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much as 20 mg/ kg. Intravenous dantrolene preparations are
available in two commercial preparations:Dantrium (JHP
Pharmaceuticals, Parsippany NJ) and Ryanodex (Eagle
Pharmaceuticals, Woodcli Lake, NJ). Dantrium is packaged as a lypholized powder with 3 grams of mannitol at a
pH of 9.5. Each 20- mg vial must be reconstituted with 60
It is important to remember that rapid recognition of
MH and prompt treatment with dantrolene are keys to
survival and the avoidance of late complications of MH.
Despite the ready availability of dantrolene, delay in the
diagnosis and treatment of MH still causes signicant morbidity and mortality.
mL of warm sterile water and shaken until the solution is
clear orange. Dantrium should be administered through a
large vein to minimize the risk of thrombophlebitis secondary to the solution’s alkalinity. Each Ryanodex vial contains
250 mg of dantrolene and 125 mg of mannitol and should
be reconstituted with 5 mL of sterile water. e preparation and administration time for Ryanodex is 1 minute
compared to 22 minutes for conventional dantrolene
preparations.
Side eects of intravenous dantrolene include muscle
weakness, phlebitis at the site of injection, and severe tissue necrosis if dantrolene extravasates into the tissues surrounding the vein. Patients receiving oral dantrolene oen
complain of nausea, emesis, dizziness, and diarrhea.
Aer initiation of dantrolene therapy, treatment is
directed at the hypermetabolic eects of the reaction. Serial
arterial blood gas measurements of pH, PaCO2, potassium,
creatine kinase (CK), and myoglobin should be performed.
Metabolic acidosis can be treated with bicarbonate, and
hyperkalemia may be treated with intravenous calcium
and/ or a glucose- insulin infusion. Intravenous calcium
has not been shown to aggravate acute MH. Urine output should be carefully measured, as myoglobin can cause
renal insuciency. Diuretics such as mannitol or furosemide may be required to maintain urine output. Cardiac
dysrhythmias may be treated according to the appropriate
advanced life support guidelines, however calcium channel
blockers (verapamil) in combination with dantrolene can
cause severe myocardial dysfunction and should be avoided.
Baseline coagulation studies should also be obtained.
Active surface cooling can be started; care must be
taken to prevent cold thermal injury to the skin. If the
patient responds rapidly to dantrolene, hypothermia may
develop if aggressive cooling continues. e patient should
remain intubated until the reaction abates. Sedation can
be provided with infusions of propofol, opioids, and dexmedetomidine. When metabolism returns to normal, the
patient can be extubated and admitted to an intensive care
unit (ICU) for further monitoring. e patient should
be closely monitored for signs of recurrence for 24 to 48
hours. e CK levels may peak at 40,000 to 60,000 within
24 hours of the episode and the patient may complain of
severe myalgia for 48 to 72hours.
Planning forthe Malignant Hyperthermia
Susceptible Patient
Any location where general anesthesia is administered must
be prepared to treat an acute episode of MH. Preparation
should include the ready availability of a completely
stocked MH cart (Table 26.4). e use of cognitive aid
checklists and education of operating room personnel with
mock drills have been shown to improve team performance
and avoid errors of omission when treating an acute MH
episode. Preparation of the anesthesia machine requires
purging of residual volatile halogenated anesthetics and
steps to prevent inadvertent administration of a triggering
agent (Box 26.2). In geographic areas with a relatively high
incidence of MH, it may be prudent to have a dedicated
MH anesthesia machine that has no vaporizers and has
never been exposed to volatile anesthetics. Machines that
have been exposed to volatile anesthetics were traditionally purged with high- ow oxygen for many hours prior to
clinical use. More recently, commercially available activated
charcoal lters attached to the inspiratory and expiratory
limbs of the anesthesia breathing circuit have been shown
to maintain volatile anesthetic concentrations at less than 5
parts per million for 12hours.
Preparation of the MH- susceptible (MHS) patient
begins with a thorough discussion of the disease and the
potential dangers of an MH reaction with the patient
and the patient’s family. ey should also be assured that
the probability of an MH episode is extremely low when
a “safe” anesthetic is employed. ey must also understand
that physical stress may trigger MH and close monitoring of
the patient is warranted at all times. e possible need for
invasive monitoring and postoperative management in the
ICU should also be discussed.
ere are a large number of anesthetic medications that
are safe for MHS patients (Table 26.5).9 ese are intravenous drugs such as propofol, barbiturates, benzodiazepines,
opioids, nondepolarizing muscle relaxants, local anesthetics, and dexmedetomidine. Nitrous oxide is also safe. Very
anxious patients can be sedated with oral midazolam prior
to insertion of an intravenous catheter aer local anesthesia is applied or injected at the insertion site. Inhalation
196 SECTION A. METABOLIC DISTURBANCES
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197
TABLE26.4 CONTENTS OFA MALIGNANT
HYPERTHERMIACART
Medications
Dantrolene (Ryanodex is preferred as the reconstitution time is shorter)
Dantrium, 36 20- mg vials in the institution
Ryanodex, two 250- mg vials
Sodium bicarbonate (8.4%) ve 50- mL vials
50% dextrose three 50- mL vials
Insulin (refrigerated, immediately available)
Calcium chloride/ calcium gluconate 1000- mg vials
Lidocaine (cardiac preparation) 100 mg
Equipment
Activated charcoal lters 2 pair
BOX 26.2 PREPARATION OFTHE ANESTHESIA MACHINE
FORAN MHS PATIENT
1. Remove all vaporizers (halogenated volatile anesthetics).
2. Change CO2 absorbent.
3. Purge the anesthesia machine with 100% oxygen at 10
liters per minute for 10 to >90 minutes. Consult the
machine manufacturer for specic details.
4. The preferred alternative to #3 is to purge the machine
for 90 seconds and then attach activated charcoal lters
to the proximal inspiratory and distal expiratory limbs of
the anesthesia breathing circuit.
parents considered this option, they felt that the anxiety
level in their son would preclude regional anesthesia.
Syringes
ve 60- mL syringes and sterile water for reconstitution of Dantrium
three 5- mL syringes for reconstitution of Ryanodex
e anesthesia machine was prepared as described in Box
26.2. e patient received oral midazolam (15 mg) 20
minutes prior to induction. Aer transfer to the operating room, a 22 gauge intravenous catheter was inserted
Intravenous catheters (various sizes)
Nasogastric tubes
Toomey syringe (gastric irrigation)
Central venous line kits
Laboratory Testing Supplies
Arterial blood gases
Creatine kinase (CK)
Myoglobin
Electrolytes
Lactate
Prothrombin time/ Partial thromboplastin time (INR)
Urine for myoglobin
Cognitive Aid Checklist from MHAUS.ORG
aer inltration of 1% lidocaine. An ECG, noninvasive
blood pressure cu, and pulse oximeter were attached
prior to induction of anesthesia. Anesthesia was induced
with propofol (3 mg/ kg) and fentanyl (2 mcg/ kg).
Rocuronium (0.6 mg/ kg) was administered to facilitate tracheal intubation. A remifentanil infusion at 0.3
mcg/ kg/ min was started. Aer adequate relaxation, the
trachea was intubated without diculty with a 6.0mm
ID tracheal tube. End- tidal CO2 was carefully monitored
during surgery and remained at 35 to 38mmHg throughout the procedure. e surgeon inltrated the incision
site with 0.25% bupivacaine during closure of the incision. Morphine (0.025 mg/ kg) was administered prior
to discontinuation of the propofol and remifentanil infusions. Aperipheral nerve stimulator was used to monitor neuromuscular function. Aer adequate spontaneous
ventilation resumed and sustained tetanus at 100 Hz was
measured with a peripheral nerve stimulator, the trachea
was extubated and the patient was transferred to the
of nitrous oxide during intravenous cannulation can also
be considered. Total intravenous anesthesia (TIVA) with
propofol and an opioid is the most frequently administered
type of anesthesia for MHS patients.
PACU. e postoperative course was unremarkable and
the patient was discharged from the hospital 16 hours
aer the conclusion of surgery. Prolonged postoperative
monitoring for MH was not indicated.
Preparation of this patient for anesthesia included a
thorough discussion of the plan for anesthesia and risk of
an acute MH episode. It was suggested to the parents that
regional anesthesia with a brachial plexus block would be
a suitable alternative to general anesthesia. Although the
FOLLOW- UP
Despite many years of research surrounding testing for MH
susceptibility, the gold standard in the United States is the
MALIGNANT HYPERTHERMIA 197
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TABLE26.5 ANESTHETIC DRUGS SAFE FORMALIGNANT
HYPERTHERMIA SUSCEPTIBLE PATIENTS
Benzodiazepines Local Anesthetics
Midazolam
Diazepam
Propofol Bupivacaine
Etomidate Ropivacaine
Barbiturates Procaine
Thiopental
Methohexital
Ketamine
Opioids
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Morphine
Hydromorphone
Oxycodone
Methadone
Naloxone (opioid antagonist)
Muscle relaxants
Cis- atracurium
Atracurium
Lidocaine
Mepivacaine
Nitrous oxide
TABLE26.6 RECOMMENDATIONS FORTESTING
FORMALIGNANT HYPERTHERMIA SUSCEPTIBILITY
Scenario Recommendation
Family history of positive CHCT 1. CHCT
2. Genetic screening
Possible MH episode 1. CHCT
2. Genetic screening if CHCT+
Suspicious MH episode 1. CHCT
2. Genetic screening if CHCT+
Known MH mutation in family 1. Genetic screening
demonstrates hypercontractility. e CHCT has a sensitivity of 97% and a specicity of 78%. It is important that
patients be referred to a reputable MH testing center. If the
test is negative, the patient is considered to be not susceptible to MH. If the test is positive, the patient can be referred
for genetic testing to determine whether a known RyR1
mutation exists. If the genetic screen is positive, rst- degree
relatives of the patient should undergo genetic screening to
determine whether they possess the mutation. If the genetic
screen of the relatives is negative, however, it does not mean
that they are nonsusceptible (Table 26.6). Much remains to
be learned about the genetics of malignant hyperthermia.
10
During the postoperative visit, the parents requested
the anesthesiologist’s advice about denitive testing. Since
the history of MH was in the mother’s family, she decided
to undergo testing with CHCT. She was referred to an
appropriate testing center and was found to be positive.
Genetic screening of both the son and mother revealed that
they shared a known RyR1 mutation. It was recommended
that other relatives of the mother be tested.
Rocuronium
Pancuronium
Mivacurium
Metocurine
D- tubocurarine
caeine- halothane contracture test (CHCT). e in vitro
contracture test (IVCT) that is used in European laboratories is similar to the CHCT. In both tests, a muscle sample
is removed from the vastus lateralis muscle of the thigh
and exposed to halothane and caeine. An MH muscle
198 SECTION A. METABOLIC DISTURBANCES
CASE- BASED LEARNING DISCUSSION
1. Based on the family history, how likely do you think it
is that this patient is susceptible to MH? Is an MH- safe
anesthetic appropriate for this patient?
2. How can an acute episode of MH be dierentiated
from other causes of intraoperative tachycardia? ere
are many causes of intraoperative tachycardia. Most
of the causes are transient, and very few would result
in increased production of carbon dioxide. Could
thyroid storm have a similar presentation as MH?
Intraoperative thyroid storm may closely mimic MH.
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199
Both exhibit tachycardia and temperature increase.
REFERENCES
MH, however, causes a more rapid and profound
acidosis than thyroid storm. e tachycardia induced by
thyroid storm generally responds very rapidly to betaadrenergic blockers.
3. Can ketamine be used for MHS patients? Although
ketamine is not a trigger of MH in animals or humans,
the increase in sympathetic activity with tachycardia
that may be caused by ketamine could be interpreted as
an early signofMH.
4. If a patient with suspected MH has a negative CHCT,
can they receive anesthesia with MH- triggering drugs?
Data from testing centers in both Europe and the
United States suggest that false- negative results from
denitive MH testing are extremely rare. What is the
downside of administering a nontriggering anesthetic
“just to besafe”?
5. Should this patient be tested prior to elective surgery?
What are the potential negative aspects of testing other
than immediatecost?
1. Van Petegem F. Ryanodine receptors:allosteric ion channel giants.
Journal of Molecular Biology. 2015;427:31– 53.
2. Rosenberg H, Pollock N, Schiemann A, etal. Malignant hyperthermia:a review. Orphanet Journal of Rare Diseases. 2015;10:93.
3. Larach MG, Brandom BW, Allen GC, etal. Malignant hyperthermia
deaths related to inadequate temperature monitoring, 2007– 2012: a
report from the NAMHR of the Malignant Hyperthermia Association
of the US. Anesthesia & Analgesia. 2014;119:1359– 66.
4. Brislin RP, eroux MC. Core myopathies and malignant hyperthermia susceptibility: a review. Pediatric Anesthesia. 2013;23:
834– 41.
5. Gurnaney H, Brown A, Litman RS. Malignant hyperthermia and
muscular dystrophies. Anesthesia & Analgesia. 2009;109:1043– 48.
6. Nelson P, Litman RS. Malignant hyperthermia in children: an
analysis of the North American Malignant Hyperthermia Registry.
Anesthesiology. 2014;118:369– 74.
7. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale
to predict malignant hyperthermia susceptibility. Anesthesiology.
1994;80:771– 79.
8. Krause T, Gerbershagen MU, Fiege M, et al. Dantrolene:a review
of its pharmacology, therapeutic use and new developments.
Anaesthesia. 2004;59:364– 73.
9. Wappler F. Anesthesia for patients with a history of malignant
hyperthermia. Current opinion in anesthesiology. 2010;23:417– 22.
10. Stowell KM. DNA testing for malignant hyperthermia:the reality
and the dream. Anesthesia & Analgesia. 2014;118:397– 406.
MALIGNANT HYPERTHERMIA 199
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27.
PORPHYRIA
Stephen F. Dierdorf
CLINICALCASE
A 34- year- old female with severe abdominal pain presented
for an emergency exploratory laparotomy for suspected
acute cholecystitis. e medical history was obtained from
her husband, as the patient was disoriented. She underwent
an appendectomy at age 27, but was told that the appendix
was normal. She has been hospitalized on three occasions in
the past ve years for emotional disturbances. For the past
6days, she has been taking an oral antibiotic (sulfonamide)
for a urinary tract infection.
Her heart rate was 142 beats per minute and her blood
pressure was 152/ 93mmHg. She was afebrile. e intraoperative course was uneventful, and the surgical exploration
revealed a grossly normal gallbladder. At the conclusion of
surgery, emergence was slow and spontaneous respiratory
eort was poor. She was transferred to the intensive care
unit (ICU) intubated and mechanically ventilated.
ACUTE PORPHYRIAS
Acute intermittent porphyria (AIP) is the most common of
the acute porphyrias, with an incidence of 1 in 75,000 people. e incidence is higher in Northern Sweden and South
Africa. e acute porphyrias are of special interest because
of the severity of the clinical manifestations and the potential precipitation of attacks by certain drugs. e most
common clinical presentation of AIP occurs in women
aer puberty and before menopause. Factors that may
trigger attacks include hormonal changes during menstruation, decreased carbohydrate intake, physical exhaustion,
acute illness, and exposure to triggering drugs. Triggering
drugs include barbiturates, estrogens, hydantoins, sulfonamides, and other drugs that induce cytochrome P- 450
(Table27.1).
Signs and symptoms of an acute attack involve the
gastrointestinal, neurologic, and cardiovascular systems
(Box 27.2). Common gastrointestinal complaints are severe
abdominal pain, emesis, and constipation. Neurologic
PATHOPHYSIOLOGY
manifestations include pain in the extremities and back,
paresis that may progress to respiratory failure (motor
e porphyrias are caused by enzymatic deciencies in the
heme synthesis pathway. Heme is essential for life and is
a basic component of hemoglobin, myoglobin, and cytochromes. Heme is synthesized from succinyl coenzyme
A and glycine in a process that requires eight enzymatic
steps (Figure 27.1). Each of the porphyrias is caused by a
deciency of one of the eight enzymes in the pathway that
results in the accumulation of porphyrin precursors with
toxic eects. Heme production occurs in the liver and erythroid tissue. Hepatic heme synthesis is very tightly controlled, and an enzyme deciency can rapidly lead to the
accumulation of toxic byproducts. ere are several classication systems for the porphyrias. e most convenient system classies porphyrias as acute or nonacute (Box 27.1).
e acute porphyrias are all hepatic in origin and causes
neurovisceral symptoms.
1
axonal neuropathy similar to Guillain- Barré), confusion,
hallucinations, and seizures. Tachycardia and hypertension
are usually present and may be secondary to autonomic dysfunction or excessive levels of circulating catecholamines.
Exposure of the patient’s urine to light and air may turn the
color of the urine to pink, dark red, orblack.
Although the precise mechanism of porphyria neurotoxicity is unknown, the accumulation of delta- aminolevulinic
acid (ALA) and porphobilinogen (PBG) adversely aects
axonal function.2 Hyponatremia, probably secondary to
secretion of inappropriate antidiuretic hormone (SIADH),
can occur during an acute attack and may cause more neurologic dysfunction. Intravenous sodium replacement
should be with a balanced salt solution. Administration of
free water will aggravate the hyponatremia and may cause a
fatal encephalopathy.
200
decarboxylase (UROD)
Congenital erythropoietic porphyria
GLYCINE + SUCCINYL CoA
HEME
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201
Aminolevulinic acid
synthase (ALAS)
Aminolevulinic acid
dehydratase (ALAD)
Hydroxymethylbilane
synthase (HMBS)
Uroporphyrinogen-III
cosynthase (UROS)
Uropophyrinogen
Coproporphyrinogen
Figure27.1 The heme biosynthetic pathway. Successive steps are
catalyzed by the enzyme listed on the left side of the diagram.
The corresponding porphyria is listed on the right side of the
diagram. SOURCE:Hift RJ, Thunell S, Brun A.Drugs in porphyria:from
observation to a modern algorithm- based system for the prediction of
porphyrinogenicity. Pharmacology and Therapeutics. 2011;132:158–69,
with permission.
Protoporphyrinogen
If not exposed to triggering drugs, many patients with
hepatic porphyrias will exhibit few manifestations during their life. Some patients, however, will enter a chronic
phase with frequent neurovisceral attacks and an increased
risk of renal failure, hypertension, and hepatocellular
carcinoma. ere is evidence that porphyrin precursors,
especially ALA, are toxic to renal and hepatic cells. Liver
X-linked protoporphyria
Sideroblastic anemia
ALAD dehydratase porphyria
Acute intermittent porphyria
Porphyria cutanea tarda
Hereditary coproporphyria
Variegate porphyria
Erythropoietic protoporphyria
oxidase (CPOX)
oxidase (PPOX)
Ferrochelatase
(FECH)
Delta-AMINOLEVULINATE
PORPHOBILINOGEN
HYDROXYMETHYLBILANE
UROPORPHYRINOGEN-III
COPROPORPHYRINOGEN-III
PROTOPORPHYRINOGEN-IX
2+
Fe
PROTOPORPHYRIN
transplantation may be of signicant benet to patients
with chronic disease.
Pregnancy is generally well tolerated in women with
acute porphyria; however, the risk of small for gestational
age (SGA) neonates and fetal demise is increased. Hemin,
an inhibitor of delta- ALA synthetase, can be administered
during pregnancy, if necessary.
BOX 27.1 CLASSIFICATION OFTHE PORPHYRIAS
Acute Porphyrias
Acute intermittent porphyria(AIP)
Most common of the acute porphyrias
Hereditary coproporphyria(HCP)
Variegate porphyria(VP)
ALA- dehydratase- decient porphyria(ADP)
Rarest of the acute porphyrias
Nonacute Porphyrias
Porphyria cutanea tarda(PCT)
Congenital erythropoietic porphyria(CEP)
Erythropoietic protoporphyria(EPP)
X- linked erythropoietic protoporphyria(XLP)
TABLE27.1 DRUGS THAT MAY TRIGGER ACUTE PORPHYRIA
Barbiturates Aminophylline
Etomidate Clindamycin
Phenytoin Fluoconazole
Carbamazepine Griseofulvin
Oxcarbazepine Nitrofurantoin
Ethosuximide Amiodarone
Clonidine Hydralazine
Erythromycin Clonazepam
Estrogens Ketorolac
Progesterones Calcium channel blockers
Sulfonamides Smoking
Alcohol ingestion
Probably Avoid
Ketamine
PORPHYRIA 201
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e most common of the cutaneous porphyrias is
BOX 27.2 CLINICAL MANIFESTATIONS OFACUTE PORPHYRIA
Gastrointestinal
porphyria cutanea tarda (PCT), which presents in adulthood and is characterized by chronic bullous lesions in
sun- exposed skin. Treatment is with phlebotomy and/ or
Abdominal pain (colicky)
Nausea andemesis
chloroquine. Chloroquine enhances the excretion of porphyrins. ere is an increased risk of cirrhosis and hepatic
carcinoma in PCT patients.
Constipation
Diarrhea
Neurologic
Pain in back andlegs
Paresthesias
Peripheral neuropathy
Respiratory failure (paralysis)
Hyponatremia
Anxiety
Hallucinations
Coma
Cardiovascular
Tachycardia
Hypertension
Dysrhythmias
RISK
is clinical case represents a common way that patients
with acute porphyria present. Porphyria is a rare disease with very diverse clinical manifestations. e clinical presentation of acute porphyria can mimic an acute
surgical abdomen, metabolic disorders, acute neurologic
syndromes, and hypertensive crises. An accurate diagnosis
of acute porphyria is oen delayed many years aer symptoms rst appear. e rarity of the disease and the protean
clinical features make it dicult for the anesthesiologist
to recognize acute porphyria. e high incidence of severe
abdominal pain and nausea frequently results in needless
appendectomies, cholecystectomies, and hysterectomies.
5
If unrecognized and untreated, patients with acute
porphyria can develop progressive polyneuropathy and
respiratory failure. Although many patients with acute
porphyria will recover, some develop a chronic neuropathy.
Autonomic dysfunction can manifest as urinary retention,
ileus, excessive sweating, labile blood pressure, tachycardia/
bradycardia, or suddendeath.
NONACUTE (CUTANEOUS) PORPHYRIAS
Although the nonacute or cutaneous porphyrias do not
have the same risks as the acute porphyrias, they are not
innocuous disorders. Porphyrins are photoreactive compounds and when activated release energy and form free
oxygen radical species that damage the skin. Patients with
cutaneous porphyrias must protect all exposed skin from
sunlight. Hemolytic anemia occurs with some forms of
cutaneous porphyrias.
3
Patients with erythropoietic protoporphyria (EPP) and
X- linked protoporphyria (XLP) can develop severe, acute
ASSESSMENT OFTHE PATIENT
e course of anesthesia for this patient was uneventful
until the conclusion of surgery, when she was unable to generate adequate respiratory eort for sustained, spontaneous
ventilation. Laboratory studies done immediately aer surgery were normal with the exception of the serum sodium
of 128 mEq per liter. Acute porphyria should be considered
in the dierential diagnosis of respiratory failure.
e negative exploratory laparotomy and the past “normal” appendix are of signicance. e recent exposure to
sulfonamides, a known trigger of acute porphyria, should
provoke strong suspicion of an acute attack of porphyria.
photosensitivity during infancy. Exposure to surgical lights
and endoscopes may precipitate a photosensitivity reaction
during surgery. Yellow lters attached to the lights reduce
MANAGEMENT
the likelihood of such a reaction. As patients with EPP age,
they develop cholelithiasis and obstructive liver disease that
may progress to hepatic failure.
202 SECTION A. METABOLIC DISTURBANCES
4
e anesthesiologist is usually confronted with two dierent clinical situations in patients with porphyria. One is for
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203
administration of anesthesia to a patient with known porphyria. e other is a complication associated with anesthesia in a patient with undiagnosed porphyria.
e plan for anesthesia for a patient with known porphyria is based on avoidance of drugs that can precipitate
an acute attack. Tests, however, for the porphyrinogenicity of drugs are conducted in murine models and chick
hepatocyte cultures and are not precise.6 ere are no
comprehensive metabolic studies of patients with porphyria undergoing anesthesia. Clinical recommendations
are based on published anecdotal case reports.7 Two orga-
Patients with undiagnosed porphyria, when unknowingly exposed to triggering agents during anesthesia may
develop acute porphyria. e signs of acute porphyria during anesthesia are nonspecic. Patients can have delayed
emergence from anesthesia and respiratory insuciency
from muscle weakness, therefore the possibility of acute
porphyria should be considered.8 Urinary PBG is markedly
elevated during an acute episode and can be detected with
a rapid test kit (ermo Scientic Porphobilinogen PBG
Kit). If the rapid qualitative test is positive, tests for quantitation of urinary PBG and ALA can be performed.
nizations (American Porphyria Foundation, European
Porphyria Network) provide lists of drugs that are considered to be safe or unsafe for patients with porphyria
(Table 27.2). e numerous genetic patterns in humans
with porphyria preclude absolute certainty with drug recommendations. Length of drug exposure and exposure to
multiple drugs may play a role in acute attacks.
TREATMENT
Treatment of an acute attack of porphyria must be prompt,
as mortality can exceed 5%. All porphyrinogenic drugs
should be immediately discontinued. Infusion of glucose may help suppress production of toxic porphyrin
precursors through inhibition of delta- ALA synthetase.9
TABLE27.2 DRUGS CONSIDERED SAFE FORPATIENTS
WITHPORPHYRIA
Carbohydrate loading (oral or intravenous) may, in fact, be
eective therapy for mild cases. Hyponatremia should be
carefully corrected. Opioids can be administered for anal-
Alfentanil Propofol
Fentanyl Succinylcholine
Morphine Hydromorphone
gesia. Nausea and emesis can be treated with ondansetron
and/ or phenothiazines. Beta- adrenergic blockers can be
used for the treatment of tachycardia and dysrhythmias.
e most specic and eective therapy is the infu-
Promethazine Nalbuphine
Ropivacaine Lidocaine
Bupivacaine Procaine
sion of hemin (Panhematin, Recordati Rare Diseases Inc.,
Lebanon, NJ, USA; Normosang, Orphans Europe, Henleyon- ames, Oxfordshire, UK). Hemin increases the cellular
levels of heme and suppresses the heme synthetic pathway
Midazolam Ranitidine
Vecuronium Cis- atracurium
Dexmedetomidine Atropine
with a subsequent decrease in the levels of ALA and PBG.10
Early treatment with hemin is essential in order to prevent
further neuropathy. Resolution of the acute attack generally resolves aer 4 to 5days of hemin therapy. Potential
Glycopyrrolate Albuterol
Dexamethasone Hydrocortisone
Furosemide Aminocaproic acid
side eects of hemin infusion are thrombophlebitis at the
injection site, coagulopathy, and renal dysfunction. Hemin
is prepared from human blood and has the potential risk of
transmission of infectious agents. If hemin is unavailable,
Neostigmine Edrophonium
Ondansetron Beta- adrenergic blockers
Dopamine Dobutamine
Epinephrine
Probably Safe
hemodialysis may be eective.
In the case presented, aer the diagnosis of acute porphyria was established, the sulfonamides were discontinued
and an infusion of glucose (300 grams per 24 hours) in normal saline was initiated. Frequent measurements of serum
sodium and magnesium were performed. e severity of the
respiratory failure and neuropathy warranted hemin ther-
Sevourane Desurane
Isourane Remifentanil
Rocuronium Sugammadex
apy. Hemin (4 mg/ kg per 24 hours) was infused for 4days.
e hemin was reconstituted in albumin to reduce the risk
of thrombophlebitis. Serum sodium gradually increased to
139 mEq/ L. Respiratory eort improved signicantly aer
PORPHYRIA 203
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72 hours of hemin therapy, and she was successfully extubated on the fourth postoperativeday.
glucose be sucient treatment for this case of acute
porphyria?
5. Two grams per kilogram of 50% dextrose was
FOLLOW- UP
Aer her recovery from the acute episode of respiratory
failure, the patient received specic instructions about the
physiologic and pharmacologic triggers of porphyria. She
was also told of the importance of a balanced diet with adequate carbohydrate intake. Females may have cyclic attacks
with their menstrual cycles. ese attacks may respond
administered intravenously to the patient. No
signicant improvement in her neurologic function
was obtained. Should therapy with hemin be
considered?
6. What recommendations concerning anesthesia should
be made to a patient with a known history of acute
porphyria scheduled for elective surgery?
favorably to hormonal therapy. Noncyclic, severe episodes
may require scheduled hemin therapy. Liver transplantation should be considered for patients with frequent, severe
REFERENCES
attacks that respond poorly to hemin. e risk for hepatocellular carcinoma is increased, and long- term surveillance
is required. Depression and the potential for suicide frequently warrant routine psychiatric therapy.
CASE- BASED LEARNING DISCUSSION
1. What is the dierential diagnosis for a patient that
has slow emergence from anesthesia and diminished
respiratory eort? e immediate concern was for
residual neuromuscular blockade; however, reversal of
the nondepolarizing muscle relaxant did not improve
respiratory eort.
2. Aer the patient is transferred to the ICU, what
recommendations should be made to the intensivist
who will care for the patient?
3. Could hyponatremia explain the neurologic
dysfunction? How should hyponatremia be corrected?
4. Aer several hours in the ICU, a urinary screen for
PBG was positive. Would therapy with intravenous
1. Bissell DM, Wang B. Acute hepatic porphyrias. Journal of Clinical
and Translational Hepatology. 2015;3:17– 26.
2. Lin CS, Lee MJ, Park SB, Kiernan MC. Purple pigments: the
pathophysiology of acute porphyric neuropathy. Clinical
Neurophysiology. 2011;122:2336– 44.
3. S chulenburg- Brand D, Katugampola R, Anstey AV, Badminton MN.
e cutaneous porphyrias. Dermatologic Clinics. 2014;32:369– 84.
4. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria.
Orphanet Journal of Rare Diseases. 2009;4:19– 28.
5. Bonkovsky HL, Maddukuri VC, Yazici C, etal. Acute porphyrias
in the USA:features of 108 subjects from Porphyrias Consortium.
American Journal of Medicine. 2014;127:1233– 41.
6. Hi RJ, unell S, Brun A. Drugs in porphyria:from observation to
a modern algorithm- based system for the prediction of porphyrinogenicity. Pharmacology & erapeutics. 2011;132:158– 69.
7. Benassi F, Righi E, Cimato P, Parravicini R. Cardiac surgery in
patients with acute intermittent porphyria. Journal of Cardiac
Surgery. 2012;27:331– 34.
8. Park EY, Kim YS, Lim KJ, et al. Severe neurologic manifestations in acute intermittent porphyria developed aer spine surgery under general anesthesia. Korean Journal of Anesthesiology.
2014;67:217– 20.
9. Pischik E, Kauppinen R. An update of clinical management of
acute intermittent porphyria. Application of Clinical Genetics.
2015;8:201– 14.
10. Siegesmund M, van Tuyll van Serooskerken AM, Poblette- Gutierrez
P, Frank J. e hepatic porphyrias:current status and future challenges. Best Practice & Research Clinical Gastroenterology.
2010;24:593– 605.
204 SECTION A. METABOLIC DISTURBANCES
https://t.me/medicina_free
205
28.
UNDIAGNOSED PHEOCHROMOCYTOMA
Andrew F.Stasic
CLINICALCASE
Measurement of metanephrines in plasma or urine has
greater diagnostic sensitivity than measurement of the parA 19- year- old, 75- kilogram male with a 9- month history
of intermittent abdominal pain was referred to the general
surgery service aer computed tomography (CT) of the
abdomen identied an 8- cm retroperitoneal mass in the
area of the celiac axis. e mass was separate from the adrenal glands and was not likely to be a pheochromocytoma.
Induction of anesthesia and tracheal intubation were uneventful, however during tumor dissection his blood pressure
increased to 223/ 120mmHg and his heart rate increased to
184 beats per minute.
ent catecholamine.2 Once biochemical evidence of PCC/
PGL has been established, tumor localization can be per-
formed with CT or MRI. e latter is more sensitive than
CT for detection of extra- adrenal PGLs. Contrast media
can be a trigger of catecholamine release and should not be
used during CT examinations. Meta- iodobenzylguanidine
(MIBG) is taken up by neuroblastomas and PCC/ PGL;
therefore, tagging MIBG with radioactive iodine (I
appropriate scanning of masses for I
123
- MIBG can assist
123
) and
with localization of thetumor.
Forty percent of patients with PCC/ PGL have a
PATHOPHYSIOLOGY
Cells from the embryologic neural crest migrate during
embryogenesis to the adrenal medulla and sympathetic ganglia. Neuroendocrine, catecholamine- secreting tumors that
known gene mutation. Syndromes associated with PCC/
PGL include neurobromatosis type 1 (NF1), multiple
endocrine neoplasia type 2 (MEN2), von Hippel Lindau
disease (vHL), and hereditary paraganglioma syndromes.
Screening for PCC/ PGL in these groups may uncover
undetected catecholamine- secreting tumors.
3
arise from chroman cells in the adrenal medulla are called
pheochromocytomas (PCC), and those tumors arising in
the extra- adrenal glands are termed paragangliomas (PGL).
Paragangliomas can develop from sympathetic paravertebral
ganglia in the pelvis, abdomen, and thorax. Paragangliomas
typically produce norepinephrine (NE), and pheochromocytomas produce NE, NE and epinephrine (EPI), or dopamine. Rarely, a tumor will produce only EPI. Sudden release
of catecholamines from the tumor can result in hypertension,
headache, diaphoresis, dizziness, palpitations, and cardiomyopathy (Table 28.1).1 e incidence in the general population is 2 per million for PCC and 8 per million for PGL.
Paragangliomas that arise from parasympathetic ganglia
along the glossopharyngeal and vagus nerves in the head and
neck typically do not secrete catecholamines.
RISK
e release of catecholamines from a PCC or PGL can
be sudden and is oen related to tumor manipulation.
Massive release of catecholamines during anesthesia can
produce a “catecholamine storm” or “pheochromocytoma
multisystem crisis” with hypertension or hypotension, lac-
tic acidosis, hyperthermia, encephalopathy, and multiple
organ failure. is is especially dangerous in patients where
the presence of a pheochromocytoma or paraganglioma is
unsuspected. Patients with coexisting coronary artery dis-
ease and/ or cerebral arteriosclerosis may sustain a myocar-
dial infarction or stroke as a result of rapid, extreme changes
in blood pressure and heartrate.
e diagnosis of PCC/ PGL is based on biochemical evidence of catecholamine production by the tumor.
Catecholamines are metabolized within chroman cells
to metanephrines. Norepinephrine is metabolized to
normetanephrine, and EPI is metabolized to metanephrine.
ASSESSMENT OFTHE PATIENT
e sudden occurrence of severe hypertension, tachycardia
or bradycardia, and physiologic instability during anesthesia
205
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