Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review

Abstract

Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents. Although this occurrence could affect virtually any patient during the perioperative time, the pediatric population is particularly vulnerable, and it has a five-fold higher incidence in children compared to adults. In the last few decades, synergistic efforts among leading anesthesiology, pediatrics, and neurology associations have produced new evidence concerning the diagnostic pathway, avoiding unnecessary testing and limiting false diagnoses. However, a personalized approach and an effective prevention policy focused on clearly recognizing the high-risk population, defining perioperative trigger-free hospitalization, and rapid activation of supportive therapy should be improved. Based on epidemiological data, many national scientific societies have produced consistent guidelines, but many misconceptions are common among physicians and healthcare workers. This review shall consider all these aspects and summarize the most recent updates.

Full text

Citation: Frassanito, L.; Sbaraglia, F.;
Piersanti, A.; Vassalli, F.; Lucente, M.;
Filetici, N.; Zanfini, B.A.; Catarci, S.;
Draisci, G. Real Evidence and
Misconceptions about Malignant
Hyperthermia in Children: A
Narrative Review. J. Clin. Med. 2023,
12, 3869. https://doi.org/10.3390/
jcm12123869
Academic Editor: Nina Bariši´c
Received: 29 April 2023
Revised: 29 May 2023
Accepted: 3 June 2023
Published: 6 June 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Journal of
Clinical Medicine
Review
Real Evidence and Misconceptions about Malignant
Hyperthermia in Children: A Narrative Review
Luciano Frassanito 1, * , Fabio Sbaraglia 1, Alessandra Piersanti 1, Francesco Vassalli 2, Monica Lucente 1,
Nicoletta Filetici 1, Bruno Antonio Zanfini 1, Stefano Catarci 1and Gaetano Draisci 1
1Department of Scienze dell’Emergenza, Anestesiologiche e della Rianimazione—IRCCS Fondazione
Policlinico A. Gemelli, 00168 Rome, Italy; fabio.sbaraglia@policlinicogemelli.it (F.S.);
alessandrapiersanti83@gmail.com (A.P.); monicalucente@gmail.com (M.L.);
nicoletta.filetici@policlinicogemelli.it (N.F.); brunoantonio.zanfini@policlinicogemelli.it (B.A.Z.);
stefano.catarci@policlinicogemelli.it (S.C.); gaetano.draisci@policlinicogemelli.it (G.D.)
2Department of Critical Care and Perinatal Medicine, Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS), Istituto Giannina Gaslini, 16147 Genoa, Italy; francescovasssalli@gmail.com
*Correspondence: luciano.frassanito@policlinicogemelli.it; Tel.: +39-630154507; Fax: +39-63013450
Abstract:
Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered
by exposure to specific anesthetic agents. Although this occurrence could affect virtually any pa-
tient during the perioperative time, the pediatric population is particularly vulnerable, and it has a
five-fold higher incidence in children compared to adults. In the last few decades, synergistic efforts
among leading anesthesiology, pediatrics, and neurology associations have produced new evidence
concerning the diagnostic pathway, avoiding unnecessary testing and limiting false diagnoses. How-
ever, a personalized approach and an effective prevention policy focused on clearly recognizing
the high-risk population, defining perioperative trigger-free hospitalization, and rapid activation of
supportive therapy should be improved. Based on epidemiological data, many national scientific
societies have produced consistent guidelines, but many misconceptions are common among physi-
cians and healthcare workers. This review shall consider all these aspects and summarize the most
recent updates.
Keywords:
malignant hyperthermia; pediatric anesthesia; general anesthesia; personalized medicine;
genetic screening; patient safety; dantrolene
1. Introduction
Since the beginning of the 20th century, cases of increased body temperature related to
general anesthesia (GA) have been observed, and several reports referred to complications
and anesthesia-related deaths, often described as “ether convulsions” [1,2].
Malignant hyperthermia (MH) is a rare but life-threatening heterogeneous pharmaco-
genetic disorder due to the dysfunction of skeletal muscle calcium channels, triggered by
exposure to volatile halogenated anesthetics (desflurane, isoflurane, sevoflurane, halothane)
and the depolarizing muscle relaxant succinylcholine, which results in abnormal contrac-
tion and a hypermetabolic state at the level of the myocyte that rapidly leads to ATP
depletion, rhabdomyolysis, and heat production [
3
–
6
]. It was first described in 1962 as
cases occurring in a single family by Denborough et al., when the authors reported a
21-year-old student who, when admitted to the Royal Melbourne Hospital in Australia for
a leg fracture, was more concerned about receiving GA than about his fracture because
10 of his family members had died during or after GA, usually administered for minor
procedures [3].
2. Epidemiology
Many physicians may believe that MH is so rare that most professionals will probably
never face a case. However, there is a wide-ranging estimate of MH incidence [
7
]. The
J. Clin. Med. 2023,12, 3869. https://doi.org/10.3390/jcm12123869 https://www.mdpi.com/journal/jcm

J. Clin. Med. 2023,12, 3869 2 of 18
actual frequency of perioperative MH is challenging to estimate due to reluctance to publish
adverse events, frequent misdiagnosis, and even poor adherence to pharmacovigilance
registries [
6
–
9
]. Although most reported MH crises (>80%) occur in phenotypically normal
children without a family history of MH-related comorbidities, we know that malignant
hyperthermia susceptibility (MHS) is an autosomal dominant genetic condition that shows
incomplete penetrance and affects all ethnic groups [
6
,
7
]. It is more common in males
than females (2:1), with an estimated incidence of 1:10,000 in children and 1:50,000 in
adults [
10
]. Indeed, MH mainly affects young patients, with a mean age of 18.3 years,
probably due to increased penetrance in children, which, in turn, varies according to a
specific genetic variant [
6
,
10
–
12
]. A higher concentration of MH-susceptible families is
reported in Wisconsin and the upper Midwest in the United States [13].
3. Pathophysiology
The root cause of MH is a dysfunction of excitation–contraction coupling in skeletal
muscles, leading to excessive intracellular calcium (Ca2+) release (Figure 1).
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 2 of 18
2. Epidemiology
Many physicians may believe that MH is so rare that most professionals will
probably never face a case. However, there is a wide-ranging estimate of MH incidence
[7]. The actual frequency of perioperative MH is challenging to estimate due to reluctance
to publish adverse events, frequent misdiagnosis, and even poor adherence to
pharmacovigilance registries [6–9]. Although most reported MH crises (>80%) occur in
phenotypically normal children without a family history of MH-related comorbidities, we
know that malignant hyperthermia susceptibility (MHS) is an autosomal dominant
genetic condition that shows incomplete penetrance and affects all ethnic groups [6,7]. It
is more common in males than females (2:1), with an estimated incidence of 1:10,000 in
children and 1:50,000 in adults [10]. Indeed, MH mainly affects young patients, with a
mean age of 18.3 years, probably due to increased penetrance in children, which, in
turn, varies according to a specific genetic variant [6,10–12]. A higher concentration
of MH-susceptible families is reported in Wisconsin and the upper Midwest in the
United States [13].
3. Pathophysiology
The root cause of MH is a dysfunction of excitation–contraction coupling in skeletal
muscles, leading to excessive intracellular calcium (Ca
2+
) release (Figure 1).
Figure 1.
Role of dysfunction in the mechanism of excitation
–
contraction coupling in
skeletal muscles primarily due to mutations in type 1 RyR1, Cav1.1, or STAC3
accessory protein in determining susceptibility to MH. Calcium release and uptake
(arrows) is in equilibrium.
In susceptible patients, exposure to halogenated volatile anesthetics (halogenate),
depolarizing muscle relaxant succinylcholine, exercise, or heat could trigger an acute MH
crisis characterized by excessive Ca
2+
release (red arrow) from the sarcoplasmic reticulum
with abnormal contraction and hypermetabolic state at the level of the myocyte that
rapidly leads to ATP depletion, rhabdomyolysis, hyperkaliemia, and heat production.
Figure 1.
Role of dysfunction in the mechanism of excitation–contraction coupling in skeletal muscles
primarily due to mutations in type 1 RyR1, Cav1.1, or STAC3 accessory protein in determining
susceptibility to MH. Calcium release and uptake (arrows) is in equilibrium.
In susceptible patients, exposure to halogenated volatile anesthetics (halogenate),
depolarizing muscle relaxant succinylcholine, exercise, or heat could trigger an acute MH
crisis characterized by excessive Ca
2+
release (red arrow) from the sarcoplasmic reticulum
with abnormal contraction and hypermetabolic state at the level of the myocyte that rapidly
leads to ATP depletion, rhabdomyolysis, hyperkaliemia, and heat production. Dantrolene
sodium, a post-synaptic muscle relaxant, can effectively revert an MH crisis by inhibiting
RyR1-mediated intracellular calcium release from the sarcoplasmic reticulum of skeletal
muscle cells (red blunted arrow).
RyR1: ryanodine receptor. Cav1.1: L-type voltage-gated calcium channel. MH: malig-
nant hyperthermia. Ach: acetylcholine. NachR: nicotinic acetylcholine receptor.
F
Ca
++
:
calcium. Sux: succinylcholine. SERCA: sarcoendoplasmic reticulum calcium ATPase.

J. Clin. Med. 2023,12, 3869 3 of 18
ATP: adenosine triphosphate. SR: sarcoplasmic reticulum. +++: end-plate potential.
‡‡‡
:
prolonged end-plate potential.
Under physiologic conditions, following the release of acetylcholine at the neuromus-
cular junction, activation of the nicotinic receptor, and depolarization of the cell membrane,
the dihydropyridine receptor (DHPR, also known as L-type voltage-gated calcium channel
Cav1.1) on the T-tubular membrane is activated, and after direct interaction with Type 1
ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) membrane, Ca
2+
stored in
the SR is released and becomes available for stimulation of the contractile apparatus [
14
].
Following muscle contraction, the sarcoendoplasmic reticulum calcium ATPase (SERCA)
pump acts to transport Ca2+ from the cytosol back to the SR.
In MH, the leading abnormality is due to mutations in the gene RYR1, on chromosome
19q13.1, encoding for RyR1: missense mutations alter the receptor with gain-of-function
mutations, inducing increased Ca
2+
release into the cytoplasm [
11
]. Mutations in the
gene RYR1 are also associated with three congenital myopathies and an isolated case
of congenital myopathy characterized on histology by cores and rods [
11
]. More rarely,
mutations in the
α
1 subunit of DHPR encoded by the gene CACNA1S may be involved:
by suppressing the Ca
2+
voltage-gated channel’s regulatory effect on RyR1, those variants
can also cause an increased Ca
2+
flux through the receptor [
13
,
14
]. Finally, mutations have
been identified in the STAC3 accessory protein, required to correctly locate the calcium
voltage-gated receptor within the skeletal muscle channel: those variants determine an
increased amount of Ca
2+
released in response to caffeine (a RyR1 agonist) and increase the
amount of Ca
2+
stored within the SR [
11
–
14
]. However, the paucity of clinical information
surrounding the MH (or MH-like) episodes noted in patients with STAC3 variants, and the
lack of robust experimental evidence in
in vitro
contracture testing, casts some doubt on an
association between STAC3 variants and MHS [11–18].
3.1. Anesthetic-Induced MH
The most well-known risk factor for MH is the use of volatile anesthetic agents, such
as halothane, isoflurane, sevoflurane, desflurane, and the depolarizing skeletal muscle
relaxant succinylcholine [
5
,
6
,
8
]. Halothane-induced MH seems to contribute to most
MH crises; however, of all volatile anesthetics, the prevalence of MH was highest when
using sevoflurane [
19
]. Succinylcholine administered alone is reported to trigger adverse
events in approximately 15.5% of MHS patients [
20
]. Combining inhaled anesthetic agents
and succinylcholine can significantly increase the risk of MH. Although rare, one report
suggested a triggering role for amide local anesthetics (lidocaine and bupivacaine), but
it has never been confirmed [
21
]. Considering the broad use of local anesthetics in the
susceptible population without new reports and the possibility of some unrecognized
interaction with volatile agents, a relationship seems to be unlikely [22].
3.2. Non-Anesthetic Induced MH
MH may occur upon exposure to other factors, even in the absence of classic anesthetic
triggering agents. Increasing evidence indicates that environmental heat stroke and exertion
rhabdomyolysis caused by vigorous exercise and environmental heat can induce a life-
threatening hyperthermic crisis in susceptible individuals [
23
–
25
]. The availability of an
animal model of MH, as certain breeds of pigs were found by chance to be susceptible to
this anesthetic complication and to have an underlying muscle disease, provided additional
evidence [
18
]. It has been demonstrated that overheating alone can trigger fatal MH in
susceptible experimental piglets, thus supporting the association between MHS and heat
stroke in humans and between MHS and sudden infant death syndrome, which may be
due to overheating [
18
]. Some patients with environmental heat stroke have been found
to have histories or family histories of MH or an association among MH-related genetic
defects [
26
–
29
]. A rare case of a non-anesthetic, stress-induced hyperpyrexia death was
described in a 12-year-old male who experienced an MH crisis during a humerus fracture

J. Clin. Med. 2023,12, 3869 4 of 18
operation and 8 months later presented MH followed by sudden death after exertion [
27
].
Furthermore, emotional stress may also cause or contribute to stress-induced MH [
30
–
33
].
4. Disorders Associated with Malignant Hyperthermia
The literature recognizes several myopathies associated with MHS and suggests
several others (Table 1) [34,35].
Table 1. Neuromuscular weakness classification for HM risk.
Disease Evidence in Adults Evidence in Children Suggested
Perioperative Pathway
Upper motor neurons disease
Amyotrophic lateral sclerosis None None standard
Myelin sheath disease
Multiple sclerosis None None Standard
Guillain–Barrésyndrome None None Standard
Chronic inflammatory
demyelinating polyneuropathy None None Standard
Alexander disease None None Standard
Krabbe disease None None Standard
Adrenoleukodystrophy None None Standard
Neuromyelitis optica spectrum disorders None None Standard
Neuromuscular junction disease
Miastenia gravis None None Standard
Muscular Dystrophy
Duchenne muscular dystrophy Mild Mild Trigger-Free
Congenital muscular dystrophy Mild Mild Trigger-Free
Facioscapulohumeral muscular dystrophy Mild Mild Trigger-Free
Emery–Dreifuss muscular dystrophy Mild Mild Trigger-Free
Becker muscular dystrophy Mild Mild Trigger-Free
Channel disease
Myotonia congenita None None Standard
Hypokalemic periodic paralysis Strong Strong Trigger-Free
Central core disease Strong Strong Trigger-Free
Cellular Metabolism disease
Mitochondrial disease None None Standard
Kearns–Sayre syndrome None None Standard
Glycogen storage disease None None Standard
Lipid storage disorder None None Standard
Other
Neonatal Palsy None None Standard
Traumatic Damage None None Standard

J. Clin. Med. 2023,12, 3869 5 of 18
Motor neuron diseases are one of the most implicated in this context. For example,
amyotrophic lateral sclerosis and spinal muscular atrophy involve the degeneration of
motor neurons, thus causing weakness, muscle atrophy, and spasticity, and therefore do
not confer an increased probability of MHS [35].
Myelin sheath disorders are another series of disorders that may cause weakness but
do not directly affect the muscle fiber and therefore do not increase susceptibility to MH [
36
].
However, areas of demyelination may be more prone to toxicity by local anesthetics; thus,
GA may be preferred [36].
Autoimmune disorders (myasthenia gravis and Lambert–Eaton syndrome) are charac-
terized by the presence of pathogenic antibodies directed against the acetylcholine receptor
at the neuromuscular junction, and although they may cause abnormal responses to de-
polarizing and non-depolarizing neuromuscular blocking agents, they do not increase
MHS [36,37].
Similarly, dystrophic and non-dystrophic myotonic syndromes, a broad class of rare
multisystemic myopathies clinically characterized by a combination of myotonia (impair-
ment of muscle relaxation after voluntary contraction), muscle weakness, wasting, and
myalgia due to genetic defects which involve the muscular isoforms of various ion chan-
nels, have traditionally, albeit erroneously, been considered at increased risk of developing
MH [
35
]. Patients with these myopathies have a chance of developing MH that is equivalent
to that of the general population, with one exception, represented by hypokalemic periodic
paralysis (HypoPP), in most cases caused by mutations in the skeletal muscle voltage-gated
Ca
2+
channel encoded by CACNA1S (HypoPP type 1) [
36
]. However, the latest research
shows that myotonic patients with MH crisis can have mutations at two distinct genetic loci,
one for myotonia and one for MHS [
14
,
38
]. Therefore, although episodes occurred without
evidence of the MH hallmark of hypermetabolism, non-triggering anesthetics should be
recommended to reduce the risk of rhabdomyolysis [38].
The dystrophinopathies, which include Duchenne and Becker muscular dystrophy,
cover a spectrum of X-linked muscle diseases, usually presenting in early childhood, charac-
terized by progressive proximal muscle weakness and muscle fiber degeneration [
37
,
39
]. In
addition, there are some concerns about the risk of MH because, in these patients, phenom-
ena of volatile anesthetic-induced rhabdomyolysis and hyperkalemia are described [
37
,
39
].
A very challenging category of neuromuscular syndromes is that of mitochondrial
diseases [
40
]. Kearns–Sayre syndrome, mitochondrial encephalomyopathy, lactic acidosis,
stroke-like episodes (MELAS), or Leigh syndrome could be manifested in many overlap-
ping patterns, but pediatric onset is generally more severe [
40
]. Because patients with
mitochondrial diseases demonstrate hypersensitivity to volatile anesthetics, many practi-
tioners avoid using volatile agents [
41
]. However, evidence denies any connection between
mitochondrial disease and MH [
42
]. On the contrary halogenated agents characterized by
rapid elimination (sevoflurane, desflurane) can be used, but caution should be paid to the
increased risk of developing propofol-related infusion syndrome [42].
Some reports put rare or very rare diseases and metabolic syndromes under the MH
spotlight, although the literature does not support suspicions in most cases. For example,
glycogen storage diseases are not considered at risk of MH due to unclear metabolic
adverse events described in some reports [
43
]. All anesthetic agents have been used for
GA in children with Pompe disease, but no complication could be clearly associated with
clinical MH [
44
]. Similarly, McArdle’s disease has been considered in the MH group for
two patients testing positive for the
in vitro
contracture test and atypical reactions [
44
].
McArdle’s patients are probably more susceptible to muscle cramps, which may cause
diagnostic confusion [
44
]. Patients with Noonan syndrome share a similar phenotypic
appearance with King–Denborough syndrome, including pterygium colli, down-slanting
palpebral fissures, eyelid ptosis, short stature, and pectus excavatum, and have long
been associated with an increased risk of MH [
45
,
46
]. However, the absence of proof
emerging from the literature, along with knowledge of the genetic basis of the 2 disorders
(mutation on chromosome 19 near the gene that encodes the ryanodine receptor in the

J. Clin. Med. 2023,12, 3869 6 of 18
King–Denbourough syndrome and on chromosome 12 for the Noonan syndrome) led to
the exclusion of MHS in Noonan syndrome patients [45,46].
Myopathies clearly recognized to be associated with MH are masseter muscle rigid-
ity (MMR), central core disease (CCD), multi-mini core disease (MmD), centronuclear
myopathy, HypoPP, Native American myopathy (NAM), and King–Denbourough syn-
drome [6–10,12,47].
Succinylcholine-induced MMR occurs in 1 in 100 children after induction with inhaled
anesthesia and succinylcholine administration, and the clinical incidence of MH after MMR
is estimated to be 15% [
48
–
50
]. However, muscle biopsy reveals that 50% of patients
experiencing MMR show MHS [
49
]. CCD refers to a rare non-progressive myopathy
caused by an RYR1 mutation with mainly autosomal dominant inheritance, presenting in
infancy, characterized by hypotonia and muscle weakness, sustained by a predominance of
type I muscular fibers containing clearly defined areas (cores) lacking oxidative enzyme
activity [
51
–
54
]. The mutation of RYR1 in CCD implies insufficient Ca
2+
concentration in
the cytoplasm, causes excitation–contraction decoupling, and finally leads to clinical muscle
weakness [
53
–
55
]. These patients often demonstrate MHS, but MH and CCD phenotypes
do not always co-segregate within families [
56
,
57
]. Patients with MH may present with
cores despite being clinically asymptomatic and with some RYR1 variants specific to CCD.
Although RYR1 variants are the most commonly identified cause of CCD, they show
genetic heterogeneity [
56
,
57
]. MmD is an autosomal recessive, early onset congenital
myopathy that strikes bulbar, respiratory, and extraocular muscles [
58
]. Some variants of
RYR1 resulting in altered Ca
2+
release from intracellular stores have been associated with
MmD [
59
]. Currently, the most accredited hypothesis is that one subset of RYR1 variants
may result in both MH and MmD while another may be associated only with MmD [
6
,
11
].
5. Clinical Presentation
MH may occur at any time during anesthesia or in the early postoperative period,
with variable progression and outcome. Clinical presentation in children is often insidious:
hemodynamic responses, the precariousness of homeostatic equilibrium, and inadequate
monitoring equipment could make a quick diagnosis more challenging. A retrospective
analysis of the North American MH Registry and the Hiroshima University MH database
revealed varying presentation, clinical course, and outcome based on the age group con-
sidered (0 to 24 months, 25 months to 12 years, and 13 to 18 years), mirroring the develop-
mental changes in body structure and muscle composition throughout childhood [
60
,
61
].
Sinus tachycardia, hypercarbia despite increased minute ventilation, and rapid temperature
increase are the most common findings in the pediatric population, together with masseter
muscle spasm, especially in the middle age group; however, it is unclear whether the latter
sign is due to physical characteristics or to the relatively high concentrations of volatile
anesthetics frequently used for anesthesia induction in this age group [
60
]. A dramatic body
temperature elevation is a common sign of MH reactions [
62
–
64
]. End-tidal carbon dioxide
(ETCO
2
) is considered a sensitive early sign of MH, and rather than an abrupt rise in CO
2
,
a more gradual rise is described [
6
,
65
]. Uncontrolled hypermetabolism is then followed by
respiratory and metabolic acidosis due to rapid consumption of ATP, while rhabdomyolysis
can result in life-threatening hyperkalemia, myoglobinuria, elevated creatine kinase, acute
renal failure, arrhythmias, bowel ischemia, and compartment syndrome; disseminated
intravascular coagulation could arise should the temperature exceed about 41 ◦C [15,62].
AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to
The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia
Association of the United States from 1987 to 2006 revealed a 1.4% death rate for 291 MH
events and a 9.5% death rate for 84 US or Canadian reports of adverse events occurring
between 2007 and 2012 in “very likely MH” or “almost certain MH” events [
60
,
62
,
63
]. In
addition, the likelihood of any complication is reported to increase 2.9 times per 2
◦
C rise
in maximum temperature [62].

J. Clin. Med. 2023,12, 3869 7 of 18
Especially in children with a small body surface area, several conditions can enter
into differential diagnosis with MH during anesthesia, including insufficient anesthesia
or analgesia, insufficient ventilation, equipment malfunction, elevated end-tidal CO
2
due
to laparoscopic surgery, and iatrogenic overheating. In their absence, even events such as
anaphylactic reactions, sepsis, thyroid storm, pheochromocytoma, transfusion reactions,
ecstasy or other recreational drugs, neuroleptic malignant syndrome, and serotonin syn-
drome should be considered in the presence of MH suspicion. Knowledge of their clinical
features and arterial and venous blood gas analysis is essential for correct diagnosis [
3
,
4
,
7
].
Drug-induced rhabdomyolysis should be considered in patients with neuromuscular
diseases, while myotonic crises may occur in patients with myotonic syndromes after
receiving succinylcholine or acetylcholinesterase inhibitors.
Another unusual situation at risk of MH is sedation with inhaled anesthetics in the
pediatric intensive care unit (PICU) [
66
–
68
]. If these types of sedation devices are used,
children susceptible to MH in the PICU may be at risk for such exposure, highlighting
the significance of MH differential diagnosis in intensive care patients admitted for other
conditions [69].
6. Clinical Diagnostic Pathway
Identifying the population at risk is of utmost importance to avoid an MH crisis. On
the other hand, hastily applying an improper diagnosis of susceptibility could affect the
medical future of an otherwise healthy child. Consequently, during preoperative evaluation,
all children must be correctly screened (Figure 2).
J. Clin. Med. 2023, 12, x FOR PEER REVIEW 7 of 18
events and a 9.5% death rate for 84 US or Canadian reports of adverse events occurring
between 2007 and 2012 in “very likely MH” or “almost certain MH” events [60,62,63]. In
addition, the likelihood of any complication is reported to increase 2.9 times per 2 °C rise
in maximum temperature [62].
Especially in children with a small body surface area, several conditions can enter
into differential diagnosis with MH during anesthesia, including insufficient anesthesia
or analgesia, insufficient ventilation, equipment malfunction, elevated end-tidal CO
2
due
to laparoscopic surgery, and iatrogenic overheating. In their absence, even events such as
anaphylactic reactions, sepsis, thyroid storm, pheochromocytoma, transfusion reactions,
ecstasy or other recreational drugs, neuroleptic malignant syndrome, and serotonin
syndrome should be considered in the presence of MH suspicion. Knowledge of their
clinical features and arterial and venous blood gas analysis is essential for correct
diagnosis [3,4,7].
Drug-induced rhabdomyolysis should be considered in patients with neuromuscular
diseases, while myotonic crises may occur in patients with myotonic syndromes after
receiving succinylcholine or acetylcholinesterase inhibitors.
Another unusual situation at risk of MH is sedation with inhaled anesthetics in the
pediatric intensive care unit (PICU) [66–68]. If these types of sedation devices are used,
children susceptible to MH in the PICU may be at risk for such exposure, highlighting the
significance of MH differential diagnosis in intensive care patients admied for other
conditions [69].
6. Clinical Diagnostic Pathway
Identifying the population at risk is of utmost importance to avoid an MH crisis. On
the other hand, hastily applying an improper diagnosis of susceptibility could affect the
medical future of an otherwise healthy child. Consequently, during preoperative
evaluation, all children must be correctly screened (Figure 2).
Figure 2. Diagnostic pathway for investigation of MH susceptibility.
Figure 2. Diagnostic pathway for investigation of MH susceptibility.
The IVCT is recommended for individuals suspected to be at increased risk of MH
either as a first-line test or when DNA analyses have failed to confirm the high-risk status.
DNA screening on a patient’s blood sample is minimally invasive and affordable, but

J. Clin. Med. 2023,12, 3869 8 of 18
sensitivity is unfortunately only approximately 50% for the detection of MH susceptibility.
If one of the known MH-associated mutations is identified, the subject should be considered
at increased risk of developing MH. If DNA testing is negative, MHS still cannot be ruled
out definitively, and the decision on the following diagnostic steps must then be based
on the clinical indication. The decision to pursue either DNA screening or muscle biopsy
and IVCT in the first instance will be made on a patient-by-patient basis by the MH
diagnostic centre in consultation with the patient and their health-care funder, taking
into consideration the availability of the respective tests, the urgency of the test, the prior
probability of a positive diagnosis, and the costs of the tests in the relevant laboratory. The
genetic laboratory is responsible for consulting the available published evidence (literature
and databases) and applying prediction algorithms to eventually classify the variant as
neutral or potentially MH-associated.
IVCT,
in vitro
contracture test; MH, malignant hyperthermia; MHS: malignant hyper-
thermia susceptibility.
Family history of undefined adverse events during surgery, unexplained perioperative
death, postoperative or recurrent rhabdomyolysis, an idiopathic increase in creatine kinase
levels, heat stroke, or rare diseases should be investigated [
6
,
8
,
9
]. In addition, previous
exposure to halogenated anesthetics without reactions is no guarantee: even though an
MH crisis may develop upon first GA with those agents, patients require an average of
three exposures to anesthesia before triggering [
6
,
8
,
9
]. However, pre-operative creatine
kinase screening is not recommended in the pediatric population [34–36].
The main red flag when evaluating children is muscle weakness because many neu-
romuscular diseases are associated with a high-risk population [
34
]. Questions should be
addressed to investigate a family or personal history of congenital hip dislocation, motor
stage delay, walking disorders, limb or limb strength defects, muscle fatigue, muscle pain,
cramps sine causa, or frequent falls. Decreased muscle tone and/or trophism, expres-
sionless myopathic facies, and ophthalmoplegia should raise suspicion of an underlying
myopathy and be further investigated [34].
Due to multisystemic involvement, possible concomitant cardiomyopathies, arrhyth-
mias, restrictive lung diseases, and endocrine and hepatorenal defects should also be
carefully investigated in children suspected of congenital myopathy [15,16].
When evaluating a child with suspected MHS, parents should be informed and re-
ferred for investigation if anesthetic, medical, and family history cannot rule out an in-
creased risk [47].
In the suspected but not overt group, allocation to the high-risk or standard-risk
group could be challenging. Despite national recommendations, a clear diagnostic pathway
must still be fully defined. Clinical signs should be accompanied by laboratory features
confirming the suspicion.
The highest sensitivity test for detecting susceptibility to MH is a pharmacologi-
cal challenge test performed on freshly excised skeletal muscle specimens under strictly
controlled laboratory conditions, collectively referred to as the
in vitro
contracture test
(IVCT) [
47
,
70
–
74
]. The IVCT is recommended for individuals suspected to be at increased
risk of MH either as a first-line test or when DNA analyses have failed to confirm the
high-risk status [
47
,
70
–
74
]. IVCT measures the contracture response to gradually increasing
concentrations of caffeine and halothane and is referred to as the caffeine/halothane con-
tracture test (CHCT) in North America and as the IVCT in Europe and elsewhere [
70
–
74
].
It is performed on a muscle biopsy of approximately 100–200 mg, measuring 20–25 mm
in length with a thickness of 2–3 mm obtained from the vastus lateralis or medialis of pa-
tients
≥
10 years old or
≥
20 kg (in this case, parents can be tested instead) and differences
among the two protocols essentially concern drug concentration and the number of muscles
bundles that need to be tested for each drug [
73
]. Achieving the threshold concentration
(producing a contracture of 2 mN or 0.2 g force) of halothane and caffeine, along with
the tension produced at 2% halothane and 2 mM caffeine, confirms MHS diagnosis in
Europe [
34
]. However, despite scientific society indications, there are very few centers

J. Clin. Med. 2023,12, 3869 9 of 18
able to provide the IVCT [
12
]; it is a highly invasive test (requiring minor surgery itself),
expensive, and many doubts have been expressed in this regard [75].
DNA screening on a patient’s blood sample is minimally invasive and affordable,
but sensitivity is unfortunately only approximately 50% for the detection of MHS; RYR1
targeted analysis of the known MH-associated mutations or screening of the entire coding
regions is possible [
70
]. If one of the known MH-associated mutations is identified, the
subject should be considered at increased risk of developing MH. If testing for an RYR1
mutation is negative, MHS still cannot be ruled out definitively, and the decision on the
following diagnostic steps must then be based on the clinical indication. When the entire
coding region of RYR1 is screened, yet-to-be-classified sequence variants may frequently
be identified [
70
,
72
]. The genetic laboratory is responsible for consulting the available pub-
lished evidence (literature and databases) and applying prediction algorithms to eventually
classify the variant as neutral or potentially MH-associated. For patient safety, individuals
carrying a likely pathogenic variant RYR1 variant should be regarded to be at increased
risk for MH until further diagnostic tests, i.e., an IVCT, can be performed [47,72,76].
The decision to pursue either DNA screening or muscle biopsy and IVCT in the
first instance should be made on a patient-by-patient basis by the MH diagnostic center
(involving pediatric anesthesiologist) in consultation with the patient and their health-
care funder, taking into consideration the availability of the respective tests, the urgency
of the test, the prior probability of a positive diagnosis, and the costs of the tests in the
relevant laboratory.
The EMHG, the MH Association of the United States (MHAUS), and the MH Group
of Australia and New Zealand (MHANZ) are the worldwide largest multidisciplinary
organizations promoting research and counseling on MH.
7. Perioperative Recommendations for High-Risk Children
Although it could be advisable to clarify the MH status of suspected patients before
surgery, suspicion of MHS should not delay treatment of the surgical pathology, even in
ambulatory settings, particularly if this would risk the progression of the condition of
the patient, because the mere avoidance of triggering substances eliminates the risk of
developing an MH event.
Trigger-free anesthesia should be performed, and careful monitoring of all vital signs,
including EtCO
2
and core temperature, should be adopted during the entire perioperative
period [
16
]. It should also be emphasized that many of these anesthetics (such as halothane)
are obsolete in modern anesthesia.
Regional anesthesia techniques (e.g., spinal, epidural, and peripheral nerve blocks) or
total intravenous anesthesia (TIVA) are safe for these patients, while classical inhalational
induction with halogenated agents must be avoided. This implies that peripheral venous
access should be established before the onset of general anesthesia; in non-cooperative
children, premedication with benzodiazepines, sedation with nitrous oxide, and topical
local anesthetics can reduce the stress associated with needle punctures. Moreover, pediatric
regional anesthesia is usually performed in combination with general anesthesia or some
degree of sedation. There is no evidence to support elective intensive care unit management
of MH-susceptible patients after uneventful trigger-free anesthesia [67].
In patients with congenital myopathies, premedication should be avoided or used
with reduced dosage due to the increased sensitivity to sedatives and opioids and the risk
of central respiratory depression, airway obstruction, and worsening of muscle weakness.
The non-depolarizing neuromuscular blocking agents may need a lower initial dose
and could have a prolonged effect in patients with neuromuscular disorders; reversal with
cholinesterase inhibitors before extubating is contraindicated.
Even the children affected by neuromuscular disorders, regardless of their associa-
tion with MH, usually require a personalized anesthetic approach: succinylcholine and
halogenated agents, the same drugs that can trigger MH in an MHS patient, can cause
rhabdomyolysis in Duchenne syndrome and should therefore be avoided, while propofol

J. Clin. Med. 2023,12, 3869 10 of 18
infusions are best avoided in patients with mitochondrial diseases (boluses are commonly
tolerated) [34,35]. Therefore, anesthesia for a child with undiagnosed myopathy may be a
challenge. In addition, myopathy might not be clinically evident in the neonate requiring
general anesthesia [34–36].
If available, a dedicated “vapor-free” machine for MH-susceptible patients is advisable,
but if not, recommendations on anesthesia workstations must be followed. Since most
vaporizers have a significant reservoir of the volatile anesthetic agent, they must be removed
from the workstation when preparing it for use, and the breathing circuits should be
replaced, as well as the soda lime canister. The circuit should be flushed with oxygen or air
with maximal flow rate for workstation-specific time or, in the absence of manufacturer
instructions, with a ventilatory pattern of 600 mL tidal volume and a ventilatory frequency
of 15 min
−1
. This process will take some time and influence the operating room planning,
often leading to scheduling the patient as the first intervention of the day. The anesthetic
workstation should be flushed according to manufacturer guidelines; however, these
recommendations are variable and may require two hours or more flushing. After the
anesthesia machine has been flushed for the recommended time, it should not be set to
standby mode before use.
Activated charcoal filters (ACFs) have been shown to rapidly and cost-efficiently
decrease the concentration of anesthetic vapors to <5 ppm in 2–3 min and to maintain this
low concentration during the course of general anesthesia for up to 12 h with fresh gas
flows of at least 3 L min
−1
and should be applied on both the inspiratory and expiratory
branches of the breathing circuit [
8
]. If available, especially in the case of limited time
before surgery, ACF could obviate the need for purging the system as described. However,
the anesthesia machine will still need to be flushed with high fresh gas flows (
≥
10 L/min)
for 90 s before placing the activated charcoal filters on both the inspiratory and expiratory
branches of the breathing circuit [8,12].
Dedicated malignant hyperthermia charts or kits should also be implemented to
reduce the response time in case of an acute crisis. Cognitive aids should be available in all
operating rooms, and simulation of these rare clinical cases should be provided to active
practitioners and residents.
8. Treatment of Malignant Hyperthermia
Since the first description of MH, it has been evident that discontinuing the anesthetic
trigger and supportive measures could lead to the spontaneous resolution of the acute cri-
sis [
77
]. Immediate management of suspected episodes includes avoiding succinylcholine
administration, removing the vaporizer from the anesthetic circuit, washing the circuit
with a maximal flow of 100% oxygen, and immediately transitioning to general anesthesia
maintenance with non-triggering agents, typically TIVA [
67
]. Changing the breathing
circuit, carbon dioxide absorber, or anesthesia workstation to accelerate the elimination of
residual volatile halogenated agents is rational but time-consuming and discouraged in
the first instance; an ACF inserted into the circuit could achieve the same objective more
rapidly [47].
The team should be rapidly notified so that help can be called, dantrolene requested,
and the surgery postponed or terminated as soon as possible. If not already performed,
the airways should be secured with an endotracheal tube. Standard anesthetic monitoring,
including pulse oximetry, ECG, non-invasive blood pressure, and EtCO
2
, should be com-
pleted with core temperature measurement; if not already in place, nasopharyngeal or low
esophageal probes are typically a good compromise between accuracy and invasiveness,
but alternative methods, such as tympanic, axillary, bladder, or skin temperature, can
be considered [
78
]. The attending anesthesiologist should review the type and caliber of
venous accesses, and large-bore venous lines should be secured early in the management;
a central venous line should also be considered [
34
]. Arterial line and urinary catheter
placement are usually performed, and blood samples for point-of-care testing and labo-
ratory analysis should be drawn, but their relevance increases with time after immediate

J. Clin. Med. 2023,12, 3869 11 of 18
management. Dantrolene sodium, introduced in 1979, is a post-synaptic muscle relaxant
that inhibits Ryr1-mediated intracellular calcium release from the sarcoplasmic reticulum
of skeletal muscle cells and should be administered as soon as MH is suspected since it
can effectively revert its pathophysiology [
4
]. Indeed, mortality of MH has precipitated
from 80% to <5% [
4
,
39
]. The drug is approved by both the Food and Drug Administration
and the European Medicines Agency for pediatric use [
79
,
80
]. The initial dantrolene dose
for MH is 2–2.5 mg
·
kg
−1
of actual body weight [
81
]. Ideal body weight calculations are
avoided due to the risk of under-treatment; further boluses of 1–2.5 mg
·
kg
−1
can be admin-
istered at a minimum of 10 min intervals and should be continued until a clinical response
is observed, such as decreasing EtCO
2
or PaCO
2
for the same minute ventilation or normal
EtCO
2
or PaCO
2
with normal minute ventilation, decreasing muscle rigidity, decreasing
body temperature and lowering heart rate [
81
]. The maximum dose of 10 mg
·
kg
−1
quoted
in the official drug information can be exceeded if clinical stability is not achieved; doses
up to 30 mg
·
kg
−1
have been reported, although lack of clinical improvement after such
high doses should prompt the clinician to consider alternate diagnoses [41].
A significant drawback of dantrolene sodium is related to its classical pharmaceutical
formulation: Dantrium/Revonto/dantrolene sodium 20 mg of lyophilized orange powder
needs to be diluted in 60 mL of sterile water (the drug will not completely dissolve in
crystalloid-containing solutions) with a filter, leading to a final concentration of 0.32 mg/mL
and a preparation time of about 3 min per vial. The water for diluting dantrolene should
not be stored in a refrigerator; it may be stored in a warming cabinet designed to maintain
fluid temperatures between 35
◦
C and 40
◦
C [
82
]. The number of vials varies widely
according to the patient’s weight: while for a 10 kg infant, a single vial can provide the
correct amount for the first bolus in 3 min, for a 50 kg pediatric patient, five vials and
potentially 15 min are needed for the initial bolus to be administered. Since the time to
intervention is critical in the prognosis of this emergency, newer formulations addressed
this issue, but availability is suboptimal: RYANODEX
®
, 250 mg per vial to be reconstituted
with 5 mL of sterile water (final concentration 50 mg/mL), is approved for the United States
only, NPJ5008, nanoparticle formulation 120 mg/20 mL (5.3 mg/mL), while it is currently
under evaluation in Europe and United States for pediatric usage. The dosage schedule
based on the patient’s body weight using 20 mg or 250 mg vials of dantrolene sodium is
reported in Tables S2 and S3 (Supplementary Files).
The half-life of dantrolene is 4–8 h, and it is highly lipophilic, protein-bound, and
undergoes hepatic metabolism [
83
]. The classical dantrolene formulation has a pH of
9.5 and is associated with injection site reactions, commonly due to extravasation and
thrombophlebitis [
83
]. Side effects of dantrolene include dose-dependent muscle weakness,
including respiratory muscles, and hepatotoxicity; mannitol 5% (3000 mg/60 mL) is also
present in each vial and may contribute to fluid overload and the development of pul-
monary edema [
83
]. Drug interactions include cardiovascular collapse in combination with
calcium channel blockers, especially verapamil, and serotonin antagonist (5HT3-antagonist)
antiemetics should be used cautiously [6].
There are no guidelines regarding the availability of sufficient dantrolene for the
management of MH crises. The EMHG and the MHAUS recommend that dantrolene be
available wherever volatile anesthetics or succinylcholine are used regularly, and 36 vials
of dantrolene (or a minimum stock of 3–250 mg vials of RYANODEX
®
) are immediately
available. The 36 vials will be enough to treat an MH crisis for 20–30 min in all adult
patients of approximately 70 kg. Further dantrolene (to a total of 60 vials within 1 h) will
need to be obtained from other sources, and each institution should carefully consider
what other sources are available locally and the time taken to obtain them. If additional
supplies cannot be obtained within 30 min, they recommend increasing the initial stock
supply to 48 vials. They further recommend that remote institutions where more dantrolene
cannot be obtained within 1 h should store 60 vials. In large hospitals with more than
one operating theatre complex, the stocked dose of dantrolene may be split between the
complexes, ensuring that it is readily at hand whenever needed [84].

J. Clin. Med. 2023,12, 3869 12 of 18
While the etiologic treatment for malignant hyperthermia is ongoing, maintaining vital
functions and correcting biochemical abnormalities is crucial for a good patient outcome.
Specifically, the following points should be addressed [8,34,61,78,85–87]:
-
Temperature management: despite the syndrome’s name, severe hyperthermia is
a sign of a delayed diagnosis or management; accordingly, dantrolene is the most
appropriate intervention for body temperature control. However, hyperthermia can
lead to coagulopathy, irreversible actin-myosin binding, and worsening of acidosis
and electrolyte disturbances; therefore, if the body temperature is >38.5–39
◦
C, active
cooling is indicated in addition to turning off heating devices. The pediatric population
can very well benefit from surface cooling due to large body surface area in relation
to weight; methods include forced air cooling, ice packs near the great arteries (neck,
axillae, groins), wet, cold sheets, cooling blankets or pads set at low temperatures
(for example used in targeted temperature management). Caution should be made
since direct contact with cold objects with the thin skin of a child can cause frostbite.
Ice immersion is the most effective method of external cooling, but not applicable
in the operating room setting. Cold intravenous fluids administration (4
◦
C) is a
simple and effective second-line cooling method: while fluid replacement can be
beneficial for perspiration and to reduce the risk of acute kidney injury, the risk of
fluid overload limits this method of cooling; adult guidelines recommend not to
exceed 10–20 mL
·
kg
−
1, and it is reasonably adequate in the pediatric population.
Invasive cooling methods are usually unnecessary in a recognized MH crisis: bladder
and gastric lavage are poorly effective, while peritoneal lavage and extracorporeal
circulation, albeit effective, require time, equipment, and expertise. Pharmacologic
interventions such as acetaminophen or ibuprofen are not effective in this setting.
Active cooling should be halted when the core temperature is <38–38.5
◦
C due to the
risk of vasoconstriction and hypothermia in resolving crises.
-
Respiratory and metabolic acidosis: minute ventilation should be increased
2–3 times
to
exhale the excess CO
2
production by muscle contraction; a normal EtCO
2
(
e.g., 40 mmHg
)
should be targeted. Metabolic acidosis with base excess <
−
8 mEq
·
L
−1
and pH < 7.2 is
treated with sodium bicarbonate 1–2 mEq·kg−1.
-
Electrolyte disturbances: first-line treatment for hyperkalemia (K
+
> 5.9 mmol/L
or QRS widening) is membrane stabilization with calcium (0.1 mmol
·
kg
−1
chloride
calcium or 60 mg
·
kg
−1
calcium gluconate) and insulin-glucose system for rapid
potassium cell entry (e.g., dextrose: 50%, 50 mL with 50 IU insulin for adults or
0.1 insulin
·
kg
−1
and dextrose 25%, 2 mL
·
kg
−1
). Blood glucose should be checked
hourly. Other potassium-lowering interventions include sodium bicarbonate, al-
buterol, furosemide, kayexalate, and hemodialysis.
-
Cardiovascular system: arrhythmias should be treated with amiodarone 3 mg
·
kg
−1
up to 300 mg. Persistent tachycardia in the absence of hemodynamic compromise can
be treated with beta-blockers, while calcium channel blockers should be avoided due
to their relevant interaction.
-
Renal system: due to rhabdomyolysis and increased creatine kinase, there is a risk
of acute kidney injury; guidelines recommend maintaining a high urine output, at
least 2 mL
·
kg
−1
, which can be achieved with cold intravenous fluids, furosemide
0.5–1 mg·kg−1
, mannitol 1 gr
·
kg
−1
(already contained in dantrolene sodium formula-
tion). Urine alkalinization with sodium bicarbonate 1 mEq·kg−1·h is also an option.
Criteria for diagnosing the resolution of an MH crisis include decreasing EtCO
2
or
PaCO
2
for the same minute ventilation or normal EtCO
2
or PaCO
2
with normal minute
ventilation, decreasing muscle rigidity, decreasing body temperature, and lowering heart
rate without arrhythmias. Dantrolene should then be stopped; continuous infusion is
not recommended due to the prolongation of weaning from mechanical ventilation. The
patient should be transferred to a PICU for at least 24 h since there is a 30% risk of re-
current malignant hyperthermia, requiring further dantrolene administration [
88
]. Other
complications include rhabdomyolysis, acute kidney injury, coagulopathy, and compart-

J. Clin. Med. 2023,12, 3869 13 of 18
ment syndrome. Laboratory analysis should include hemoglobin, coagulation panel, renal
and hepatic function, creatine kinase, myoglobin, glucose, electrolytes, and arterial blood
gases. The prognosis of malignant hyperthermia depends on rapid recognition and early
treatment of the crisis, and patients with high muscular mass are at higher risk for adverse
outcomes [86,87].
Due to the possibility of a recrudescence of the syndrome within the first 24 h after
the initial resolution, patients should be intensively monitored for 48–72 h, and further
treatment with dantrolene should be administered.
Conversely, in case of an effective reversal of an MH episode, a continuous infusion or
intermittent dantrolene boluses are not recommended, being associated with a high inci-
dence of thrombophlebitis and dose-dependent muscle weakness that may delay weaning
from mechanical ventilation [89,90].
The healthcare professional should report the acute MH event to the EMHG or the
MHAUS, and the patient and family should be referred for specialized counseling. In
addition, medical identification bracelets/necklaces are advisable for these patients, and
the importance of notifying the event to health care providers in case of future elective
procedures should be emphasized.
9. Future Perspectives
Next-generation sequencing facilitates a fast, accurate, and cost-effective genetic anal-
ysis, and it is gradually becoming the first-line diagnostic test for genetically heterogenous
disorders (such as congenital myopathies) [
91
]. It caused a “paradigm shift” in MHS
diagnostics [
72
]. As discussed above, RYR1 variants may cause a wide spectrum of muscle
diseases, and next-generation sequencing is frequently used in the neuromuscular clinic
for RYR1 analysis in patients with an unresolved neuromuscular phenotype [
72
,
92
]. This
has resulted in a considerable rise in the number of referred patients with a potential risk
of MH, even though they have no personal or family history of adverse anesthetic events
suspected to be MH.
Bioinformatic model prediction tools need to be improved to classify RYR1 missense
variants of unknown significance [
91
,
92
]. Future strategies for MH susceptibility diagnos-
tics should focus on the classification of RYR1, CACNA1S, and STAC3 variants utilizing
common databases and functional studies in order to prevent unnecessary invasive diag-
nostic procedures [72].
There are complex variations in genetic and environmental factors underlying the
diseases associated with RyR1 dysfunction. Recently, complex models using machine
learning techniques and integrating heterogeneous data from different types of tests to
diagnose diseases and predict treatment outcomes in a real-world context are being devel-
oped [93,94].
10. Conclusions
MH still represents a rare but life-threatening disease to which the pediatric population
undergoing GA is particularly vulnerable. While genetic predisposition has been linked to
MHS, the potential for the involvement of further unknown genes cannot be discounted.
Moreover, a number of environmental stressors have also been implicated as risk factors in
MHS individuals, but there is as yet no clear consensus from the literature.
An effective prevention policy focused on clearly recognizing the high-risk population,
defining perioperative trigger-free hospitalization, and rapid activation of supportive
therapy is paramount to avoid adverse outcomes. The incidence of death due to MH has
decreased in the last thirty years, but vigilance must be maintained where triggering drugs
are administered.

J. Clin. Med. 2023,12, 3869 14 of 18
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/jcm12123869/s1. Table S1: Dosage schedule based on patient’s
weight calculated using 20-mg vials of dantrolene reconstituted with 60 mL of sterile water for
injection. To calculate mg dosage, multiply patient weight in kg by desired mg
·
kg
−1
dose. Multiply
the mg dose needed by 60 and divide by 20 for the mL needed. Table S2. Dosage schedule based on
patient’s weight calculated using 250-mg vials of dantrolene (Ryanodex
®
) reconstituted with 5 mL of
sterile water for injection. To calculate mg dosage, multiply patient weight in kg by desired mg/kg
dose. Divide the mg dose by 50 for the mL needed.
Author Contributions:
All authors had substantial contributions to the conception and design of
the paper, approved the submitted version, agree to be personally accountable for the author’s own
contributions and for ensuring that questions related to the accuracy or integrity of any part of the
work, even ones in which they were not personally involved, are appropriately investigated, resolved,
and documented in the literature. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
ACFs Activated charcoal filters
Ca2+ Calcium
CCD Central core disease
CHCT Caffeine/halothane contracture test
DHPR Dihydropyridine receptor
EMHG European Malignant Hyperthermia Group
ETCO2End-tidal carbon dioxide
GA General anesthesia
HypoPP Hypokalemic periodic paralysis
IVCT In vitro contracture test
MELAS Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
MH Malignant hyperthermia
MHANZ Malignant Hyperthermia Group of Australia and New Zealand
MHAUS Malignant Hyperthermia Association of the United States
MHS Malignant hyperthermia susceptibility
MmD Multi-mini core disease
MMR Masseter muscle rigidity
PICU Pediatric intensive care unit
RyR1 Type 1 ryanodine receptor
SERCA Sarcoendoplasmic reticulum calcium ATPase
SR Sarcoplasmic reticulum
TIVA Total intravenous anesthesia
References
1. Brown, R.C. Hyperpyrexia and Anaesthesia. BMJ 1954,2, 1526–1527. [CrossRef] [PubMed]
2. Bigler, J.A. Body temperatures during anesthesia in infants and children. J. Am. Med. Assoc. 1951,146, 551–556. [CrossRef]
3.
Denborough, M.A.; Forster, J.F.A.; Lovell, R.R.H.; Maplestone, P.A.; Villiers, J.D. Anaesthetic deaths in a family. Br. J. Anaesth.
1962,34, 395–396. [CrossRef]
4.
Denborough, M.; Ebeling, P.; King, J.; Zapf, P. Myopathy and malignant hyperpyrexia. Lancet
1970
,295, 1138–1140. [CrossRef]
[PubMed]
5. Denborough, M. Malignant hyperthermia. Lancet 1998,352, 1131–1136. [CrossRef] [PubMed]
6.
Rosenberg, H.; Pollock, N.; Schiemann, A.H.; Bulger, T.; Stowell, K.M. Malignant hyperthermia: A review. Orphanet J. Rare Dis.
2015,10, 93. [CrossRef]

J. Clin. Med. 2023,12, 3869 15 of 18
7.
Brady, J.E.; Sun, L.S.; Rosenberg, H.; Li, G. Prevalence of Malignant Hyperthermia Due to Anesthesia in New York State, 2001–2005.
Obstet. Anesth. Dig. 2009,109, 1162–1166. [CrossRef]
8.
Hopkins, P.M.; Girard, T.; Dalay, S.; Jenkins, B.; Thacker, A.; Patteril, M.; McGrady, E. Malignant hyperthermia 2020: Guideline
from the Association of Anaesthetists. Anaesthesia 2021,76, 655–664. [CrossRef]
9.
Rüffert, H.; Bastian, B.; Bendixen, D.; Girard, T.; Heiderich, S.; Hellblom, A.; Hopkins, P.M.; Johannsen, S.; Snoeck, M.M.; Urwyler,
A.; et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from
the European Malignant Hyperthermia Group. Br. J. Anaesth. 2021,126, 120–130. [CrossRef]
10.
Rosenberg, H.; Sambuughin, N.; Riazi, S.; Dirksen, R. Malignant Hyperthermia Susceptibility. In GeneReviews
®
[Internet]; Adam,
M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Amemiya, A., Eds.; GeneReviews
®
[Internet]; University
of Washington: Seattle, WA, USA, 1993–2023.
11.
Carpenter, D.; Robinson, R.L.; Quinnell, R.J.; Ringrose, C.; Hogg, M.; Casson, F.; Booms, P.; Iles, D.E.; Halsall, P.J.; Steele, D.S.; et al.
Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br. J. Anaesth. 2009,103, 538–548. [CrossRef]
12. European Malignant Hyperthermia Group (EMHG). Available online: www.emhg.org (accessed on 10 April 2023).
13.
Watt, S.; McAllister, R.K. Malignant Hyperthermia. In StatPearls [Internet]; StatPearls Publishing: Treasure Island, FL, USA, 2023.
14.
Parness, J.; Bandschapp, O.; Girard, T. The Myotonias and Susceptibility to Malignant Hyperthermia. Obstet. Anesth. Dig.
2009
,
109, 1054–1064. [CrossRef] [PubMed]
15.
Larach, M.G. A Primer for Diagnosing and Managing Malignant Hyperthermia Susceptibility. Anesthesiology
2018
,128, 8–10.
[CrossRef] [PubMed]
16.
Brislin, R.P.; Theroux, M.C. Core myopathies and malignant hyperthermia susceptibility: A review. Pediatr. Anesth.
2013
,23,
834–841. [CrossRef] [PubMed]
17. Bin, X.; Wang, B.; Tang, Z. Malignant Hyperthermia: A Killer If Ignored. J. PeriAnesthesia Nurs. 2022,37, 435–444. [CrossRef]
18.
Denborough, M.; Hopkinson, K.C.; O’Brien, R.O.; Foster, P.S. Overheating Alone Can Trigger Malignant Hyperthermia in Piglets.
Anaesth. Intensiv. Care 1996,24, 348–354. [CrossRef]
19.
Sumitani, M.; Uchida, K.; Yasunaga, H.; Horiguchi, H.; Kusakabe, Y.; Matsuda, S.; Yamada, Y. Prevalence of Malignant Hyperther-
mia and Relationship with Anesthetics in Japan: Data from the diagnosis procedure combination database. Anesthesiology
2011
,
114, 84–90. [CrossRef]
20.
Riazi, S.; Larach, M.G.; Hu, C.; Wijeysundera, D.; Massey, C.; Kraeva, N. Malignant hyperthermia in Canada: Characteristics of
index anesthetics in 129 malignant hyperthermia susceptible probands. Anesth. Analg. 2014,118, 381–387. [CrossRef]
21.
Tatsukawa, H.; Okuda, J.; Kondoh, M.; Inoue, M.; Terashima, S.; Katoh, S.; Ida,K. Malignant Hyperthermia Caused by Intravenous
Lidocaine for Ventricular Arrhythmia. Intern. Med. 1992,31, 1069–1072. [CrossRef]
22.
Schieren, M.; Defosse, J.; Böhmer, A.; Wappler, F.; Gerbershagen, M.U. Anaesthetic management of patients with myopathies. Eur.
J. Anaesthesiol. 2017,34, 641–649. [CrossRef]
23.
Hopkins, P.; Ellis, F.; Halsall, P. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet
1991,338, 1491–1492. [CrossRef]
24.
Lehmann-Horn, F.; Klingler, W.; Jurkat-Rott, K. Nonanesthetic Malignant Hyperthermia. Anesthesiology
2011
,115, 915–917.
[CrossRef]
25.
Larach, M.G.; Allen, G.C.; Rosenberg, H. Confirmation of Nonanesthetic-induced Malignant Hyperthermia. Anesthesiology
2012
,
116, 1398–1399. [CrossRef] [PubMed]
26. Tobin, J.R. Malignant Hyperthermia and Apparent Heat Stroke. JAMA 2001,286, 168–169. [CrossRef] [PubMed]
27.
Carsana, A. Exercise-Induced Rhabdomyolysis and Stress-Induced Malignant Hyperthermia Events, Association with Malignant
Hyperthermia Susceptibility, and RYR1 Gene Sequence Variations. Sci. World J. 2013,2013, 531465. [CrossRef] [PubMed]
28.
Landau, M.E.; Kenney, K.; Deuster, P.; Campbell, W. Exertional Rhabdomyolysis. J. Clin. Neuromuscul. Dis.
2012
,13, 122–136.
[CrossRef]
29.
Laitano, O.; Murray, K.; Leon, L.R. Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence
vs. Conjecture. Sports Med. 2020,50, 1581–1592. [CrossRef]
30.
E Nelson, T.; Jones, E.W.; Venable, J.H.; Kerr, D.D. Malignant Hyperthermia of Poland China Swine. Anesthesiology
1972
,36, 52–56.
[CrossRef]
31.
Corona, B.T.; Rouviere, C.; Hamilton, S.L.; Ingalls, C.P. FKBP12 deficiency reduces strength deficits after eccentric contraction-
induced muscle injury. J. Appl. Physiol. 2008,105, 527–537. [CrossRef]
32.
Maryansky, A.; Rose, J.C.; Rosenblatt, M.A.; Lai, Y.H. Postoperative Hyperthermia and Hemodynamic Instability in a Suspected
Malignant Hyperthermia–Susceptible Patient: A Case Report. A A Pract. 2021,15, e01314. [CrossRef]
33.
Gronert, G.A.; Tobin, J.R.; Muldoon, S. Malignant hyperthermia—Human stress triggering. Biochim. Biophys. Acta
2011
,1813,
2191–2192. [CrossRef]
34.
Sbaraglia, F.; Racca, F.; Maiellare, F.; Longhitano, Y.; Zanza, C.; Caputo, C.T. Prevenzione, Gestione e Trattamento Dell’ipertermia
Maligna. 2020. Available online: www.siaarti.it (accessed on 10 April 2023). (In Italian)
35.
Radkowski, P.; Suren, L.; Podhorodecka, K.; Harikumar, S.; Jamrozik, N. A Review on the Anesthetic Management of Patients
with Neuromuscular Diseases. Anesthesiol. Pain Med. 2023,13, e132088. [CrossRef]
36.
Adams, D.C.; Heyer, E.J. Problems of anesthesia in patients with neuromuscular disease. Anesthesiol. Clin. N. Am.
1997
,15,
673–689. [CrossRef]

J. Clin. Med. 2023,12, 3869 16 of 18
37.
Montagnese, F.; Schoser, B. Dystrophische und nicht-dystrophische Myotonien [Dystrophic and non-dystrophic myotonias].
Fortschr. Neurol. Psychiatr. 2018,86, 575–583. [CrossRef]
38.
Bandschapp, O.; Iaizzo, P.A. Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic
paralyses. Pediatr. Anesth. 2013,23, 824–833. [CrossRef] [PubMed]
39.
Gurnaney, H.; Brown, A.; Litman, R.S. Malignant Hyperthermia and Muscular Dystrophies. Obstet. Anesthesia Dig.
2009
,109,
1043–1048. [CrossRef]
40. Rivera-Cruz, B. Mitochondrial diseases and anesthesia: A literature review of current opinions. AANA J. 2013,81, 237–243.
41.
Morgan, P.G.; Hoppel, C.L.; Sedensky, M.M. Mitochondrial Defects and Anesthetic Sensitivity. Anesthesiology
2002
,96, 1268–1270.
[CrossRef]
42.
Parikh, S.; Goldstein, A.; Koenig, M.K.; Scaglia, F.; Enns, G.M.; Saneto, R.; Anselm, I.; Cohen, B.H.; Falk, M.J.; Greene, C.; et al.
Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society. Anesthesia
Analg. 2015,17, 689–701. [CrossRef]
43.
Sakamizu, A.; Yaguchi, E.; Hamaguchi, S. Anesthetic Management for an Adult With Glycogen Storage Disease Type 0. Anesthesia
Prog. 2020,67, 233–234. [CrossRef]
44.
Bollig, G. McArdle’s disease (glycogen storage disease type V) and anesthesia—A case report and review of the literature. Pediatr.
Anesthesia 2013,23, 817–823. [CrossRef]
45.
Hunter, A.; Pinsky, L. An evaluation of the possible association of malignant hyperpyrexia with the Noonan syndrome using
serum creatine phosphokinase levels. J. Pediatr. 1975,86, 412–415. [CrossRef]
46.
Benca, J.; Hogan, K. Malignant Hyperthermia, Coexisting Disorders, and Enzymopathies: Risks and Management Options. Obstet.
Anesth. Dig. 2009,109, 1049–1053. [CrossRef] [PubMed]
47.
Hopkins, P.M.; Rüffert, H.; Snoeck, M.M.; Girard, T.; Glahn, K.P.; Ellis, F.R.; Müller, C.R.; Urwyler, A.; European Malignant
Hyperthermia Group. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia
susceptibility. Br. J. Anaesth. 2015,115, 531–539. [CrossRef] [PubMed]
48.
Schwartz, L.; Rockoff, M.A.; Koka, B.V. Masseter Spasm with Anesthesia: Incidence and implications. Anesthesiology
1984
,61,
772–775. [CrossRef] [PubMed]
49.
Lazzell, V.A.; Carr, A.S.; Lerman, J.; Burrows, F.A.; Creighton, R.E. The incidence of masseter muscle rigidity after succinylcholine
in infants and children. Can. J. Anaesth. 1994,41, 475–479. [CrossRef]
50.
O’Flynn, R.P.; Shutack, J.G.; Rosenberg, H.; Fletcher, J.E. Masseter Muscle Rigidity and Malignant Hyperthermia Susceptibility in
Pediatric Patients An Update on Management and Diagnosis. Anesthesiology 1994,80, 1228–1233. [CrossRef]
51.
Vukcevic, M.; Broman, M.; Islander, G.; Bodelsson, M.; Ranklev-Twetman, E.; Müller, C.R.; Treves, S. Functional Properties of
RYR1 Mutations Identified in Swedish Patients with Malignant Hyperthermia and Central Core Disease. Obstet. Anesth. Dig.
2010,111, 185–190. [CrossRef]
52. Jungbluth, H.; Sewry, C.A.; Muntoni, F. Core Myopathies. Semin. Pediatr. Neurol. 2011,18, 239–249. [CrossRef]
53.
Quinlivan, R.M.; Muller, C.R.; A Davis, M.; Laing, N.; A Evans, G.; Dwyer, J.; Dove, J.B.; Roberts, A.P.; A Sewry, C. Central core
disease: Clinical, pathological, and genetic features. Arch. Dis. Child. 2003,88, 1051–1055. [CrossRef]
54.
Ríos, E. Calcium-induced release of calcium in muscle: 50 years of work and the emerging consensus. J. Gen. Physiol.
2018
,150,
521–537. [CrossRef]
55.
Chen, W.; Koop, A.; Liu, Y.; Guo, W.; Wei, J.; Wang, R.; MacLennan, D.H.; Dirksen, R.T.; Chen, S.R.W. Reduced threshold for store
overload-induced Ca
2+
release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core
disease. Biochem. J. 2017,474, 2749–2761. [CrossRef] [PubMed]
56.
Wu, S.; Ibarra, M.C.A.; Malicdan, M.C.V.; Murayama, K.; Ichihara, Y.; Kikuchi, H.; Nonaka, I.; Noguchi, S.; Hayashi, Y.K.; Nishino,
I. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain
2006
,129, 1470–1480. [CrossRef] [PubMed]
57. Jungbluth, H. Central core disease. Orphanet J. Rare Dis. 2007,2, 25. [CrossRef] [PubMed]
58.
Wei, L.; Dirksen, R.T. Ryanodinopathies: RyR-Linked Muscle Diseases. Curr. Top Membr.
2010
,66, 139–167. [CrossRef] [PubMed]
59.
Ducreux, S.; Zorzato, F.; Ferreiro, A.; Jungbluth, H.; Muntoni, F.; Monnier, N.; Müller, C.R.; Treves, S. Functional properties of
ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central
core disease, expressed in immortalized lymphocytes. Biochem. J. 2006,395, 259–266. [CrossRef] [PubMed]
60.
Nelson, P.; Litman, R.S. Malignant Hyperthermia in Children: An analysis of the North American malignant hyperthermia
registry. Obstet. Anesth. Dig. 2014,118, 369–374. [CrossRef]
61.
Otsuki, S.; Miyoshi, H.; Mukaida, K.; Yasuda, T.; Nakamura, R.; Tsutsumi, Y.M. Age-Specific Clinical Features of Pediatric
Malignant Hyperthermia: A Review of 187 Cases Over 60 Years in Japan. Obstet. Anesth. Dig. 2021,135, 128–135. [CrossRef]
62.
Larach, M.G.; Brandom, B.W.; Allen, G.C.; Gronert, G.A.; Lehman, E.B. Malignant Hyperthermia Deaths Related to Inadequate
Temperature Monitoring, 2007–2012: A report from the North American malignant hyperthermia registry of the malignant
hyperthermia association of the United States. Obstet. Anesth. Dig. 2014,119, 1359–1366. [CrossRef]
63.
Litman, R.S.; Flood, C.D.; Kaplan, R.F.; Kim, Y.L.; Tobin, J.R. Postoperative malignant hyperthermia: An analysis of cases from the
North American Malignant Hyperthermia Registry. Anesthesiology 2008,109, 825–829. [CrossRef]
64.
Sessler, M.D.I.; Warner, D.S.; Warner, M.A. Temperature Monitoring and Perioperative Thermoregulation. Anesthesiology
2008
,
109, 318–338. [CrossRef]

J. Clin. Med. 2023,12, 3869 17 of 18
65.
Karan, S.M.; Crowl, F.; Muldoon, S.M. Malignant Hyperthermia Masked by Capnographic Monitoring. Obstet. Anesth. Dig.
1994
,
78, 590–592. [CrossRef] [PubMed]
66.
Klincová, M.; Štˇepánková, D.; Schröderová, I.; Klabusayová, E.; Štouraˇc, P. Malignant Hyperthermia in PICU—From Diagnosis to
Treatment in the Light of Up-to-Date Knowledge. Children 2022,9, 1692. [CrossRef] [PubMed]
67.
Uitenbosch, G.; Sng, D.; Carvalho, H.N.; Cata, J.P.; De Boer, H.D.; Erdoes, G.; Heytens, L.; Lois, F.J.; Rousseau, A.-F.;
Pelosi, P.; et al.
Expert Multinational Consensus Statement for Total Intravenous Anaesthesia (TIVA) Using the Delphi Method. J. Clin. Med.
2022
,
11, 3486. [CrossRef]
68.
Yassen, K.A.; Jabaudon, M.; Alsultan, H.A.; Almousa, H.; I Shahwar, D.; Alhejji, F.Y.; Aljaziri, Z.Y. Inhaled Sedation with Volatile
Anesthetics for Mechanically Ventilated Patients in Intensive Care Units: A Narrative Review. J. Clin. Med.
2023
,12, 1069.
[CrossRef]
69.
Johannsen, S.; Mögele, S.; Roewer, N.; Schuster, F. Malignant hyperthermia on ICU—Sudden attack of the “snake”. BMC
Anesthesiol. 2014,14, A11. [CrossRef]
70.
Miller, D.; Daly, C.; Aboelsaod, E.; Gardner, L.; Hobson, S.; Riasat, K.; Shepherd, S.; Robinson, R.; Bilmen, J.; Gupta, P.; et al.
Genetic epidemiology of malignant hyperthermia in the UK. Br. J. Anaesth. 2018,121, 944–952. [CrossRef]
71. Litman, R.S.; Rosenberg, H. Malignant Hyperthermia: Update on susceptibility testing. JAMA 2005,293, 2918–2924. [CrossRef]
72.
Bersselaar, L.R.v.D.; Hellblom, A.; Gashi, B.M.; Kamsteeg, E.-J.; Voermans, N.C.; Jungbluth, H.; de Puydt, J.; Heytens, L.; Riazi,
S.; Snoeck, M.M.J. Referral Indications for Malignant Hyperthermia Susceptibility Diagnostics in Patients without Adverse
Anesthetic Events in the Era of Next-generation Sequencing. Anesthesiology 2022,136, 940–953. [CrossRef] [PubMed]
73.
Larach, M.G. Standardization of the caffeine halothane muscle contracture test. North American Malignant Hyperthermia Group.
Anesth. Analg. 1989,69, 511–515. [CrossRef]
74.
Riazi, M.S.; Kraeva, N.; Hopkins, M.P.M. Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old
Concept. Anesthesiology 2018,128, 168–180. [CrossRef]
75.
Larach, M.G. Should We Use Muscle Biopsy to Diagnose Malignant Hyperthermia Susceptibility? Anesthesiology
1993
,79, 1–4.
[CrossRef] [PubMed]
76.
White, R.; Schiemann, A.H.; Burling, S.M.; Bjorksten, A.; Bulger, T.; Gillies, R.; Hopkins, P.M.; Kamsteeg, E.-J.; Machon, R.G.;
Massey, S.; et al. Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia. Br. J.
Anaesth. 2022,129, 879–888. [CrossRef]
77.
Britt, B.A.; Gordon, R.A. Three cases of malignant hyperthermia with special consideration of management. Can. J. Anaesth.
1969
,
16, 99–105. [CrossRef] [PubMed]
78. Bissonnette, B. Temperature monitoring in pediatric anesthesia. Int. Anesthesiol. Clin. 1992,30, 63–76. [PubMed]
79. Available online: www.accessdata.fda.gov/drugsatfda_docs/label/2008/018264s025lbl.pdf (accessed on 10 April 2023).
80. Available online: www.ema.europa.eu/en/medicines/human/orphan-designations/eu3141379 (accessed on 10 April 2023).
81.
Kim, H.J.; Koh, W.U.; Choi, J.M.; Ro, Y.J.; Yang, H.S. Malignant hyperthermia and dantrolene sodium. Korean J. Anesthesiol.
2019
,
72, 78–79. [CrossRef] [PubMed]
82.
Toyota, Y.; Kondo, T.; Shorin, D.; Sumii, A.; Kido, K.; Watanabe, T.; Otsuki, S.; Kanzaki, R.; Miyoshi, H.; Yasuda, T.; et al. Rapid
Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant
Hyperthermia Events. BioMed Res. Int. 2023,2023, 8340209. [CrossRef]
83. Chan, C.H. Dantrolene sodium and hepatic injury. Neurology 1990,40, 1427. [CrossRef]
84. Glahn, K.P.; Bendixen, D.; Girard, T.; Hopkins, P.M.; Johannsen, S.; Rüffert, H.; Snoeck, M.M.; Urwyler, A.; European Malignant
Hyperthermia Group. Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant
Hyperthermia Group guidelines. Br. J. Anaesth. 2020,125, 133–140. [CrossRef]
85.
Miller, C.; Bräuer, A.; Wieditz, J.; Klose, K.; Pancaro, C.; Nemeth, M. Modeling iatrogenic intraoperative hyperthermia from
external warming in children: A pooled analysis from two prospective observational studies. Pediatr. Anesth.
2022
,33, 114–122.
[CrossRef]
86.
Safety Committee of Japanese Society of Anesthesiologists JSA guideline for the management of malignant hyperthermia crisis
2016. J. Anesthesia 2017,31, 307–317. [CrossRef]
87.
Glahn, K.P.E.; Ellis, F.R.; Halsall, P.J.; Müller, C.R.; Snoeck, M.M.J.; Urwyler, A.; Wappler, F.; European Malignant Hyperthermia
Group. Recognizing and managing a malignant hyperthermia crisis: Guidelines from the European Malignant Hyperthermia
Group. Br. J. Anaesth. 2010,105, 417–420. [CrossRef] [PubMed]
88.
Burkman, J.M.; Posner, K.L.; Domino, K.B. Analysis of the Clinical Variables Associated with Recrudescence after Malignant
Hyperthermia Reactions. Anesthesiology 2007,106, 901–906. [CrossRef]
89.
Krause, T.; Gerbershagen, M.U.; Fiege, M.; Weißhorn, R.; Wappler, F. Dantrolene–A review of its pharmacology, therapeutic use
and new developments. Anaesthesia 2004,59, 364–373. [CrossRef] [PubMed]
90.
Ward, A.; Chaffman, M.O.; Sorkin, E.M. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and
therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity.
Drugs 1986,32, 130–168. [CrossRef] [PubMed]
91.
Snoeck, M.; van Engelen, B.G.M.; Küsters, B.; Lammens, M.; Meijer, R.; Molenaar, J.P.F.; Raaphorst, J.; Verschuuren-Bemelmans,
C.C.; Straathof, C.S.M.; Sie, L.T.L.; et al. RYR1-related myopathies: A wide spectrum of phenotypes throughout life. Eur. J. Neurol.
2015,22, 1094–1112. [CrossRef]

J. Clin. Med. 2023,12, 3869 18 of 18
92.
Johnston, J.J.; Dirksen, R.T.; Girard, T.; Gonsalves, S.G.; Hopkins, P.M.; Riazi, S.; Saddic, L.A.; Sambuughin, N.; Saxena, R.; Stowell,
K.; et al. Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia
susceptibility. Genet. Med. 2021,23, 1288–1295. [CrossRef]
93.
Yang, L.; Dedkova, E.N.; Allen, P.D.; Jafri, M.S.; Fomina, A.F. T lymphocytes from malignant hyperthermia-susceptible mice
display aberrations in intracellular calcium signaling and mitochondrial function. Cell Calcium 2021,93, 102325. [CrossRef]
94. Zitnik, M.; Nguyen, F.; Wang, B.; Leskovec, J.; Goldenberg, A.; Hoffman, M.M. Machine learning for integrating data in biology
and medicine: Principles, practice, and opportunities. Inf. Fusion 2019,50, 71–91. [CrossRef]
Disclaimer/Publisher’s Note:
The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.