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INT’L. J. PSYCHIATRY IN MEDICINE, Vol. 17(2), 1987
RHABDOMYOLYSIS IN RETROSPECT:
ARE PSYCHIATRIC PATIENTS
PREDISPOSED TO THIS
LITTLE-KNOWN SYNDROME?
STEVEN B. JOHNSON, M.D.
Department of Psychiatry and Human Behavior
University of California lrvine Medical Center
WILLIAM A. ALVAREZ, M.D.
Department of Psychiatry and Human Behavior
California College of Medicine- University
of California, lrvine
JACK P. FREINHAR, M.D.
Department of Psychiatry and Human Behavior
University of California lrvine Medical Center
ABSTRACT
Rhabdomyolysis is a potentially lethal syndrome that follows skeletal muscle injury,
both traumatic and nontraumatic. The literature on this syndrome remains sketchy,
and rhabdomyolysis may often go unrecognized. The history, clinical presentation,
laboratory findings, etiology, and treatment of rhabdomyolysis axe reviewed. Factors
which predispose psychiatric patients in particular to this syndrome are discussed.
Recommendations to reduce morbidity and mortality axe offered.
Rhabdomyolysis is a potentially lethal syndrome characterized by muscle pain,
weakness, and dark red or brown urine following skeletal muscle injury [ I ] .
Acute renal failure, severe hemorrhage, and disseminated intravascular coagulation
are common complications [ l ] . Involved muscles may be tender and feel
“doughy” with hemorrhagic discoloration of overlying skin [ 11 . However,
edema can develop, especially after intravenous fluid administration, and
muscles may therefore feel firm and swollen instead [ l , 21. Edematous
163
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164 / S. 0. JOHNSON, W. A. ALVAREZ AND J. P. FREINHAR
compartmental compression of nerves and arteries can cause weakened foot
pulses, paresthesias, foot drop, and absent deep tendon reflexes [ 1, 31 .
Information on rhabdomyolysis remains incomplete and confined mostly to
scattered case reports. Rhabdomyolysis ma.y go unrecognized, at least in
psychiatric patients, on a regular basis [4]. No specific numerical values for its
incidence are available. Rhabdomyolysis has been variously called “rare” [5J ,
“not an uncommon disorder” [2] , and “exceptionally common” [ 11 . The
incidence of mortality associated with rhabdomyolysis is likewise not known,
but among seventy-seven patients involved in eighty-seven episodes of
rhabdomyolysis studied by Gabow et al., eight died [2].
Injury can trigger the liberation of skeletal muscle intracellular contents like
creatine phosphokinase (CPK), myoglobin, aldolase, potassium, phosphate,
purines, lactate dehydrogenase, and glutamic oxaloacetic transaminase [2] .
Their release into the circulation is reflected by subsequent elevated serum CPK,
myoglobinuria, hyperkalemia, and hyperphosphatemia [ 1 J . Acid-base
derangements (e.g., lactic acidosis), proteinuria, fibrin split products in serum
and/or urine, hypofibrinogenemia, thrombocytopenia, and prolongation of
prothrombin time are other laboratory features seen in rhabdomyolysis [ 1 , 2 ] .
In addition, the conversion of muscle creatine to creatinine in the circulation
may cause the blood urea nitrogen to creatinine ratio to fall to less than 10: 1
[l , 3 , 6 ] . Hyperuricemia due to the catabolism of escaped muscle purines may
be observed, too 131. By the second to fourth day after the onset of
rhabdomyolysis, the deposition of calcium salts in damaged muscle tissue may
lead to hypocalcemia [ 11 . Hypoalbuminemia can also develop a few days after
severe rhabdomyolysis, evidently because capillary injury allows the escape of
albumin from plasma [ 11.
Myoglobin is cleared from plasma in one to six hours by metabolism to
bilirubin and, if plasma levels exceed 1.5 mg/dl, by renal excretion [2].
Myoglobin in the urine can be confirmed by a positive orthotolidine dipstick
test, in the absence of hematuria (this “occult blood” test merely detects heme
and thus does not distinguish between hemoglobin and myoglobin) [ 1, 21 .
Urine myoglobin concentrations above 100 mg/dl lead to red or brown
discoloration of the urine [2] .
The MM, or type 111, isoenzyme of CPK is the most sensitive marker of
skeletal muscle injury severity [2]. CPK levels peak about twenty-four hours
after muscle injury and decline approximately 39 percent each day thereafter
[2] .Peak CPK values in mild cases of rhabdomyolysis will be 500-5,000 IU/L
(normal is less than 86) [l J . CPK levels in the vicinity of 100,000 IU/L are
common in more severe cases [ 11 . Johnson et al. report a CPK value of 914,000
IU/L in a schizophrenic man who developed rhabdomyolysis following
molindone administration [7 J .
The causes of rhabdomyolysis are legion and may include all of the following:
1) excessive muscular contraction associated with strenuous exercise, seizures,
RHABDOMYOLYSIS IN RETROSPECT I 165
delirium tremens, status asthmaticus, malignant hyperthermia, neuroleptic
malignant syndrome (NMS), dystonias, psychotic posturing, or Wilson’s disease;
2) temperature extremes, i.e., heat stroke and hypothermia; 3) direct muscle
trauma due to crush or compression injury, burns, electric shock, lightning, or
intramuscular injection; 4) exposure to perphenazine, loxapine, molindone ,
amoxapine, amitriptyline, lorazepam, diazepam glutethimide, codeine,
methadone, heroin, amphetamines, phencyclidine (PCP), lysergic acid
diethylamide (LSD), barbiturates, toluene (paint sniffing), ethanol, isopropyl
alcohol, ethylene glycol, salicylate, mercuric chloride, phenylpropranolamine,
diphenhydramine, epsilon aminocaproic acid, succinylcholine, propoxyphene,
carbenoxolone, clofibrate, carbon monoxide, licorice, snake or brown spider
venom, hornet or wasp venom, fish flesh (Haff disease), or quail meat
(hemlock?); 5) immunological disorders such as dermatomyositis and
polymyositis; 6 ) genetic disorders, including muscular dystrophies and lipid or
glycogen storage/metabolism enzyme deficiencies, e.g., carnitine palmityltransferase deficiency; 7) muscle ischemia arising from compression, shock,
sickle cell trait, embolism, or immobilization in one position; 8) infections like
tetanus, Legionnaire’s disease, pyomyositis, influenza, mononucleosis, Rocky
Mountain Spotted Fever, gas gangrene, leptospirosis, coxsackie, and shigellosis;
9) metabolic disorders such as diabetes mellitus and myxedema; and
10) electrolyte imbalances, including hypokalemia, hypernatremia,
hyponatremia, and hypophosphatemia [2,3,5-181. Figure 1 summarizes these
causes of rhabdomyolysis.
Probably the first reported cases of rhabdomyolysis were the ancient
Israelites, as described in the Bible (Numbers, xi), who died after feasting on
quail during their exodus from Egypt 1191. Quail consumption has led to
myoglobinuric acute renal failure in several modern cases in Algeria and Greece
[ 18-20] . The hemlock (Conium maculatum) seeds on which quail occasionally
feed may be responsible for the rhabdomyolysis associated with quail
poisoning [ 181 .
The clinical triad of muscle pain, weakness, and dark urine was described by
Meyer-Betz in 191 1 [21], and was formerly called Meyer-Betz disease [ l ] .
The term “myoglobinuria” is sometimes used as if it were synonymous with this
syndrome. However, myoglobinuria is only one feature of this syndrome. The
term “rhabdomyolysis” on the other hand refers to the entirety of the described
syndrome. Furthermore, while rhabdomyolysis can occur without myoglobinuria,
myoglobinuria cannot occur in the absence of rhabdomyolysis [ 1 , 2 ] .
“Rhabdomyolysis” is thus the more specific and the preferred term for this
syndrome [ 1 , 2 ] .
Beall and Bywaters reported acute renal failure among London air raid
casualties who incurred crush injuries during the Battle of Britain in 1941 [22].
As many as 33 percent of the rhabdomyolysis victims may develop acute renal
failure [2] . The pathogenesis of renal failure associated with rhabdomyolysis
166
I
S. 6. JOHNSON, W. A. ALVAREZ AND .J. P. FREINHAR
CXCESSIVE
MUSCULAR
ACTIVITY
(EXERCISE, SEIZURES
PSYCHOSIS)
HY PERTHERMIA/
HEAT STROKE
IMRAVASCULAR
COAGULATION
1
PRIMARY MUSCLE
INJURY
DRUGSITOXINS
IMMUNOLOGICAL
DISORDERS
RHABDOMYOLYSS
LAC1Ic
AC IDOSIS
(DERM*TOMYOSITIS)
HYPERURICEMIA
GENETIC
DISORDERS
MUSCLE
ISCHEMIA
INFECTIONS
MElABOLlC
DERANGEMENTS
I
I-
FALURE
I J
HYPERURICOSURI
ELECTROLYTE
DISORDERS
Figure 1. Rhabdomyolysis and acute renal failure.
remains unclear. Hypovolemia, myoglobinuria, intravascular coagulation,
acidosis, and hyperuricosuria appear to be causative, either singly or in some
combination [23]. Hypovolemia is apparently not directly nephrotoxic; instead,
it seems to potentiate the nephrotoxic effects of other factors like
myoglobinuria by concentrating the urine [ 1, 171. Figure 1 depicts the relationship between rhabdomyolysis and acute renal failure.
PSYCHIAT R IC IMPLICATIONS
Psychiatric patients, especially those who are psychotic or in seclusion, are
often less able to communicate distressing symptoms to staff and less able to
cooperate with physical examinations and diagnostic tests. For various other
reasons, it may prove difficult to rigorously monitor psychiatric patients'
physical condition, vital signs, and laboratory data. The diagnosis of
rhabdomyolysis in psychiatric patients can therefore be delayed, thus increasing
the risk of mortality.
Several factors predispose psychiatric patients in particular to developing
both rhabdomyolysis and renal complications [4, 241. For example, when
RHABDOMYOLYSIS IN RETROSPECT I 167
psychiatric patients refuse oral medication, they may be subjected to
intramuscular injections, leading to muscle necrosis and possible rhabdomyolysis
v11.
Psychiatric patients are also placed at high risk by erratic oral intake, a not
uncommon manifestation of psychopathology. Fasting seems to encourage the
development of exertional rhabdomyolysis [l] , and, as mentioned above,
dehydration contributes to the development of acute renal failure [4].
Neuroleptics can cause dystonias and NMS, and both in turn can cause
rhabdomyolysis [5,9,161. In addition, restraint and seclusion can contribute
to the development of rhabdomyolysis if the patient is immobilized in one
position for some time or if the patient struggles vigorously against the
restraints [14, 151 .
Psychosis itself predisposes patients to rhabdomyolysis as described by Coryell
et al., who reported a case of rhabdomyolysis and acute renal failure in a
psychotic former college football player who assumed a rigid three-point stance
for an hour [8] . Similarly, Finlayson et al. reported a middle-aged psychotic
woman who developed rhabdomyolysis because she was unable to free herself
or call out for help after becoming trapped in a Murphy bed [4] .
Acutely psychotic, drug-free patients are known to have increased
histochemical abnormalities of a myopathic type and elevated serum levels of
skeletal muscle enzymes such as CPK and aldolase [25, 261. CPK elevations
associated with psychosis are generally two- or threefold greater than normal but
can be as high as 100,000 IU/L [ 111 . Such myopathies and enzyme elevations
suggest that acute psychosis is associated with increased skeletal muscle
membrane permeability [27] .
Many substances abused by psychiatric patients-alcohol, LSD, PCP, heroin,
amphetamines, and barbiturates-may cause rhabdomyolysis [2, 141 . Many of
the psychotropic medications used to treat psychiatric patients-loxapine,
perphenazine, molindone, amoxapine, amitriptyline, lorazepam, diazepam,
glutethimide, and methadone-have also been implicated as causes of this
syndrome [2, 7, 14, 171. Together, these represent nearly every class of
psychoactive agent: neuroleptics, antidepressants, benzodiazepines, barbiturates,
amphetamines, opiates, hallucinogens, and alcohol.\
Alcohol, the most frequent cause of rhabdomyolysis, is directly myotoxic [2].
It is not clear however how other psychoactive agents cause rhabdomyolysis. It
has been suggested that at least amoxapine is also directly myotoxic [ 171.
However, reports of rhabdomyolysis associated with psychoactive agents other
than alcohol remain relatively rare despite the epidemic abuse of illicit drugs and
the liberal use of licit psychotropics (for instance, in 1976, 128 million
prescriptions were written just for sedative-hypnotics in the United States alone
[28]). Perhaps the psychoactive agents other than alcohol are myotoxic only in
certain predisposed patients, just as inhalational anesthetics trigger malignant
hyperthermia in only rare, susceptible individuals. Or perhaps they are not
168 / S. B. JOHNSON, W. A. ALVAREZ AND J. P. FREINHAR
myotoxic enough to cause rhabdomyolysis unless they are taken in massive doses
or in the presence of other factors. In their study of eighty-seven episodes of
rhabdomyolysis, Gabow et al. identified multiple factors capable of injuring
muscle in fifty-one cases [2]. Ralph suggests, “Multiple mechanisms of injury
may contribute to rhabdomyolysis, e.g., ischemia, acidosis and trauma with
Severe exercise” [ 6 ] .In our own review of the literature, most case reports of
rhabdomyolysis associated with psychoactive agents involved at least one other
factor capable of injuring muscle: psychosis, catatonic posturing, repeated
intramuscular injections, dystonias, seizures, NMS, immobilization in and
exertion against restraints, or erratic oral intake [5,7,8-11, 151.
As stated before, psychosis apparently increases muscle membrane permeability
as indicated by elevated aldolase and CPK. Both NMS and intramuscular injection
are also associated with moderate increases in serum CPK [1 11,which, again, might
represent a disturbance of muscle membrane integrity. Elevated serum CPK levels
have been used to screen patients for susceptiblility to malignant hyperthermia
[29] (ths practice has been challenged by Paasuke and Brownell [30]). In
malignant hyperthermia, the triggering anesthetic blocks the reentry of calcium
into the sarcoplasmic reticulum, leading to cell membrane depolarization [311 .
Intracellular ions such as potassium, magnesium, and phosphate then escape into
the plasma, followed by larger molecules like myoglobin [3 11 . NMS is thought
to be related to malignant hyperthermia [lo] and may injure muscle membranes
by depolarization, too.
It thus appears that at least several disordels reported to cause rhabdomyolysis
may do so by disrupting skeletal muscle membrane integrity, either in a direct,
physically traumatic manner like intramuscular injection or by somehow
depolarizing the membrane. Presumably, one factor acting alone produces a mild
to moderate membrane disturbance and thus a mild to moderate CPK elevation,
as often seen in NMS, intramuscular injection, and psychosis. If the offending
factor is unusually traumatic (e.g., drug overdose), then the muscle
membrane permeability is more severely disturbed. When the cumulative effect
of several factors or, less commonly, the effect of one very traumatic event
exceeds some threshold of permeability, enough muscle contents are released to
constitute rhabdomyolysis. This theory would account for 1) the preponderance
of cases involving multiple etiologic factors, and 2) the rarity or absence of cases
arising from routine neuroleptic doses and non-alcohol drug abuse, excluding
overdoses. Research is needed to resolve this question of how psychoactive
agents and rhabdomyolysis are related.
RECOMMENDATIONS
Rhabdomyolysis and accompanying complications like acute renal failure and
severe hemorrhage are potentially lethal. Early detection and treatment can
reduce morbidity and mortality [ 6 , 24,]. Patients, psychiatric or otherwise, who
are exposed to one or more rhabdomyolysis-predisposingfactors (e.g., alcohol
RHABDOMYOLYSIS IN RETROSPECT /
169
or drug abuse, high doses of psychotropic medication, overdosage of any
psychoactive drug, psychosis, catatonic posturing, intramuscular injection,
dystonia, NMS, seclusion and restraint, seizures, or malnutrition) merit
periodic evaluation for muscle tenderness, weakness, and dark red or brown
urine. It should be remembered, however, that this classic triad is not always
clinically observed. For example, in the aforementioned study by Gabow
et al., half of the patients experienced no myalgias, and only four of the
eighty-seven episodes involved muscle swelling [ 2 ] . Less than half of
rhabdomyolysis victims have dark urine [2]. Thus this screening interview is
useful as an inexpensive tool for large populations, but any suspicion should
be followed by appropriate laboratory tests. The presence of both
myoglobinuria and elevated serum levels of skeletal muscle contents,
particularly CPK, will confirm the diagnosis [ 1 ] . A fivefold or greater increase
in serum CPK is, by itself, diagnostic if cardiac and brain injury have been
ruled out [2].
Because drug overdose by definition implies a massive dose, often of more
than one drug, we recommend serial assessments of serum CPK and urine
myoglobin in all patients suspected of psychoactive drug overdose. A state of
euhydration and adequate nutrition should be maintained in patients taking
psychotropic medication.
Initial treatment of rhabdomyolysis consists of 1) prompt fluid replacement
to counter volume depletion and 2 ) mannitol to further promote volume
expansion and renal perfusion [3]. Alkalinization of the urine with bicarbonate
to increase myoglobin excretion may aggravate hypocalcemia [ 1] . Oral
phosphate-binding antacids are generally sufficient to treat hyperphosphatemia
[l ] . Hyperkalemia, an occasionally fatal complication, will eventually resolve
with normal renal perfusion and excretion; in the presence of renal failure,
treatment with dialysis or exchange resins may prove necessary [6].
Nerve damage presumably precedes signs like paresthesias and absent tendon
reflexes. Pressure transducers can be used to monitor interstitial pressure in
muscle compartments, especially the anterior tibia1 muscles, the soleus, the
lateral muscles’of the thigh, and the glutei [ I ] . Fasciotomy is recommended if
pressure exceeds 35 mm Hg [ I ] .
Furosemide may worsen volume depletion and should not be used [6].
Hypocalcemia usually resolves spontaneously after several days; furthermore,
the administration of calcium salts may actually promote further muscle damage
and is thus contraindicated [ 11 . Disseminated intravascular coagulation
complicating rhabdomyolysis is often accompanied by severe hemorrhage, so
herapin administration is controversial [ I ] .
ACKNOWLEDGMENT
The authors thank Mildred D. Brown and Catherine D. Wheeler for typing
this manuscript.
170 / S. 6. JOHNSON, W. A. ALVAREZ AND J. P. FREINHAR
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Direct reprint requests to:
Steven B. Johnson, M.D.
Department of Psychiatry and Human Behavior
University of California Irvine Medical Center
101 The City Drive South
Orange, CA 92668