aphasia was defined as patients with no neurological deficits unable to speak in the recovery room despite their intention to speak. If the recovery room nurse informed the anesthesiologist of a suspected aphasia case, they were given flumazenil 0.2 mg after a brief neurological examination. If the initial flumazenil dose did not have an immediate response, it could be administered repeatedly up to a total dose of 0.5 mg.
Duration	March 2011 to May 2016
Outcome Measures	Incidence of aphasia
Results		Expressive aphasia (n= 12)	No aphasia (n= 6,166)	p-value
	Age, years	70 ± 9	58 ± 18	0.02
	Female	11 (92%)	3,658 (59%)	0.02
	General anesthesia General only General + nerve block	9 (75%) 4 (33%) 5 (42%)	2,700 (44%) 1,269 (21%) 1,431 (23%)	0.03
	Overall, the average age was 57 years, and 57% of patients were female. The dose of midazolam use, anesthesia time, and American Society of Anesthesiologists (ASA) class did not differ significantly between patients who experienced and did not experience aphasia.
Aphasia Patient Characteristics	Age/Sex	ASA Class	Operation time	Midazolam dose	Flumazenil dose	Time to recovery
	80/M	2	175 mins	1 mg	0.2 mg	3 mins
	F/59	2	170 mins	2 mg	0.5 mg	90 mins
	F/59	1	140 mins	5 mg	0.5 mg	150 mins
	F/72	2	135 mins	1 mg	0.5 mg	5 mins
	F/77	2	160 mins	1 mg	0.2 mg	5 mins
	F/59	1	170 mins	2 mg	0.4 mg	5 mins
	F/56	3	110 mins	2 mg	0.2 mg	3 mins
	F/71	2	140 mins	2 mg	0.2 mg	3 mins
	F/77	2	150 mins	2 mg	0.2 mg	3 mins
	F/81	2	105 mins	2 mg	0.5 mg	60 mins
	F/70	2	220 mins	1 mg	0.3 mg	5 mins
	F/73	2	170 mins	1 mg	0.4 mg	3 mins
	The mean flumazenil dose used to reverse aphasia was 0.3 mg. Nine of 12 (75%) patients with EA experienced relief of their EA within 4 minutes of flumazenil administration. Six of these 12 patients (50%; mean age, 75 years) could not recall being unable to speak at the time of the aphasia episode, while one more patient was unable to communicate because of a perioperative cerebral vascular incident. Of the remaining five patients (mean age, 61 years) who recalled the aphasia episode, four were panicked by the idea that they would never be able to speak again. All aphasia patients showed negative results on neurological examination by the neurologist, and the brain MRI study results were also negative.
Study Author Conclusions	Intravenous midazolam administration for preoperative sedation caused transient expressive aphasia in 0.19% of patients, especially elderly women who received general anesthesia, and expressive aphasia could be reversed by flumazenil. Rapid diagnosis and proper treatment can minimize the duration of this terrifying state.
InpharmD Researcher Critique	This study is limited by the single-center nature of elderly patients from an institution in South Korea. Nine of the 12 (75%) aphasia patients recovered within 4 minutes of flumazenil, which suggest the aphasia was an adverse effect of midazolam. But this study cannot exclude the possibility of a transient ischemic attack (TIA) in the three patients who did not respond to flumazenil. Additionally, because the incidence of aphasia was so small (12/6,178; 0.19%), it is impossible to determine odds ratios or use a logistic regression to determine risk factors.

References:

Oh S, Chung J, Baek S, Park YJ. Postoperative expressive aphasia associated with intravenous midazolam administration: a 5-year retrospective case-control study. J Int Med Res. 2020;48(8):300060520948751. doi:10.1177/0300060520948751

Emergence Delirium with Transient Associative Agnosia and Expressive Aphasia Reversed by Flumazenil in a Pediatric Patient
Design	Case report
Case Presentation	A 12-year-old girl who was otherwise healthy was scheduled for removal of a small abdominal wall nervus. The patient received midazolam 10 mg over 40 minutes before inhaled induction via nitrous oxide and sevoflurane. The procedure lasted 13-minutes and was uneventful until awakening in the postanesthesia care unit (PACU). The patient began crying and hyperventilating, became anxious, unable to speak, and unresponsive to parent's attempt to console her. Vital signs were normal aside from increased respiratory rate. Pediatric Anesthesia Emergence Delirium score was marked as 13 which corresponded with a diagnosis of emergence delirium (ED) and the patient was given flumazenil 0.2 mg IV which produced an instant calming effect. The patient remembered the entire incident and was aware of their surrounding but was unable to speak. She did not completely recognize her parents during the episode and her anxiety and crying was attributed to her inability to speak and relate to those around her. Pain or nausea was denied. The patient was discharged 2 hours later and an interview several months later did not reveal any concerns. The interview revealed that the patient was startled during the episode but administration of flumazenil immediately projected a "cooling, relaxing, calming effect" that led to full recognition of parent identity.
Study Author Conclusions	Postanesthetic ED with transient associative agnosia and expressive aphasia may occur with the atypical offset of midazolam. This phenomenon may be obscured by the drug’s amnestic properties and may be difficult to detect in younger, less articulate children. Rapid emergence and, though not a factor in the present case, untreated pain triggering sudden changes in arousal state, are likely contributory. Patients experiencing these reactions should be treated in a calm manner because forceful voices can be frightening to both patients and parents. Expeditious diagnosis and proper treatment can minimize the duration of this terrifying state. Further work is needed to determine which patients are predisposed to this phenomenon so that they can be identified and managed appropriately.

References:

Drobish JK, Kelz MB, DiPuppo PM, Cook-Sather SD. Emergence delirium with transient associative agnosia and expressive aphasia reversed by flumazenil in a pediatric patient. A A Case Rep. 2015;4(11):148-150. doi:10.1213/XAA.0000000000000140