Malignant hyperthermia:

Clinical diagnosis
Your company information
and
management of acute crisis

Dr.Muhammed Muhsin Ahmed Damudi

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 Introduction

Malignant hyperthermia (MH) manifests clinically as a

hypermetabolic crisis when an MH-susceptible (MHS)
individual is exposed to a volatile anesthetic (eg,
halothane, isoflurane,enflurane, sevoflurane, desflurane)
or succinylcholine .
• This topic will discuss the incidence, pathophysiology,
clinical manifestations, and acute management of MH.
 Incidence
• The incidence of episodes of MH in the
general population is estimated as
1:100,000 administered anesthetics
 Pathophysiology in brief
• Malignant hyperthermia-susceptible (MHS) patients have
genetic skeletal muscle receptor abnormalities, allowing
excessive calcium accumulation in the presence of
certain anesthetic triggering agents. Very little is known
about the specific mechanisms by which anesthetics
interact with these abnormal receptors to trigger an MH
crisis. During an episode of MH, the clinical
manifestations are due to cellular hypermetabolism,
leading to sustained muscular contraction and
breakdown (rhabdomyolysis), anaerobic metabolism,
acidosis, and their sequelae.
• The only known therapy for MH, DANTROLENE, binds to the RYR1
receptor to inhibit the release of calcium from the sarcoplasmic reticulum;
 Trigger Agents
• Majority of cases have implcated- Volatile anesthetic agent (eg,
halothane, enflurane, isoflurane, sevoflurane, desflurane) with or
without administration of succinylcholine [7].

• MH has been reported following administration of succinylcholine in

the absence of an inhalational agent (eg, to facilitate endotracheal
intubation). The majority of such cases come from a series of 129
patients who were biopsy-proven MH-susceptible (MHS); 20 of
whom manifested their signs of MH with succinylcholine alone
(without coadministration of a volatile agent) [30].

• Acute MH has also been reported in MHS patients exposed to heat

stress or vigorous exercise.
 Clinical Presentation
• The clinical manifestations of malignant hyperthermia typically
includes hypercarbia, sinus tachycardia, or masseter or generalized
muscle rigidity [7,33]. The most common initial sign of an MH crisis
is an unexpected rise in end-tidal carbon dioxide (ETCO2), which is
difficult to decrease as minute ventilation is increased. Generalized
muscle rigidity in the presence of neuromuscular blockade is
virtually pathognomonic for MH when other signs are present.
• ●Following successful treatment, recrudescence occurs in up to 25
percent of patients and is more likely in patients with increased
muscle mass [44].
• There is a widespread misconception that acute MH begins with
hyperthermia as the presenting sign. Hyperthermia is generally a
later sign of MH and is typically absent when the diagnosis is initially
suspected; in a large series of 255 patients, rapidly-increasing or
inappropriately-elevated temperature was one of the first signs in
only 8.2 percent of MH crises, and was the sole initial sign in only
 Clinical Features
• CLINICAL FEATURES
• Early signs — The early signs of malignant hyperthermia (MH) are
(table 2):
• ●Hypercarbia
• ●Sinus tachycardia
• ●Masseter muscle rigidity (MMR)
• ●Generalized muscle rigidity
• Hypercarbia — The most reliable initial clinical sign heralding the
development of acute MH is hypercarbia resistant to increasing the
patient's minute ventilation
• Later signs — Later signs of MH are (table 2):
• ●Hyperthermia
• ●Electrocardiogram changes related to hyperkalemia (see "Clinical
manifestations of hyperkalemia in adults", section on 'Cardiac
manifestations')
 Cont….
• Masseter muscle rigidity — MMR is the inability to open a patient's
mouth after the administration of a triggering agent. Only severe
MMR is thought to indicate the development of MH [33]; mild MMR
following succinylcholine is typical and of no particular concern, as
long as it terminates within approximately one minute and is not
associated with generalized rigidity.
• Generalized muscle rigidity — Generalized muscle rigidity (ie,
sustained contracture) in the presence of neuromuscular blockade is
considered pathognomonic for MH, provided other confirmatory
signs of hypermetabolism are also present.
 Later signs..
●Hyperthermia
• ●Electrocardiogram changes related to hyperkalemia
• ●Ventricular ectopy/bigeminy
• ●Ventricular tachycardia/fibrillation
• ●Myoglobinuria
• ●Excessive bleeding
• Hyperthermia — Hyperthermia is often a later sign of MH and may
be absent when the diagnosis is initially suspected, even though it is
a common clinical sign of MH. An analysis of reports of MH events
to the North American MH Registry (NAMHR) for 1987 to 2006
found that elevated or rapidly increasing temperature was one of the
first signs noted in only 8.2 percent, and the only initial sign in 3.9
percent, but was among the first three signs of an MH event in over
60 percent of patients with a mean temperature of 39.1ºC
• An updated analysis of NAMHR reports from 2007 to 2012 found
that the risk of death with an MH event was twice as likely when no
temperature monitoring was used, compared with core temperature
monitoring [48].
• We agree with the recommendation of the Malignant Hyperthermia
Association of the United States that core temperature should be
monitored for general anesthetics lasting more than 30 minutes [49].
• Myoglobinuria — Brownish-, cola-, or tea-colored urine indicates
the presence of myoglobinuria, which peaks about 14 hours after an
acute MH episode.
 Lab.Findings
• TYPICAL FINDINGS include..
• Mixed metabolic and respiratory acidosis — In a series of 196
cases of MH crisis with arterial blood gas (ABG) measurements
available, 99 percent of patients developed respiratory acidosis and
26 percent of these MH cases developed a metabolic acidosis (all
but one also had respiratory acidosis) [7].
• Hyperkalemia — Elevated potassium levels from muscle
breakdown can occur rapidly, especially in muscular patients.
• Elevated creatine kinase and myoglobinuria — Plasma creatine
kinase (CK) and urine myoglobin levels peak approximately 14
hours after an acute MH episode. Peak CK levels depend upon the
muscle mass of the patient and severity of muscle breakdown; in
muscular patients, levels may exceed 100,000 units/L.
 Clinical Diagnosis
• Mostly presumptive, based upon a presence of one or more of the
typical clinical manifestations associated with MH . The diagnosis
must be considered in all patients receiving triggering agents, as
over 90 percent of patients developing acute MH episodes have
negative family histories for MH, and over half have had uneventful
general anesthetics in the past [7].
• Treatment must be initiated emergently, as soon as the diagnosis of
MH is considered reasonable;
• Early clinical features reflect increased metabolic demand; the most
important of these is the presence of a mixed metabolic and
respiratory acidosis, presenting as an increased end-tidal carbon
dioxide (ETCO2) level which does not normalize with increasing
ventilation.
• MH should be suspected when one or more of the clinical features
arise without another persuasive clinical explanation; more features
increase the strength of the presumptive diagnosis:
• ●An increased ETCO2 level (>55 mmHg), which does not normalize
with increasing ventilation
• ●Generalized muscle rigidity, especially in the presence of
neuromuscular blockade
• ●Hyperkalemia-related arrhythmias and electrocardiographic
changes
• ●Tachycardia (not explained by clinical scenario)
• ●Tachypnea (not explained by clinical scenario)
• ●Myoglobinuria
• ●Hyperthermia
Lab studies to support diagnosis

• ●Arterial blood gas with pH <7.25, base excess below -8 mEq/L

• ●K >6 mEq/L
• ●Creatine kinase (CK) >10,000 international units
(without succinylcholine)
• ●CK >20,000 international units (with succinylcholine)
• ●Serum myoglobin >170 mcg/L
• ●Urine myoglobin >60 mcg/L
• Following an acute event, the determination of whether a suspected
clinical event represents a true MH episode can be estimated using
the MH clinical grading scale .
• Definitive diagnosis can be achieved through susceptibility testing.
 Differential diagnosis.

• Anesthesia/surgery-related issues
• ●Insufficient anesthesia/analgesia
• ●Insufficient ventilation/fresh gas flow – Patients with
insufficient ventilation/fresh gas flow commonly have hypercarbia,
respiratory acidosis, and, possibly, tachycardia and hypertension;
• ●Anesthesia machine malfunction – A malfunctioning expiratory
valve on the anesthesia machine will lead to rebreathing of exhaled
CO2,
• ●Increased CO2 absorption during laparoscopy – Hypercarbia
resistant to increases in minute ventilation may be due to continuous
CO2 absorption during laparoscopy. The presence of subcutaneous
emphysema, or known insufflation of CO2 into tissues
• Coexisting medical conditions
• ●Infection/septicemia – Sepsis may be accompanied by fever,
 Cont……
• Drug-related issues
• ●Anaphylaxis
• ●Transfusion reaction – Signs common to both transfusion
reaction and MH may include fever, brown urine, hypotension, and
signs of hyperkalemia.
• ●Drugs of abuse – A number of drugs of abuse may cause signs
that overlap with MH:
• •Cocaine may cause tachycardia, cardiac arrhythmias,
hypertension, and rhabdomyolysis.
• •MDMA (ecstasy)
• •Methamphetamine may lead to tachycardia, hypertension, sudden
cardiovascular collapse, and tachypnea.
 Cont…..
• ●Alcohol withdrawal – may include tachycardia, hypertension, and
fever.
• ●Neuroleptic malignant syndrome – The slow onset of neuroleptic
malignant syndrome (NMS) (heralded by mental status changes
evolving over one to three days) generally distinguishes it from MH.
Both syndromes may include fever, rigidity, and autonomic
instability, but NMS does not generally occur during administration
of general anesthesia. (See "Neuroleptic malignant syndrome".)
• ●Serotonin syndrome – This can result from excess ingestion or
inadvertent interactions of the many drugs that increase
serotonergic activity. It has many signs in common with MH
(tachycardia, volatile blood pressure, hyperthermia, and muscle
rigidity),
• ●Extrapyramidal side effects of antipsychotic medications –
include muscle spasms, but rapid onset and characteristic
localization (usually neck, tongue, or jaw) distinguish them from MH.
 Coexisting medical conditions

• ●Infection/septicemia – Sepsis may be accompanied by fever,

metabolic acidosis, and elevations in CK; this makes it difficult to
distinguish from MH. Generalized rigidity would not be seen in
sepsis.
• ●Pheochromocytoma – Undiagnosed pheochromocytoma may
present during surgery with episodic severe hypertension and
tachycardia [53].
• ●Thyroid storm – Thyroid storm may occur in patients with
untreated hyperthyroidism, precipitated by surgery or trauma.
Symptoms which overlap with MH include tachycardia, cardiac
arrhythmia, and hyperthermia to 104 to 105.Muscular signs
(generalized rigidity, masseter spasm, rhabdomyolysis, and
hyperkalemia) would not be present with thyroid storm.
 Cont…
• ●Cerebral pathology – Fever may result from hypoxic
encephalopathy, intracranial bleed, traumatic brain injury, or
meningitis.
• ●Neuromuscular disorders – Patients with various muscular
disorders, including Duchenne and Becker muscular dystrophy, may
develop rhabdomyolysis or hyperkalemia when exposed to volatile
anesthetics or succinylcholine; this is not fulminant MH (although
these drugs are contraindicated in patients with these conditions).
• ●Rhabdomyolysis – Rhabdomyolysis may occur from other causes
 APPROACH TO SUSPECTED MH CRISIS

• — Acute malignant hyperthermia (MH) is strongly suspected when

the anesthesiologist cannot bring down a rising end-tidal carbon
dioxide (ETCO2) level despite compensatory increases in minute
ventilation. The diagnosis is further supported by muscle rigidity
(generalized or prolonged masseter muscle rigidity [MMR]) or an
otherwise unexplained metabolic acidosis. When these clinical signs
occur without a persuasive alternative diagnosis, treatment of
presumed MH must be initiated
• Evaluate and manage hypercarbia — An unexpected rise in the
ETCO2 level is often the earliest sign of MH
• ●Increase minute ventilation – Hypercarbia that returns to normal
levels when ventilation is increased is not likely to be due to MH.
 Cont…..
• ●Eliminate obstruction of ventilation –A reasonable method to
correct this is to look sequentially:
• •Examine the patient (look for bronchial obstruction or
pneumothorax, mainstem intubation)
• •Inspect the breathing circuit (look for leaks, disconnects,
malfunctioning expiratory valve)
• •Inspect the anesthesia machine/ventilator (look for exhausted
CO2 absorbent, low fresh gas flow, tidal volume not being delivered)
• A high ETCO2 that decreases with increased ventilation without
becoming normal may also be due to a faulty CO2 monitor
• ●Seek sources of increased CO2 – During laparoscopic surgery,
ETCO2 may rise due to absorption of insufflated CO2. Temporarily
releasing the pneumoperitoneum should restore CO2 levels to
normal levels
• The use of a vascular clamp (eg, aortic cross clamp) or tourniquet
for prolonged periods of time leads to retention of metabolic
 Survey for supporting signs of MH

• ●Increasing ETCO2
• ●Generalized rigidity
• ●Premature ventricular contractions (or other signs of hyperkalemia)
• ●Tachycardia (not explained by the clinical situation)
• ●Unstable arterial pressure (high or low)
• ●Masseter spasm
• ●Unexplained metabolic acidosis
• If one or more of these signs is present without an alternate working
diagnosis, the patient should be presumed to have MH, and therapy
initiated.
 Initiate MH Protocol
• The MH treatment cart should be brought into the immediate area
(table 7).
• ●Optimize oxygenation and ventilation – Increase inspired
oxygen to 100 percent. Increase ventilation rate and/or tidal volume
to maximize ventilation and reduce the ETCO2. If the patient is not
intubated, should be intubated
• ●Discontinue triggering agents – Immediately discontinue volatile
anesthetic agents and inform the operating surgeon of the
diagnosis. The surgical procedure should be terminated as quickly
as possible; a surgical procedure that cannot be aborted should be
completed under intravenous anesthesia with non-triggering agents
(most often propofol). A charcoal filter should be attached to the
inspiratory and expiratory limbs of the breathing circuit (picture 1). It
is not necessary to change the anesthesia machine.
 Cont…
• ●Monitor and treat hyperkalemia – Hyperkalemia is treated (ie,
calcium, bicarbonate, and insulin-glucose) based upon the presence
of abnormal electrocardiogram waveforms (eg, peaked T waves) to
prevent the development of life-threatening arrhythmias or cardiac
arrest. Individuals with greater muscle mass appear to be at an
increased risk for hyperkalemia from rhabdomyolysis
• Use of calcium channel blockers during an acute MH crisis
is contraindicated because of the possibility that it can worsen
hyperkalemia and hypotension.
• ●Check labs – Measure electrolytes, blood gasses
for acid/base status, CK, serum myoglobin, coagulation parameters,
and fibrin split products (table 3). Arterial or venous blood gases
should be collected initially
 Cont..
• ●Administer DANTROLENE – Dantrolene is the only known
antidote for MH. It should be administered as a loading bolus of
2.5 mg/kg intravenously (IV), with subsequent bolus doses of
1 mg/kg IV until the signs of acute MH have abated. The ETCO2 will
generally return to normal as the dantrolene takes effect; in most
cases, dantrolene reverses the acute hypermetabolic process within
minutes., some patients, especially muscular males, may require
initial dantrolene doses approaching 10 mg/kg IV.
• A new dantrolene formulation (Ryanodex), which is dissolves
rapidly, became available for clinical use in 2014. It is supplied in
250 mg vials, reconstituted with only 5 mL of sterile water, and
warming is not needed. Because it is hyperconcentrated, blood
concentrations will be achieved faster in patients with acute MH
• All facilities where general anesthesia is administered should have
an adequate stock of dantrolene on site to treat an MH event. Each
facility should have a treatment protocol and a dedicated MH
 Initiate supportive care

• •Monitor and treat acidosis; consider bicarbonate

• •Treat cardiac arrhythmias as per advanced cardiac life support. (s
• •Monitor core temperature continuously (eg, esophageal, tympanic,
rectal probe). Patients with core temperature >39ºC should be
cooled (infuse cold saline intravenously; lavage open body cavities;
apply ice to surface; other techniques as needed) and continued
until the patient's temperature drops below 38.5ºC (101.3ºF).
• •Insert a bladder catheter to monitor urine color and volume. A urine
dipstick positive for heme (without red blood cells) indicates
myoglobinuria. Urine output should be kept above 1 mL/kg/hour until
the urine color returns to normal and the CK begins to decrease
• •Monitor muscle compartments for acute compartment syndrome;
rhabdomyolysis can result in compartment syndrome
• •Institute measures to prevent myoglobinuria-induced renal failure
(ie, hydration, diuretics, bicarbonate).
• •Monitor for DIC.
 Refractory MH
• ● Extracorporeal membrane oxygenation
(ECMO) may be considered as a last
resort for patients with persistent cardiac
arrest unresponsive to the treatments in
the MH protocol
 ONGOING CARE

• — Following completion of the surgical procedure, the patient

should be transferred to an intensive care unit for ventilatory support
(as needed) and hemodynamic monitoring for at least 24
hours. Dantrolene can be stopped, or the interval between doses
increased to every 8 or 12 hours if all of the following criteria are
met:
• ●Metabolic stability for 24 hours
• ●Core temp is less than 38°C
• ●Creatine kinase (CK) is decreasing
• ●No evidence of myoglobinuria
• ●Muscle is no longer rigid
 ..
• Recrudescence occurs in up to 25 percent of patients after initial
treatment, at a mean of 13 hours Maintenance doses
of dantrolene (1 mg/kg intravenous [IV] every four to six hours)
should continue for 24 to 48 hours after the last observed sign of
acute malignant hyperthermia (MH) .
• Dantrolene - Its most common local adverse reaction is venous
irritation or thrombosis at the site of administration due to its high
pH; side effects include nausea, malaise, lightheadedness, and mild
to moderate muscle weakness [57]. Respiratory muscle weakness
may occur when larger doses are used, especially in patients who
are debilitated.
 Mortality
• —Mortality from MH has declined significantly with the routine use of
end tidal CO2 monitoring and availability of dantrolene and is
reported to be between 1 and 17 percent [57,58].
• MHAUS receives notice of approximately 100 cases of MH per year,
and reports of one or two MH related deaths every one to two years.
Thus a rough estimate of mortality is 0.5 percent.
• . In theory, continuous core temperature monitoring allowed more
rapid diagnosis of an MH event, more rapid treatment, and
reductions in peak temperature and duration of hyperthermia.
 COUNSELING AFTER ACUTE MH

• — Following recovery from an acute malignant hyperthermia (MH)

event, we counsel patients that, until definitive testing for MH
susceptibility (MHS) is complete, they should:
• ●Not have anesthesia with triggering agents
• ●Avoid exercise in excessive heat or humidity, as this may trigger an
event
• ●Inform family members of the possible MH episode, as MHS is a
genetic condition and family members may also need to be
evaluated
 SUMMARY AND RECOMMENDATIONS

• ●Malignant hyperthermia (MH) is an autosomal dominant disorder

that may present with a hypermetabolic crisis when susceptible
individuals are exposed to volatile anesthetics or succinylcholine.
• ●MH-susceptible (MHS) individuals have skeletal muscle receptor
abnormalities, most often in ryanodine receptors (RYR1), which
allow excessive intracellular calcium to accumulate in response to
triggering agents. This triggers intracellular events leading to
skeletal muscle hypermetabolism.
• ●Although the initial clinical signs of MH typically occur within one
hour of anesthesia induction, the onset of MH can occur any time
during the administration of triggering agents.
• ●We suggest continuous core temperature monitoring during
anesthetics lasting more than 30 minutes.
 Clinical diagnosis

• ●The diagnosis of acute MH is based upon clinical signs (eg,

hypercapnia, tachycardia, muscle rigidity, rhabdomyolysis,
hyperthermia, and arrhythmia); the most reliable sign is hypercapnia
that is resistant to increasing the patient's minute ventilation, with a
mixed metabolic and respiratory acidosis. Other prominent early
clinical signs include sinus tachycardia and muscle rigidity.
Hyperthermia is a later sign of MH.
• ●Technical factors that would account for hypercapnia should be
excluded; this includes decreased carbon dioxide elimination (eg,
inadequate ventilation, rebreathing exhaled CO2) or increased
production (eg, absorption of laparoscopic CO2). Other medical
causes of these clinical signs are numerous and more common than
MH. consideration of the differential diagnoses should not interfere
with a presumptive diagnosis of MH and initiation of the acute MH
management protocol.
 Acute management

• ●As soon as the presumptive diagnosis of MH is made, call for

assistance and the MH treatment cart (table 7) and initiate the
following (see 'Initiate MH protocol' above):
• •Discontinue volatile anesthetic agents; if available, add charcoal
filters to anesthesia breathing circuit .
• •Hyperventilate with 100 percent oxygen.
• •If surgery cannot be terminated immediately, begin non-triggering
anesthetic (eg, propofol).
• •We recommend immediate administration of dantrolene (Grade
1A). The initial dose is 2.5 mg/kg intravenous (IV), to be given
rapidly through a large-bore IV. The end-tidal carbon dioxide
(ETCO2) typically normalizes within minutes; subsequent bolus
doses of 1 mg/kg (up to 10 mg/kg) may be needed if signs of MH
have not abated, most often in muscular males.
• •Assess for hyperkalemia and treat if present
 Cont…….
• •Monitor blood gases, core temperature, creatine kinase (CK), urine
output, urine color, electrolytes, coagulation parameters, and fibrin
split products, and treat abnormalities as needed.
• •Treat cardiac dysrhythmias, which are usually responsive to
treatment of acidosis and hyperkalemia. Advanced cardiac life
support protocols should be used as indicated
• ●Patients should have supportive care in an intensive care unit for at
least 24 hours and be closely monitored for recurrence.
Continue dantrolene for 24 to 48 hours. (See 'Ongoing care' above.)
• ●Following an acute event, the likelihood that a suspected clinical
event represents a true MH episode can be estimated using the MH
clinical grading scale. Definitive diagnosis requires susceptibility
testing. While awaiting evaluation, the patient should be counseled
to receive only non-triggering anesthetics, to limit exposure to
excessive heat and humidity, and to inform family members of the
diagnosis.
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