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PARTV.
METABOLIC AND ENDOCRINE CRISES
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25.
INTRODUCTION TOMETABOLIC AND ENDOCRINE DISEASES
Stephen F. Dierdorf
he metabolic and endocrine systems perform a myriad of
functions in order to maintain the physiologic homeo-
T
stasis of the individual. e control and feedback systems
are complex, and subtle changes in their function can lead to
serious disease. e interaction of surgery and anesthesia with
activation of the surgical stress response aects control of the
metabolic and endocrine systems. Anesthesiologists must
understand the changes in metabolism that occur during the
perioperative period. Metabolic/ endocrine dysfunction may
be a primary part of the patient’s surgical problem, or such
dysfunction may be a secondary result of the condition. e
ability to monitor metabolic function during the perioperative period has markedly improved over the past three decades.
INFLUENCE OFANESTHESIA ONOUTCOME
e increase in knowledge about the surgical stress response
has led to considerable interest in surgical and anesthetic
techniques that may reduce the negative impact of the
stress response on patient outcome. Many questions have
been posed. Is there less stress with endoscopic surgery?
Does regional anesthesia reduce surgical stress? Does an
opioid- based anesthetic reduce stress better than anesthesia with a halogenated, volatile anesthetic? How does the
patient’s preoperative physiologic status inuence the stress
response? Despite many studies that have attempted to
resolve these controversies, the answers remain elusive.
4,5
It
is, however, quite likely that the answers to these questions
SURGICAL STRESS RESPONSE
require information not yet known. e anesthesiologist
must always strive to integrate new knowledge of metabolism and endocrine function into changes in clinical prac-
Disease and the trauma of surgery trigger local tissue and
systemic inammatory responses. e stress response
tice.6 e answers to improved patient outcome may well
reside in theseareas.
produces changes in function of the central nervous system, immune system, and endocrine system. e normal response to trauma (surgical or nonsurgical) has two
REFERENCES
phases. e rst phase (shock) occurs during the rst 24
hours and promotes immediate survival. Shock is characterized by cardiovascular responses (e.g., vasoconstriction)
that direct blood ow to critical organs. e second phase
is characterized by hypermetabolism and is directed at
repair of damaged organs and healing. Physiologic manifestations of the hypermetabolic phase include tachycardia, hyperthermia, hyperglycemia, and uid retention.1
ese gross physiologic responses have been well described
for decades. Cellular and subcellular mediation of the
stress response, however, have only been elucidated in
recent years. ese mechanisms include release of inammatory chemicals such as cytokines, changes in ion transport across cell membranes, and eects on the immune
2,3
system.
1. Kohl BA, Deutschman CS. e inammatory response to surgery and trauma. Current Opinion in Critical Care. 2006;12:
325– 32.
2. Borsook D, George E, Kussman B, Becerra L. Anesthesia and
perioperative stress:consequences on neural networks and postoperative behaviors. Progress in Neurobiology. 2010;92:601– 12.
3. Arias J- I, Aller M- A, Arias J. Surgical inammation: a pathophysiological rainbow. Journal of Translational Medicine. 2009;
7:19– 33.
4. Banz VM, Jakob SM, Inderbitzen D. Improving outcome aer
major surgery: pathophysiological considerations. Anesthetis &
Analgesia. 2011;112:1147– 55.
5. Wol AR. Eects of regional analgesia on stress responses to pediatric surgery. Pediatric Anesthesia. 2012;22:19– 24.
6. Scott MJ, Miller TE. Pathophysiology of major surgery and the
role of enhanced recovery pathways and the anesthesiologist to
improve outcomes. Anesthesiology Clinics. 2015;33:79– 91.
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SECTIONA
METABOLIC DISTURBANCES
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26.
MALIGNANT HYPERTHERMIA
Christopher L.Heine
CLINICALCASE
troponin that permits the interaction of actin and myosin
and resultant muscle contraction. Muscle relaxation occurs
A 12- year- old healthy male is scheduled for an open reduction, internal xation of a fractured right wrist sustained
when he fell from a trampoline. He has never had anesthesia
or surgery. Although neither of his parents have had anesthesia, his mother reports that she has an aunt and a cousin
who had complications surrounding surgery. It is unclear
to her what the specic complication was, but it may have
involved high fevers. e patient’s parents are more anxious
about the anesthesia than the surgery. ey want to know
how their son’s anesthesia will be managed.
when Ca+2- ATPase transports free Ca+2 back into the SR.
is decline in cytoplasmic Ca+2 returns troponin, actin,
and myosin to their restingstate.
Most individuals susceptible to MH have mutations
in the RyR1. Aer exposure to a triggering agent, these
RyR1 mutations produce an increased ux of Ca+2 from
the SR into the myoplasm. e increased release of Ca+2
causes a marked contracture response, hypermetabolism,
and rhabdomyolysis. Relaxation in MH is also abnormal,
as the RyR1 does not close and the control of Ca+2 reuptake islost.
PATHOPHYSIOLOGY
Malignant hyperthermia (MH) is a pharmacogenetic dis-
e triggers of MH are succinylcholine and volatile, halogenated inhaled anesthetics. e precise mechanism by which these triggers interact with the RyR1 is
notknown.
ease of skeletal muscle that, when triggered, results in a
hypermetabolic process that is associated with high morbidity and mortality. Although the likelihood of survival from an episode of MH has greatly improved due to
advances in monitoring and the ready availability of dantrolene, it is still one of the most feared adverse reactions
to anesthesia.
GENETICS OFMALIGNANT HYPERTHERMIA
Human MH is an autosomal dominant disorder with
incomplete penetrance and variable expression. Swine
models that have historically served as the best model for
MH research actually have an autosomal recessive pattern
of inheritance. e RyR1 mutations responsible for 50%–
MECHANISM
Normal muscle contraction occurs when acetylcholine that
is released by a motor neuron binds to nicotinic receptors
on the sarcolemma of the muscle cell. is depolarizes the
muscle membrane and the transverse tubules (TTs). e
TTs contain dihydropyridine receptors (DHPR, voltagegated Ca+2 channels). e TTs are intertwined with the
sarcoplasmic reticulum (SR) and linked with ryanodine
receptors (RyR1s). Depolarization of the TT results in
a conformational change of the DHPR that opens the
RyR1 and releases Ca+2 into the myoplasm.1 Ca+2 binds
to troponin- C, which causes a conformational change in
70% of MH susceptibility are located on chromosome 19.
Also, DHPR mutations on chromosomes 1 and 7 have
been identied in MH- susceptible humans. e genetics
of human MH are much more complex than the genetics
of MH- susceptible swine. is complexity may explain the
variation in severity and the clinical presentation of MH in
humans. Although genetic testing is valuable, it is not denitive for the diagnosis of MH susceptibility.
ere are other factors concerning MH that are not
easily explained by our current knowledge. A history of
uneventful prior exposure to potential triggering agents
does not preclude the possibility of MH susceptibility.
Individuals that are weak MH responders may not manifest
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evidence of MH during a brief exposure to inhaled, halogenated anesthetics. Physical stress is a well- known trigger in susceptible swine, and stress as a trigger of MH in
humans has been reported with increasing frequency in
recentyears.
RISK
BOX 26.1 DISORDERS WITH CLINICAL FEATURES SIMILAR
TOMALIGNANT HYPERTHERMIA
Hyperthyroidism
Sepsis
Pheochromocytoma
e incidence of MH varies from 1:40,000 to 1:250,000
anesthetics in the adult population. e incidence in
children may be as high as 1:15,000 anesthetics. It is
unclear whether the likelihood of MH in children is
truly increased or whether children are more likely to
be exposed to triggering agents (e.g., inhalation induction with volatile anesthetics). Although the incidence
Metastatic Carcinoid
Cocaine Intoxication
Neuroleptic Malignant Syndrome
Serotonin Syndrome
Muscular Dystrophy
of acute MH episodes is low, the prevalence of MH
susceptibility in the general population may be as high
as 1:3000.
2
Prior to the discovery of the ecacy of dantrolene,
reported mortality was as high as 70% from an acute episode of MH. e two most recent reviews of the North
American Malignant Hyperthermia Registry (NAMHR)
reported a mortality of 1.4% from 1987 to 2006 and a mortality of 9.5% from 2007 to 2012. e increase in mortality
may have been due to inadequate core temperature monitoring.3 e MH- susceptible patients that receive a nontriggering anesthetic have virtually no reported mortality.
Identication of MH susceptibility prior to administration
of anesthesia is, consequently, of paramount importance.
ere are a number of diseases that have been historically linked to MH susceptibility. e three diseases most
clearly associated with MH susceptibility are central core
disease, multiminicore disease, and King- Denborough
syndrome. e precise genetic linkage of these diseases to
MH remains to be elucidated.4 Patients with muscular dystrophy may experience anesthesia- induced rhabdomyolysis
that mimics certain features of MH. ere is, however, no
Muscle rigidity can be severe and is not amenable to neuromuscular blockade. Arterial blood gas analysis initially
reveals hypercarbia and a pure respiratory acidosis. e acidosis very quickly, however, shows a metabolic component,
as hypermetabolism creates more lactate. Arecent review
of pediatric cases identied tachycardia (73.1%), hypercarbia (68.6%), and rapid temperature increase (48.5%)
as the most common signs of an acute MH episode.6 If
not rapidly treated, patients can exhibit skin mottling,
rhabdomyolysis, hyperkalemia, cardiac dysrhythmias, and
coagulopathy.
ere are some simple causes of isolated features
of MH such as hyperthermia secondary to excessive
warming, hypercarbia due to inadequate ventilation or
exhausted soda lime, and tachycardia secondary to an
inadequate level of anesthesia. ese causes would not
produce all the features of MH. ere are some disorders
that more closely mimic MH (Box 26.1). Ascoring system
has been developed to assist the clinician in diagnosing a
true MH reaction (Tables 26.1, 26.2,).
7
convincing evidence that muscular dystrophy patients are
MH susceptible.
5
MANAGEMENT
ASSESSMENT OFTHE PATIENT
e rst sign of an MH reaction is generally an increase in the
end- tidal CO2 (ETCO2) level that does not decrease with
an increase in minute ventilation. Tachycardia as a manifestation of the hypermetabolism is also an early sign of MH.
Although temperature increase occurs, the rate of temperature rise is variable and is a later sign of hypermetabolism.
194 SECTION A. METABOLIC DISTURBANCES
e anesthesiologist is confronted with two dierent
clinical situations with MH. e rst is an MH reaction
in a patient without known susceptibility. e second is
planning an anesthetic for a patient with known MH susceptibility. e website for the Malignant Hyperthermia
Association of the United States (MHAUS) provides
valuable information about MH for healthcare providers
and patients.
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TABLE26.1 CLINICAL GRADING SYSTEM TOASSIST WITH THE
DIAGNOSIS OFA MALIGNANT HYPERTHERMIA REACTION
Process Indicator Points
Rigidity Generalized muscle rigidity 15
Masseter spasm after succinylcholine 15
Muscle
breakdown
Respiratory
acidosis
Temperature
increase
Cardiac
involvement
Family history + family history rst- degree relative 15
CK > 20,000 IU after succinylcholine 15
CK > 10,000 IU without succinylcholine 15
Cola- colored urine 10
Myoglobin in urine >60 mcg/ L 5
Myoglobin in serum >170 mcg/ L 5
Serum K >6 mEq/ L 3
ETCO2 > 55 with controlled ventilation 15
PaCO2 >60 with controlled ventilation 15
ETCO2 >60 spontaneous ventilation 15
PaCO2>65 spontaneous ventilation 15
Inappropriate hypercarbia 15
Inappropriate tachypnea 10
Inappropriate rapid increase in temp 15
Inappropriate temp >38.8 degrees C 10
Inappropriate sinus tachycardia 3
Ventricular tachycardia or brillation 3
+ family history, not rst- degree 5
TABLE26.2 PREDICTION OFMALIGNANT HYPERTHERMIA
FROMCLINICAL GRADINGSCALE
Score Range MH rank Likelihood of MH Episode
0 1 Almost never
3–9 2 Unlikely
10–19 3 Less than likely
20–34 4 Greater than likely
35–49 5 Very likely
50+ 6 Almost certain
SOURCE:Reprinted with permission from Larach MG, etal. Aclinical grading scale to
predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771– 9.
eliminate other causes and begin treatment. Unexplained
tachycardia and/ or an increase in ETCO2 warrant an
arterial blood gas analysis. During an acute MH reaction,
arterial blood gas analysis typically reveals a severe mixed
respiratory and metabolic acidosis. An acute MH reaction
is a true operating room emergency, and multiple personnel should be engaged to assist with management. Surgery
should be discontinued as quickly as possible. All triggering
agents should be discontinued and charcoal lters inserted
in the inspiratory and expiratory limbs of the anesthesia
breathing circuit. e charcoal will rapidly scrub the system of halogenated volatile anesthetics. Hyperventilation
with 100% oxygen should be instituted. Dantrolene
(2.5 mg/ kg) should be reconstituted and administered
intravenously as soon as possible (Table 26.3). Dantrolene,
a postsynaptic muscle relaxant, is the most specic therapy
for MH. Dantrolene inhibits Ca+2 release at some point
in the excitation- contraction coupling process, thereby
halting uncontrolled muscle contraction.8 Dantrolene
administration should be continued until the signs of
hypermetabolism subside. Some patients have required as
Other indicators Base decit - 8 mEq or greater 10
Arterial pH < 7.25 10
Rapid reversal of MH after dantrolene 5
Resting elevated CK level
Treatment ofan Acute Malignant
Hyperthermia Reaction
e key to successful management of an acute MH episode
is early recognition and prompt treatment with dantrolene.
If MH is suspected, the anesthesiologist must quickly
MALIGNANT HYPERTHERMIA 195
TABLE26.3 MEDICATIONS FORTREATMENT OFAN ACUTE
EPISODE OFMALIGNANT HYPERTHERMIA
Drug Initial Dose Indication
Dantrolene 2.5 mg/ kg Suspected MH
NaHCO
3
25% Dextrose 1–2 g/ kg Hyperkalemia
Insulin (regular) 0.1 U/ kg Hyperkalemia
CaCl2 or gluconate 20–30 mg/ kg Hyperkalemia
Furosemide 0.5 mg/ kg Oliguria
1–2 mEq/ kg Metabolic acidosis
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