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4 Metabolic disorders
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a pathology view of physiologic changes. Ann. Hepatol. 2006; 5: 219â€“23. 268: 239â€“40.
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thrombocytopenia. Can. J. Anesth. 2000; 47: 1253â€“5. 79. Tank, P. D., Nadanwar, Y. S. & Mayadeo, N. M. Outcome of pregnancy with
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56. Hill, M. A., Albert, T., Zieske, A. et al. Successful resection of multifocal in pregnancy. Obstet. Gynecol. 1987; 69: 131â€“3.
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M. Joanne Douglas
Introduction molecular genetic analysis of umbilical cord blood to diagnose
MH susceptibility in the newborn of a known MH susceptible
Malignant hyperthermia (MH) is an inherited disorder of skeletal
mother.25 The authors suggest that pregnant women with a his-
muscle, which produces a hypermetabolic syndrome when sus-
tory of MH in themselves or their family be offered the option of
ceptible individuals (MHS) are exposed to the triggering anes-
molecular genetic testing of umbilical cord blood.
thetic agents.1 The known triggering agents are volatile
anesthetics (halothane, isoflurane, enflurane, sevoflurane, and
Clinical picture of MH
desflurane)1,2,3,4,5,6,7 and succinylcholine. They act by causing a
sudden increase in intramyoplasmic calcium (Ca2Ã¾), which
The classic picture of MH is that of an increase in end-tidal
results in increased skeletal muscle metabolism.8 The diagnostic
CO2, increased oxygen consumption (may result in cyanosis or
characteristics of acute MH are acidosis (combined metabolic
decreased SaO2), acidosis (metabolic and respiratory), and mus-
and respiratory), muscle dysfunction (increased creatinine kinase
cle destruction (increased CK, myoglobinuria, hyperkalemia).
[CK], myoglobinuria, rigidity, hyperkalemia) and evidence of
These result in tachycardia, tachypnea, unstable blood pressure
inheritance. Although called malignant hyperthermia, marked
(BP), dysrhythmias, and an increased temperature. Muscle rigid-
elevation of temperature is often a late sign but may occur as
ity (either masseter muscle rigidity [MMR] at the time of intuba-
early as 15 minutes following initiation of a volatile anesthetic
tion or generalized rigidity) is another sign. Approximately 10% of
agent in fulminant MH.9 The increase in intracellular Ca2Ã¾ may
MH cases are fulminant and require rapid diagnosis and aggres-
be due to a mutation in the ryanodine receptor such that the
threshold stimulus for Ca2Ã¾ release is lowered or a defect in
While much debate has focused on the significance of MMR,
modulation at the receptor.9
especially in children, most consider its development a warning
In a study of MH in susceptible swine, Ryan et al. demonstrated
sign of impending MH. While some use the terms MMR and
the sequence of events during a reaction.8 An increase in free
trismus interchangeably, Hannalah and Kaplan have classified
myoplasmic Ca2Ã¾ precedes the increase in end-tidal CO2, fol-
MMR as an inability to open the mouth fully but intubation is
lowed by a decrease in arterial oxygen saturation (SaO2). These
possible, while trismus is the total inability to open the mouth
changes are followed by tachycardia and lastly hyperthermia.
and intubate.27 They consider both to be an early sign of MH and
Dantrolene reversed these in the same order. Hypermetabolism
recommend discontinuing anesthesia unless required urgently.
(increased end-tidal CO2) begins when the intracellular Ca2Ã¾
Some cases of incomplete relaxation (increased force is required
increases above 0.6â€“0.7 mM, while muscle contracture and rigidity
to open the mouth), may be a normal variant of response to
occur with a level above 1.0 mM.8
succinylcholine.28 Under these circumstances, some advocate
continuing anesthesia with nontriggering agents and close mon-
itoring.29 In one series of adult patients with MMR, 25% tested
MH and inheritance
positive for MH using the caffeine halothane contracture test.30
In pigs, hyperthermia31 can trigger MH in the absence of anes-
MH is inherited in an autosomal dominant fashion with variable
penetrance.10 The RyR1 gene (responsible for the ryanodine thetic triggers, while prior hypothermia attenuates MH.32,33
Elevated CO2, hyperkalemia, exogenous Ca2 Ã¾, and adrenergic
receptor in skeletal muscle) appears causal for MH in pigs11 and
in some humans.12,13,14,15,16,17,18,19,20 Linkage studies attempting agents do not increase the chance of MH.34,35,36,37
to isolate a single responsible gene in humans have demonstrated
that human MH is multigenic.20,21 Correlation between DNA
testing and results of the caffeine halothane contracture test
(CHCT, also known as the in vitro contracture test, IVCT) has Diseases that mimic MH include sepsis, neuroleptic malignant
not been conclusive.13 A possible reason for this is the lack of syndrome (NMS), cocaine overdose, hyperthyroidism,9 and 3,4-
100% specificity for the CHCT.22 A recent study identified defects methylenedioxymethamphetamine (MDMA, â€˜â€˜ecstasyâ€™â€™) toxi-
city.38 Some congenital disorders can result in a hyperthermic
in the RYR1 gene that were causal for 70% of MH/MHS indivi-
duals and the authors recommend the use of denaturing high- response during anesthesia, which is not MH. These include
performance liquid chromatography as a valid screening osteogenesis imperfecta, familial dysautonomia (Riley Day
method.23 Mutation analysis has recently become available in Syndrome), and arthrogryposis multiplex congenita.
the United States.24 There is a report describing the use of Myopathies that result in a hypermetabolic picture in association
Obstetric Anesthesia and Uncommon Disorders, eds. David R. Gambling, M. Joanne Douglas and Robert S. F. McKay. Published by Cambridge University Press.
# Cambridge University Press 2008.
4 Metabolic disorders
with masseter rigidity include the myotonias (congenita, fluc- rigidity and neonatal fasciculations that was secondary to central
core disease, a disease associated with MH.60 As noted earlier in
tuans, myotonic dystrophy, paramyotonia congenita and
Schwartz-Jampel syndrome, periodic paralysis), central core dis- this chapter, a newborn was diagnosed with MH susceptibility
ease, mitochondrial myopathies,9 King (King-Denborough) syn- using molecular genetic analysis of umbilical cord blood.25
drome,39,40 and muscular dystrophy. It is important to exclude
these disorders by a neurological examination and electromyo-
Anesthesia for an MHS parturient
graphy (EMG) testing, as the CHCT may be positive. A response to
dantrolene does not prove the diagnosis of MH.9 Ideally the patient with known MH susceptibility will be seen in
In order to aid the clinical definition of MH and research on consultation prior to her admission to hospital. This allows a full
MH, Larach et al. developed a clinical grading scale to predict MH discussion of the implications of the diagnosis on the manage-
susceptibility.41 This scale assigns points to various indicators, ment of her labor and delivery. As the greatest risk relates to
based on their predictive value for MH. The total score indicates general anesthesia (GA), insertion of an epidural catheter early
the qualitative likelihood for MH. in labor will allow it to be used for analgesia as well as for an
operative delivery, should the need arise.
All of the local anesthetics are safe. There were questions in the
Treatment of MH
past about the use of adrenergic agents in MHS patients, but
Treatment of an MH episode consists of stopping the volatile evidence in humans suggests that epinephrine and norepineph-
rine are not triggers for MH.36 There is an overwhelming adrener-
anesthetic agent, hyperventilation with 100% oxygen, adminis-
tration of dantrolene (2.5 mg/kg initially, and up to 10 mg/kg) and gic response during an MH crisis and epinephrine should not be
instituting other measures to treat acidosis, hyperkalemia, dys- used at that time. In doses used clinically, ephedrine is probably
rhythmias, promote urine output, and cool the patient.9 The safe although an in vitro study of ephedrine, in significantly
changing of the anesthetic machine to a â€˜â€˜cleanâ€™â€™ machine is not greater amounts than would be used clinically, found that it
increased halothane-induced contractures.36 Other agents com-
considered a high priority. Dantrolene is effective and may have
to be repeated until the reaction is controlled. Research indicates monly used in obstetrics, such as narcotics, ketamine, nitrous
that very low concentrations of dantrolene open isolated Ca2 Ã¾ oxide/oxygen in a 50:50 mixture are safe (see Table 15.1).
release channels whereas higher concentrations block the chan- When anesthesia is required for an emergency cesarean section
nel.42 This may be the mechanism of mild hypermetabolism (C/S) and a functioning epidural is not in place the preferred
following treatment of an MH episode and may be important in technique is spinal anesthesia. Although insufficient time may
myopathies (other than MH) that produce a similar hypermeta- be present in which to adequately preload the patient with intra-
bolic picture.43 Creatinine kinase levels should be assessed every venous fluids, a recent study suggests that administration of a
fixed volume is not essential.61 Rarely, regional anesthesia may
six hours for 24 hours following an alleged episode to assess
rhabdomyolysis. fail or there is a contraindication to its use and so GA must be
At the time of a reaction the diagnosis of MH is made on clinical used. In this situation the triggering agents must be avoided. In
grounds and subsequently confirmed by the CHCT. Reviews of
experience in administering anesthetic triggering agents to Table 15.1 Safety of drugs for the MHS parturient
patients who have tested negative for MH indicate that this is
Induction agents thiopental, propofol, ketamine, etomidate,
benzodiazepines: all are safe
Muscle relaxants succinylcholine: not safe;
Malignant hyperthermia and obstetrics atracurium, vecuronium, rocuronium, mivacurium, pancuronium: all
Strazis and Fox reviewed the worldwide literature on all reported
Reversal agents neostigmine, physostigmine (Ã¾ atropine,
cases of MH and found that MH predominated in the pediatric
glycopyrrolate): all safe
and male population.47 Previous uneventful anesthesia was
Inhalational agents nitrous oxide: safe;
found in 20.9% and absent positive family history 75.9% of the
isoflurane, halothane, sevoflurane, desflurane: not safe
time. Congenital defects and musculoskeletal surgical proce-
Analgesics for labor/delivery all narcotics: safe;
dures were associated clearly with MH. This study has confirmed
local anesthetics (Ã¾ epinephrine): safe
the apparent lower incidence of MH in pregnancy than in the rest
Oxytocics oxytocin PGF2alpha, ergot preparations: safe, may mimic
of the population. Reported cases in pregnancy are
MH. Avoid during a reaction unless specifically indicated.
rare,48,49,50,51,52,53 with most reports relating to management of
Tocolytics B-sympathomimetics: safe, may mimic MH; nitroglycerin,
the MHS parturient.54,55,56,57,58,59 This apparent lower incidence
magnesium sulphate: safe
may be due to regional anesthesia being used more frequently in
Cardiovascular drugs ephedrine: probably safe;
obstetrics for procedures of shorter duration. There are two
epinephrine, norepinephrine: Safe a
reports of obstetric and anesthetic management of parturients
with King (King-Denborough) syndrome, a nonspecific myopa- a
Do not use during a reaction due to the overwhelming adrenergic
thy with MH-susceptibility and dysmorphic features similar to
Noonan syndrome.38,40 There is one report of maternal masseter
animal studies, thiopental does not induce MH and has some
Table 15.2 Common causes of tachycardia and fever in the
protective effect.62 Other induction agents, propofol, benzodiaze-
pines, and ketamine, are also safe. The greatest risks to all parturi-
ents during GA are pulmonary aspiration of gastric contents and Cause Tachycardia Fever
difficult or failed intubation. Therefore, it is essential to adequately
Ã¾Ã¾ Ã¾ to Ã¾ Ã¾ Ã¾ Ã¾
Sepsis (e.g. chorioamnionitis)
assess the airway prior to induction of GA. Where possible, pro-
phylactic H-2 receptor blockers and metoclopramide should be
Pain, anxiety â€“
administered to neutralize gastric acid and promote gastric emp-
Epidural analgesia â€“
tying. Sodium citrate, given minutes before induction, raises the
pH of gastric contents. Succinylcholine is contraindicated in MHS
patients even though it is the preferred agent for intubation in
obstetric patients due to its rapid onset and, if difficulties are can produce tachycardia and dysrhythmias, while the prostaglan-
dins can alter arterial oxygen saturation68 and increase tempera-
encountered with intubation, rapid offset. The intermediate acting
ture.69,70 Oxytocin is safe71 and is the preferred agent to increase
nondepolarizing muscle relaxants such as atracurium, vecuro-
nium, and rocuronium are favored for the MHS parturient. uterine tone in the MHS parturient. Obviously in the face of life-
Adequate intubating conditions can be achieved rapidly with threatening hemorrhage when oxytocin is ineffective one may
rocuronium providing the induction dose of thiopental is have to use an ergot preparation or a prostaglandin. Two of the
increased to 6 mg/kg and a dose of 0.9â€“1.0 mg/kg of rocuronium â€˜â€˜hallmarkâ€™â€™ signs of MH are tachycardia and increased tempera-
is used (the normal recommended intubating dose is 0.6 mg/kg).63 ture, and these are common in obstetrics due to pain, infection
Some recommend the use of prophylactic dantrolene in the (chorioamnionitis), and anxiety (see Table 15.2).
setting of GA, but I feel that it is not necessary providing one
avoids the known anesthetic triggers. It should be readily avail-
Anesthetic management of the MH-negative
able in the operating room and all personnel (nurses and anesthe-
mother with a possible MH-positive fetus
siologists) should be familiar with its use. The use of warm sterile
water (408C) to dilute the dantrolene allows for more rapid recon-
If one of the parents of a fetus is MHS the fetus has a 50% chance
stitution.64 As an alternative to volatile anesthetics to obtund
of inheriting the gene for the syndrome, as MH is inherited in an
awareness during surgery, the use of a small dose of midazolam
autosomal dominant manner. Concern is often raised about
or diazepam following anesthetic induction or after delivery, is a
anesthetic management of an MH negative mother where the
reasonable option. Of greatest importance is the monitoring of
father of the fetus is MHS. The anesthetic agents cross the pla-
the parturient, irrespective of the type of anesthesia. This includes
centa and theoretically the fetus could develop MH if triggering
the use of the routine monitors of automatic blood pressure, EKG,
agents are used in the mother.72,73 It probably is advisable to
pulse oximetry, end-tidal CO2 (for GA), and, if concern arises
avoid the known anesthetic triggers, but to date there has been
about the development of a reaction, arterial cannulation in
only one reported case of an infant with rigidity at birth.
order to serially monitor blood gases (theoretically a venous gas
Malignant hyperthermia was considered a possible diagnosis
is of greater value), electrolytes, and other parameters.
but there was no follow-up.74
Temperature should be monitored in two sites: esophageal or
rectal and axillary (close to large muscle groups).65
One can rapidly eliminate volatile agents from a standard anes-
Dantrolene and pregnancy
thetic machine (convert it to a â€˜â€˜cleanâ€™â€™ machine).66,67 As noted
Dantrolene crosses the placenta.75 In the gravid ewe, during an
above, turning the vaporizers off and running high-flow oxygen in
infusion rate of 2.2 mg/kg/h, the fetal to maternal ratio is 0.48.75
the case of a developing crisis is sufficient until other measures
have been undertaken, e.g. confirmation of diagnosis and admin- This is similar to that reported by Morison in two parturients
following oral dantrolene.76 Prophylactic oral administration pro-
istration of dantrolene. Then attention can be paid to removing
the vaporizers, changing the circuit, and replacing the CO2 absor- duces minor maternal side effects and no adverse fetal or neona-
tal effects.77 There is one reported case of postpartum uterine
bent. In the elective situation, remove the vaporizers, flush the
atony following dantrolene administration,78 but recent evidence
anesthetic machine with a high flow of oxygen (10 liters) using the
suggests that this is probably not due to the dantrolene itself.79 At
ventilator for 20 minutes, replace the fresh gas outlet hose, use a
new disposable circuit, and change the CO2 absorbent.9 a cumulative concentration of 20 g/ml of dantrolene Shin et al.
found depression of spontaneous uterine muscle contractility,
but this also occurred with mannitol. The authors felt that dan-
Differential diagnosis of MH during labor
trolene, per se, did not have any effect on isolated uterine smooth
muscle and that any reaction was due to its solvent vehicle,
mannitol.79 Lecithin-coated microcrystals dissolve more rapidly
Several drugs used in obstetrics may mask or mimic the signs
and symptoms of MH. These include the ergot preparations, (no mannitol) and form an effective preparation in the treatment
of MH in swine.80 Although this preparation may eliminate the
beta-sympathomimetics (ritodrine, terbutaline), and the prosta-
problem of potential uterine hypotonia it is not yet available.81
glandins. The ergot preparations and beta-sympathomimetics
4 Metabolic disorders
Levels of dantrolene have been measured in breast milk follow- 18. Hogan, K., Couch, F., Powers, P. A. et al. A cysteine-for-arginine substitution