The selection of general anesthetics for patients with mitochondrial diseases is a serious concern due to anesthesia-associated risks, including malignant hyperthermia related to inhaled anesthetics or depolarizing muscle relaxants [3, 4], PRIS [5], hyperlactatemia [13, 14], and increased sensitivity to non-depolarizing muscle relaxants [17]. Most pediatric anesthesiologists in the USA choose inhaled anesthetics for GA because there is no clear evidence that they increase the risk of malignant hyperthermia in these patients [11]. Another report recommends propofol over inhaled anesthetics in patients with mitochondrial diseases because perioperative lactic acidosis occurs more frequently with inhaled anesthetics than with propofol [14]. Moreover, propofol is anti-epileptic, but some types of inhaled anesthetics are pro-epileptic [6]. Since propofol can depress mitochondrial function and cause PRIS [5], it should be administered carefully, especially in large doses or long-term administration. Compared to propofol, midazolam (benzodiazepine) has several advantages, including less circulatory depression, less injection pain, and has a specific antagonist (flumazenil) [7,8,9]. Benzodiazepines, as well as propofol, have an anti-epileptic effect. GA with midazolam is reportedly safe in patients with mitochondrial diseases [11]. However, because of its long half-life, it can cause delayed awakening and long-lasting respiratory depression [12]. Flumazenil can antagonize midazolam but also cause re-sedation and serious side effects, including epileptic seizures, by diminishing the benzodiazepine-related desirable effects [12].

Remimazolam may be a good choice in patients with mitochondrial diseases because it has midazolam-like pharmacological effects and an ultra-short-acting property that can avoid flumazenil use. Flumazenil can cause re-sedation after the antagonism of remimazolam [18,19,20] as well as midazolam [12]. In our report, the patient could wake up relatively soon (19 min) after remimazolam discontinuation without flumazenil use. Since she had low BIS values (approximately 30) intraoperatively, she might awaken more quickly if a lower dose of remimazolam were used and higher BIS values had been maintained. Although she could not tolerate wearing the oxygen mask after extubation, she revealed good oxygenation without oxygen supplement, indicating that remimazolam can awake fully soon and has no long-lasting respiratory depression effect.

Opioids and local anesthetics (regional anesthesia) are considered to be safe in patients with mitochondrial diseases [11]. In our case, intraoperative analgesia was provided by remifentanil, fentanyl, and TAP block. TAP block provided good post-operative analgesia presumably because the painful site was localized to the gastrostomy area. No requirement for post-operative opioids may be another reason for no postanesthesia respiratory depression.

Patients with mitochondrial diseases may have increased sensitivity to nondepolarizing muscle relaxants [17]. In this case, rocuronium at the dose of 0.3 mg/kg extinguished the ulnar nerve-stimulated twitch response and cough reflex during intubation. In ordinary adults, this dose is the 95% effective dose (ED95) in the adductor pollicis muscle but less than ED95 in the diaphragm (0.5 mg/kg) [21]. This fact might represent the patient’s increased sensitivity to rocuronium; however, there was no other apparent evidence of increased sensitivity, because the intraoperative rocuronium requirement was almost the same as usual.

In August 2022, we searched the PubMed database using the following keywords: <remimazolam> AND <MELAS> or <mitochondrial disease>. The results yielded two case report articles [22, 23], neither of which reported on pediatric cases. Since MELAS is a very rare disease, further reports are desirable for more appropriate anesthetic management.

In conclusion, we safely managed GA with remimazolam in a pediatric MELAS patient undergoing open gastrostomy. No intraoperative or early postoperative epileptic seizures occurred. Remimazolam could be a new anesthetic option for MELAS patients with epilepsy.

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