Clinical Chemistry 46:4
577581 (2000)
Propofol-associated Rhabdomyolysis with Cardiac
Involvement in Adults: Chemical and Anatomic
Findings
Edward B. Stelow, Vandita P. Johari, Stephen A. Smith, John T. Crosson, and
Fred S. Apple*
Propofol, a central-acting sedative agent, has been im-
plicated in the development of rhabdomyolysis in chil-
dren. We describe two adults who developed rhabdo-
myolysis after receiving high rates of propofol infusion.
Rhabdomyolysis of both skeletal and cardiac muscle
was suggested in both patients by marked increases of
creatine kinase (>170 000 U/L) and cardiac troponin I (11
and 46 g/L in patients one and two, respectively).
Creatine kinase and cardiac troponin I values were
highly correlated in each patent (r 0.786 and 0.988 in
patients one and two, respectively). Autopsy of one
patient confirmed the diagnosis of skeletal and cardiac
rhabdomyolysis.
2000 American Association for Clinical Chemistry
Rhabdomyolysis is a clinical entity that evolves after
skeletal muscle injury. The symptoms and signs are
secondary to muscle injury and the effects of the release of
toxic intracellular contents. They include muscle weak-
ness, myoglobinuria, and renal failure. The causes of the
initial injury can range from trauma to venom (1, 2 ).
Drug-induced rhabdomyolysis has been reported as re-
sulting from many possible agents, including the use of
propofol for sedation of children in the intensive care unit
(3 8 ). We present two cases in which adults developed
rhabdomyolysis after receiving high infusion rates of
propofol for extended periods of time. We use chemical
and anatomic findings to demonstrate rhabdomyolysis
secondary to both skeletal and cardiac muscle injury and
secondary acute renal failure.
Department of Laboratory Medicine and Pathology, Hennepin County
Medical Center, Minneapolis, MN 55415.
*Address correspondence to this author at: Hennepin County Medical
Center, Clinical Laboratories (812), 701 Park Ave., Minneapolis, MN 55415. Fax
612-904-4229; e-mail fred.apple@co.hennepin.mn.us.
Received December 3, 1999; accepted January 28, 2000.
577
Case Report
Case Reports
case 1
The patient was a 47-year-old white woman with a long
history of steroid-dependent asthma for which she had
been intubated twice previously. She presented after
worsening shortness of breath at home that had not been
relieved with multiple nebulizer treatments. Her past
medical history was significant for obesity, depression,
gastroesophageal reflux disorder, herniorrhaphy, chole-
cystectomy, and steroid-induced myopathy. She had no
known drug allergies. She was medicated at home with
theophylline, prednisone, albuterol, and zafirlukast.
Upon reaching the emergency department (ED)1 she had
one-word dyspnea that was not relieved with nebulizer
therapy. She was hypertensive, tachycardic, and tachy-
pneic; however, she was afebrile. Her oxygen saturation
while receiving oxygen therapy by face-mask was 8792%
before it rapidly began to worsen. It improved quickly
after a difficult intubation that lasted nearly 10 min. The
patient received intravenous corticosteroids, midazolam,
albuterol, vecuronium, and succinylcholine in the ED. She
also received lidocaine for multiple premature ventricular
contractions after her hypoxic episode. An electrocardio-
gram taken at that time was without signs of infarct or
ischemia. Because of a possible infiltrate on her chest
x-ray and an increased white blood cell count, the patient
received ceftriaxone. She was admitted to the medical
intensive care unit (MICU) where she was treated with
albuterol, ipratropium, intravenous corticosteroids, ceftri-
axone, and theophylline. Propofol was used for sedative
purposes and was to be titrated to desired effect. She
remained afebrile and was stable with good urine output
throughout the next day while her propofol was infused
at 200 g kg1 min1. An attempt to wean her ventila-
1
Nonstandard abbreviations: ED, emergency department; MICU, medical
intensive care unit; CK, creatine kinase; and cTnI, cardiac troponin I.
578 Stelow et al.: Propofol-associated Rhabdomyolysis in Adults
tor support was unsuccessful. The next morning, the
patient was afebrile and stable. Her chest x-ray demon-
strated a possible worsening infiltrate, and her antibiotic
was changed to trovafloxacin. In the morning, serum
creatinine and urea did not demonstrate change in renal
function. Later that morning, her urine darkened and was
positive for blood by reagent strip. No cells were seen.
Her creatine kinase (CK) activity (Fig. 1A) was increased
at 3900 U/L (reference interval, 40 200 U/L). Her cardiac
troponin I (cTnI) concentration (Fig. 1A) was within the
reference interval (0.8 g/L). She was treated with fluid,
diuretics, and bicarbonate therapy. In the afternoon, hy-
perkalemia, increased creatinine, metabolic acidosis, and
hypocalcemia were present. Her CK activity, measured
11 h after the first, was 171 000 U/L, reflecting a 50-fold
increase, and her cTnI concentration was increased at 1.4
g/L. Her urine output decreased, and she became anuric
early the next morning. Throughout the day, she was
treated with diuretics, fluid replacement, calcium replace-
ment, and bicarbonate therapy. Her white blood cell
count increased. She became hypotensive and required
dopamine and phenylephrine. Her creatinine concentra-
tion continued to increase, and her hyperkalemia and
metabolic acidosis worsened. The following morning,
propofol was discontinued; her serum CK was 762 000
U/L and her cTnI concentration was 4.0 g/L. With her
worsening hyperkalemia, arrhythmias and episodes of
ventricular tachycardia developed, followed by cardiac
arrest. Severe hypotension persisted for 15 min before a
supraventricular rhythm was re-established. Hemodialy-
sis was started to treat severe hyperkalemia. During this
time, her temperature rose to 103.1 F. She was treated
with continuous hemodialysis, calcium, bicarbonate, and
phenylephrine and was given dantrolene for possible
malignant hyperthermia. Her hyperkalemia worsened
nonetheless. Supportive therapy was continued through
the night. The following morning, neurology was con-
sulted, who deemed return of previous neurologic status
very unlikely because of major anoxic brain injury. Sup-
portive therapy was withdrawn, and the patient expired.
Autopsy was performed.
case 2
The patient was a 41-year-old white man with a history of
asthma for which he had been admitted multiple times
but had never been intubated. He presented with wors-
ening shortness of breath that had not been relieved at
home with his metered-dose inhalers. Other than his
asthma, he had no known medical problems or drug
allergies. At home, he was medicated with albuterol,
theophylline, zafirlukast, and fludrocortisone, although
there was some question of his compliance. He com-
plained of a 1-day history of worsening shortness of
breath but did not complain of any symptoms of infection.
He was hypertensive and afebrile. Arterial blood gas
analysis in the ED demonstrated hypercapnia and acido-
sis. He was intubated without complication and received
ketamine, intravenous corticosteroids, lorazepam, and
vecuronium throughout his time in the ED before being
admitted.
In the MICU, he was placed on propofol infusion to
maintain sedation and received ipratropium, albuterol,
and intravenous corticosteroids. He remained stable and
afebrile throughout his first and second days. On day 2,
he was started on low-molecular weight heparin for deep
venous thrombosis prophylaxis. On his third day in the
MICU, he was afebrile and stable. Fentanyl was added for
analgesic purposes. He required propofol infusion at 222
g kg1 min1 to maintain sedation for 4 h. On day 4,
trovafloxacin was added for a possible infiltrate on his
chest x-ray. He remained afebrile with stable vital signs
and good urine output. On day 5 in the MICU, his CK
activity was 3800 U/L (Fig. 1B; reference interval, 60 300
U/L) in the morning, an increase from 980 U/L the day
before. By the afternoon, it was 8090 U/L. Diuretic and
fluid therapy was begun after it was noticed that his urine
was brown and positive for blood by reagent strip. He
was oliguric for a short time, but responded well to
diuretic and fluid therapy. Propofol was weaned and
discontinued the following morning. His serum myoglo-
bin concentration was increased at 6800 g/L (reference
interval, 0 85 g/L). Over the next 4 days, the patients
CK activity and cTnI concentration (Fig. 1B) continued to
rise to maximum values of 204 000 U/L and 46 g/L,
respectively. Echocardiography demonstrated globally re-
duced left ventricular function without a focal lesion. His
CK activity and cTnI concentration returned to normal
over the next few days.
Materials and Methods
CK activity was measured with a Vitros analyzer (John-
son & Johnson). The reference (normal) intervals were
60 300 U/L (males) and 40 200 U/L (females) (9 ). cTnI
was measured on plasma or serum using the Stratus II
(Dade Behring). The reference (normal) interval was 0.8
g/L (10 ). Myoglobin concentrations were measured at
an outside facility by immunoassay with a reference
interval of 0 85 g/L.
An autopsy was performed on patient 1. Representa-
tive tissue sections from the lungs, heart, skeletal muscle,
and kidneys were fixed in formalin, processed routinely,
and embedded in paraffin. All tissues were stained by
hematoxylin and eosin and examined by light micros-
copy.
Statistical analysis was performed using regression
analysis on StatView 4.1 on a power Macintosh 6000
computer.
Results
CK activities and cTnI concentrations increased in patient
1 (Fig. 1A) and patient 2 (Fig. 1B) after propofol infusions.
In both patients, CK activities and cTnI concentrations
were highly correlated (r 0.786 and 0.988, respectively).
Microscopic examination of the skeletal muscle from
 Clinical Chemistry 46, No. 4, 2000
Fig. 1. CK activities () and cTnI concentrations () as a function of
time after MICU admission for patient 1 (A) and patient 2 (B).
patient 1 showed a disorganization of myofibrils and
sarcomeres (Fig. 2). Most of the muscle fibers showed an
acute necrotic reaction with swelling, loss of striations,
and vacuoles. Many nuclei had degenerated. No inflam-
matory response was present, and vessels were intact.
Sections of the heart revealed numerous focal areas of
Fig. 2. Hematoxylin and eosin stain of skeletal muscle (125)
demonstrating an acute necrotic reaction with swelling, loss of stria-
tion, and vacuole formation.
579
myofibril degeneration surrounded by an acute inflam-
matory reaction with macrophages and neutrophils (Fig.
3). Sections through the kidneys showed the presence of
reddish brown pigment casts (myoglobin casts) in 50%
of the tubular lumens. The tubules were dilated with a
marked effacement of the brush border, suggesting severe
acute tubular necrosis (Fig. 4).
Discussion
These two cases of rhabdomyolysis occurred after high
rates of infusion of propofol (200 222 g kg1 min1).
The propofol package insert states a range of infusion
necessary for sedation of MICU patients with chronic
obstructive pulmonary disease or asthma of 1775
g kg1 min1 (n 49) (11 ). A review of the literature
found that rates between 1 and 142 g kg1 min1 had
been used, with rates 100 g kg1 min1 being un-
common (12, 13 ).
Propofol, a central nervous system sedative that inter-
acts with -aminobutyric acid aminotransferase receptors
(14 ), has been implicated in the development of rhabdo-
myolysis in children (4 6, 8 ). In these cases, the children
were intubated for respiratory distress or seizures and
were sedated with continuous infusion of propofol. The
maximal infusion rate in these cases was between 133 and
449 g kg1 min1. That these events occurred in chil-
dren and not in adults was postulated to be because
children generally require higher rates of infusion than
adults. It should be noted that propofol is not recom-
mended for sedation of children in the ICU setting (15 ).
In our cases, the clinical diagnoses of rhabdomyolysis
were made after the patients were noted to have dark
urine. Urinalysis of both patients was positive for blood
by reagent strip likely secondary to the passage of myo-
globin through the glomerulus (1, 2 ). Indeed, serum myo-
globin was found to be extremely increased in patient 2
(6800 g/L). CK activity was severely increased in both
cases (maximum, 762 000 U/L in case 1 and 204 000 U/L
Fig. 3. Hematoxylin and eosin stain of cardiac muscle (288) demon-
strating an acute necrotic reaction with swelling, loss of striation, and
vacuole formation with mild acute inflammation.
580 Stelow et al.: Propofol-associated Rhabdomyolysis in Adults
Fig. 4. Hematoxylin and eosin stain of the kidney (125) demonstrat-
ing myoglobin casts and acute tubular necrosis.
in case 2). Increased CK activity is essential for the
diagnosis of rhabdomyolysis in cases in which no trauma
has occurred, and it reflects the leakage of that enzyme
out of the injured myocytes (1, 2 ).
Injury to the myocardium was demonstrated in both
cases by increases in the concentrations of cTnI (maxi-
mum, 11.6 g/L in case 1 and 46.4 g/L in case 2). cTnI
is found exclusively in cardiac muscle (16 ). Increased
concentrations of cTnI in serum, even during skeletal
muscle injury, are indicative of cardiac muscle injury
(16 19 ). Cardiac involvement in rhabdomyolysis has
been noted, although it has not been demonstrated using
serum chemistry results (20 ). Nor has cardiac injury been
demonstrated in the cases of propofol-induced rhabdo-
myolysis in children (4 6, 8 ).
Myopathic changes secondary to pharmacotherapy
and the further development of rhabdomyolysis have
been well documented (2129 ). The anatomic findings in
case 1 support this etiology because there was such
ubiquitous involvement of skeletal and cardiac muscle.
The lack of inflammatory infiltrate confirms the acuity of
this process. The findings in the kidneys are secondary to
muscle destruction because myoglobin is nephrotoxic and
depletes renal adenine nucleotide pools and inhibits prox-
imal tubular cell proliferation (30, 31 ). The severe renal
involvement in case 1 gives evidence of the massive
rhabdomyolysis that occurred.
The etiology of the rhabdomyolytic process in both of
our cases is more difficult to establish. In general, there
are many possible etiologies of rhabdomyolysis, the most
common being trauma, seizure, and alcohol use (1, 2 ).
Infection, drugs, and toxins have also been implicated
(1 8, 2129, 3239 ). Neither of our cases had a history or
evidence of trauma. Although patient 1 experienced an
hypoxic event in the ED, it seems very unlikely that this
could have caused rhabdomyolysis. Both patients had
otherwise stable oxygen and hemodynamic status before
they developed rhabdomyolysis. Infection was consid-
ered in both cases, and it can predispose asthmatics to
bronchospasm. In addition, patients who are intubated
are at increased risk for infection. Neither of our patients
developed a clinically obvious infection, however, and the
anatomic findings in patient 1 did not suggest infection.
Furthermore, neither patient showed the signs of the
degree of infection one would expect to account for the
overwhelming rhabdomyolysis that developed.
Both patients were given multiple medications
throughout their stay in the MICU before they developed
rhabdomyolysis. Steroids, vecuronium, succinylcholine,
and theophylline have all been implicated in the develop-
ment of rhabdomyolysis (2, 3, 24, 27, 3339 ). Neither of
our patients received excessive doses of any of these
medications, and the myopathy that has been demon-
strated with most of those drugs seems insufficient to
have caused the massive rhabdomyolysis that occurred in
our two patients.
In both cases, it is essential to consider the use of
corticosteroids, especially because the first patient we
presented had a history of steroid myopathy. The acute
and necrotizing myopathy that can develop in patients
who receive high doses of corticosteroids for asthma in
the MICU has been well documented (3339 ). This my-
opathy may be induced by the subsequent infusion of
neuromuscular-blocking agents, although it has also been
described in patients who received subsequent infusions
of propofol alone (35 ). That none of those patients devel-
oped the severe rhabdomyolysis that occurred in our
patients may be attributable to the higher doses of propo-
fol that our patients received. If these cases developed in
part because of the corticosteroid treatment given, it
might support the theory of priming and triggering
factors. In such a case, high-dose propofol would be the
myotoxic triggering factor after substantial priming fac-
tors have occurred (36 ).
Consistent with the role of propofol in the develop-
ment of rhabdomyolysis in our two cases are the facts (a)
that cases of propofol-induced rhabdomyolysis have been
reported in children who require higher rates of infusion
than adults; (b) that the adults in our cases required higher
rates of infusion than are typical; and (c) that there is no
other sufficient cause to explain the rhabdomyolysis that
developed in our cases. How propofol infusion is related
to subsequent development of rhabdomyolysis remains
unclear. It appears to be idiosyncratic and dose-related
and may be potentiated in the critical care setting by the
use of high-dose steroids in asthmatic patients.
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