Rhabdomyolysis as a Rare Complication in Theophylline Intoxication
Stefan Teweleit¹, Marion Hippius¹, Rüdiger Pfeifer², Annemarie Hoffmann¹
Summary
- Case Study: The report is about a 73-year-old man with rhabdomyolysis related to acute theophylline
intoxication. The man had been admitted to the hospital with tachycardia, nausea, and motor
restlessness after the ingestion of an unknown amount of sustained-release theophylline in combination
with furosemide. The maximum theophylline level was 66.5 mg/l. Initial lab results showed hypokalemia
(2.8 mmol/l), hyponatremia (123 mmol/l), as well as increased myoglobin (3789 μg/l) and creatine
kinase (32.29 μmol/l/s). Activated charcoal was administered immediately in combination with
hemodialysis (CVVH) and forced diuresis, as well as intravenous administration of potassium chloride,
sodium chloride and metoprolol. Serum values for theophylline, creatine kinase and myoglobin
normalized within a short period of time without the occurrence of a secondary rise in the theophylline
level.
- Conclusion: Rhabdomyolysis is a rare complication of theophylline intoxication. Only a few cases have
been mentioned in the literature. The present case study emphasizes the necessity of a prompt
diagnosis followed by the purposeful initiation of treatment to avoid acute renal failure or a fatal course.
Risk factors and treatment principles are formulated and discussed with the aid of the literature survey
based upon the pathology and epidemiology of theophylline-induced rhabdomyolysis.
Key Words: Theophylline intoxication – Rhabdomyolysis – Myoglobin – Risk factors – Therapy
Med Klin 2001; 96: 40-4
DOI 10.1007/s00063-001-1006-y
¹Insitute for Clinical Pharmacology and
²Clinic for Internal Medicine III, Friedrich-Schiller-University Jena.
Research project for the intensified spontaneous registration of adverse medication effects,
Sponsored by the BfArM, sponsorship number Fo 2.1-68502-201.
Manuscript received: 2/2/2000
Manuscript accepted: 4/13/2000
Rhabdomyolysis has traumatic and non-traumatic causes. It is known as a result of a muscular ischemia
in multi-trauma, compartment syndrome, shock, or overuse (jogging disease). Toxic rhabdomyolysis can
be caused by disturbances of the electrolyte balance, endocrine diseases, malignant hyperthermia, food
poisoning (toxic oil syndrome), and a multitude of drugs and medications [5]. Besides opiates and
cocaine, barbiturates, diphenhydramine, narcotics, and neuroleptics are involved, among others. The
trigger is often multi-factorial; it could be a combination of ischemia and medication effects.
The first case of theophylline intoxication with rhabdomyolysis was described in 1985 by Robertson [18].
A total of 24 similar cases have been published in the international literature [1, 4, 5, 7, 8, 11-14, 16-19,
22, 25-29]. Most of the authors report of acute intoxications with significantly elevated serum
theophylline levels. A swift diagnosis and the purposeful initiation of a sufficient therapy is required to
avoid potential complications.
CASE STUDY
-Case History
A 73-year-old patient with a known four-year history of heart failure stage III to IV (NYHA), related to
dilated cardiomyopathy, was admitted with severe shortness of breath and nausea and vomiting.
Furthermore, a three-year history of atrial fibrillation, chronic obstructive bronchitis with pulmonary
emphysema, and a reactive depression are worth mentioning. Prior to admission, the patient took 240
mg verapamil, 5 mg benazepril, 50 mg trimipramine and 700 mg of sustained release theophylline daily.
Due to the atrial fibrillation, the patient was orally anti-coagulated with phenprocoumon. The patient
had been taking his medications erratically and arbitrarily, including two of the formerly prescribed
“water pills” here and there, which turned out to be furosemide 40 mg tablets.
-Clinical Findings
Dyspnea at rest and cyanosis of the lips were the foremost symptoms during the admission assessment
of the markedly weak patient measuring 184 cm with a weight of 94 kg. The patient appeared restless,
anxious, and agitated with a depressed mood. There were no obvious injuries or biting of the tongue;
the patient denied any seizures or loss of consciousness. Ubiquitous dry rattling could be auscultated
across the chest. Central heart rate was 145/min, arrhythmic and with a pulse deficit; blood pressure
was 80/50 mm HG. The liver was palpable at 4 cm below the rib cage. Neurological examination showed
increased deep tendon reflexes and a fine resting tremor.
-Laboratory Diagnostic
The admission lab work showed the following abnormal values: Sodium 123 mmol/l, potassium 2.83
mmol/l, BUN 14.9 mmol/l, creatinine 220 μmol/l, theophylline level 61.5 mg/l (normal 10 to 20 mg/l),
myoglobin 3789.0 μg/l (normal 20 to70 μg/l), creatine kinase 32.29 μmol/l/s (normal up to 1.33
μmol/l/s), lactate 5.08 mmol/l (normal 0.5 to 2.2 mmol/l), and INR 2.8. Capillary blood gas analysis
showed a slight respiratory partial insufficiency: pO₂ 7.75 kPa, pCO₂ 3.93 kPa, O₂ saturation 90.4%. A
slight compensated metabolic acidosis was present: pH 7.41, HCO₃ 20.6, BE -4.4.
-Technical Exams
The 12-lead EKG showed an absolute tachyarrhythmia with a rate of 146/min and isolated multifocal
premature ventricular contractions. There was a complete right bundle branch block. There were some
short ventricular salvos present the next day. Chest radiography showed a significantly enlarged heart
with signs of chronic pulmonary vascular congestion.
Treatment and Course
With the suspicion of theophylline intoxication, repeated oral doses of activated charcoal were
administered immediately after the lab results had been available. A one-time hemodialysis (CVVH) over
five hours was performed since the markedly increased myoglobin pointed to rhabdomyolysis. The
hypertension was resolved within in a short period of time with a continuous dopamine infusion.
Administration of furosemide and electrolyte solutions forced diuresis, amounting to an hourly urine
output of about 500 ml during the first day of treatment. Continuous central venous infusion of
Potassium and sodium chloride solutions compensated for the hypokalemia and hyponatremia. The
patient received oxygen via O₂ mask as well as a continuous infusion of metoprolol.
The success of the prompt interventions in an intensive care setting could be documented with the lab
work. After a further rise of the theophylline level to 66.5 mg/l just prior to the begin of hemodialysis,
the level was almost cut in half after just three hours of hemodialysis (figure 1).Taking the
pharmacokinetics of the sustained release theophylline preparation into account, the treatment with
activated charcoal was continued for one more day, while hemodialysis, forced diuresis, and electrolyte
replacement could be stopped.
The patient was able to be transferred to a regular floor after two days in intensive care. The patient
complained in repeated in-depth conversations about the unbearable loneliness after the death of his
wife. He stated that he repeatedly had been taken his medications arbitrarily out of desperation,
sleeplessness, and constantly varying aches and pains. A consulted psychiatrist ruled out suicidal
ideation. According to his wishes, the patient was able to be discharged to a nursing home after
spending 18 days in the hospital.
Figure 1. Serum levels of creatine kinase and theophylline levels over time.
DISCUSSION
Although just a few cases theophylline induced rhabdomyolysis have been reported in the literature,
there appears to be a higher incidence than assumed thus far. Higgins et al. [8] found four cases with
hypokalemia and rhabdomyolysis among 53 cases of theophylline intoxication. Sessler [22] was able to
identify one case with rhabdomyolysis among 116 incidences of acute or chronic theophylline
intoxication.
Different trigger mechanisms for rhabdomyolysis are being discussed. While some authors attribute
theophylline with a direct toxic effect on myocytes [11, 12, 29], others assume a direct influence of the
theophylline induced hypokalemia [11, 13, 14, 18, 19, 27, 28]. Hypokalemia is regarded by itself as a
trigger for rhabdomyolysis [2], along with hypophosphatemia [5], and hyponatremia [10]. Hypokalemia
was present in just about all the cases of acute theophylline intoxication and in about half of the chronic
intoxications [22]. Substances that increase the Na-K-ATPase activity in a similar fashion as theophylline
does, like β₂-agonists or insulin, can exacerbate the hypokalemia and hence increase the likelihood of
rhabdomyolysis [2]. The same holds true for potassium loss of different origin, like diuretics use or
gastro-intestinal potassium depletion [23].
Repeated grand-mal seizures, which may occur within the framework of theophylline intoxication, have
also been mentioned as a trigger in a series of cases [12, 14, 18, 19, 27, 28]. The underlying
pathomechanisms are complex. A special significance has been attributed to the imbalance between
oxygen supply and demand of the musculature [3, 11]. Hypoxia is, on one hand, often caused by a
severe asthma attack but can also occur within a diffusion deficit in left-sided heart failure, as it
happened in the present case. Increased lactate levels are regarded as an expression of tissue hypoxia
[9]. On the other hand, the muscular oxygen consumption might be increased by a heightened demand
of the respiratory muscles and their accessories during an asthma attack or as sequel to tonic-clonic
seizures. Also drugs, like β₂-agonists and theophylline, are capable of increasing the oxygen
consumption of the musculature through an induction of tremors, motoric restlessness, or seizures.
A decreased O₂-supply with an increased muscular O₂-demand followed by tissue hypoxia might
therefore present a central pathomechanism of rhabdomyolysis. Energy-dependent intra-cellular
processes come to a halt with an ATP-deficit in the myocytes. Protein- biosynthesis as well as transport
and repair mechanism of the cell membrane is affected, among others. This leads to a leaking of
intracellular components like myoglobin [3, 11], which can induce acute renal failure in a massive attack.
The processes occurring in the skeletal musculature are comparable to processes in an ischemic
myocardium. The effects of the disturbed membrane integrity in rhabdomyolysis are much more
relevant for the entire organism because of the much greater mass of skeletal musculature in contrast
to the myocardium [6].
Taking these pathogenetic connections into account, it is possible to formulate several risk factors for
the occurrence of a theophylline induced rhabdomyolysis (table 1).
The relevance of these risk factors is confirmed by the case studies reported in the literature. Thus the
theophylline levels in most of the reported cases were greater than 80 mg/l, concurrent hypokalemia
was present in most of the reported cases and/or generalized seizures [1, 4, 5, 7, 8, 11-14, 16-19, 22, 2529]. β₂-agonists were sometimes involved as an additional medication [5, 19].
Table 1. Risk factors for theophylline induced rhabdomyolysis.




Severe intoxication with high theophylline levels (> 80-100 mg/l)
Factors that cause hypokalemia
Illnesses leading to hypoxia
Increased muscular oxygen demand due to - muscle activity
- seizures
- medications
The theophylline level in the case at hand was with 66.5 mg/l not yet excessively high. Initially, there
was an increasing concentration (figure1). Hypoxia was present at the time of admission due to preexisting pulmonary and cardiac conditions. Seizures did not occur. The uncontrolled intake of
furosemide by the patient might have contributed to the hypokalemia and hyponatremia present at
admission to the hospital.
Rhabdomyolysis was diagnosed by determining myoglobin levels in serum. Further complications could
be prevented with the prompt initiation of emergency measures like detoxification, correction of
electrolytes, oxygen administration, and antiarrhythmic therapy. Acute renal failure is the most common
complication mentioned in the literature [26]. At least three of the 24 referenced cases had a fatal
outcome [16, 18, 22].
Primary measures in the treatment of theophylline intoxication mentioned are methods of toxin
elimination like hemoperfusion, oral administration of activated charcoal, and forced diuresis (table 2).
Hemoperfusion is considered to be the safest measure [8, 14, 15]. The combined use of hemodialysis
and hemoperfusion achieves an extraction rate of up to 86% [16]. Hemodialysis can be effective by itself
if hemoperfusion is not available [15], although a lower medium extraction rate of about 26% is to be
expected [8].
Table 2. Treatment principles for theophylline induced rhabdomyolysis.

Elimination of toxins: Oral administration of activated charcoal
Hemoperfusion and/or hemodialysis
Forced diuresis

Prophylaxis of acute renal failure (increase urine pH, volume therapy)

General measures:
Correction of electrolyte imbalances (hypokalemia!)
Anticonvulsive therapy
Sufficient oxygenation
Circulatory stabilization, antiarrhythmic therapy
Oral administration of activated charcoal gets a mixed review in the literature. Its use is limited on the
one hand by nausea and vomiting that is a frequent symptom in theophylline intoxication and there are
different opinions about the possibility of avoiding a secondary rise in theophylline levels if sustainedrelease theophylline preparations had been ingested [8, 12, 20]. Nonetheless, this kind of reabsorption
inhibitor should be employed if possible.
The present case demonstrated that the use of hemodialysis in combination with the oral administration
of activated charcoal and forced diuresis cut the theophylline concentration in half within about three
hours. This avoided a further progression of rhabdomyolysis, which was documented with the rapid
decrease of creatine kinase and myoglobin (see figure 1).
The further treatment is dictated by the pathophysiology of theophylline induced rhabdomyolysis and
includes correction of hypokalemia, sufficient oxygenation, volume therapy as well as the administration
of antiarrhythmic and antiemetic drugs [20, 22]. In case of hemodynamic instability, observed by Sessler
[22] in about a quarter of all patients with acute theophylline intoxication, it is recommended to
normalize the heart rhythm and the fluid balance (volume administration) prior to using vasopressors. A
urine pH of > 6, achieved with sodium bicarbonate infusion, should be the goal to reduce the tubular
toxicity of the myoglobin and therefore prevent acute renal failure [24].
CONCLUSIONS
It is the purpose of this case study of rhabdomyolysis in theophylline intoxication to draw attention to a
rarely considered adverse effect of a much prescribed drug with a narrow therapeutic spectrum. Risk
factors for these adverse effects have been formulated and explained. Timely identification of
myoglobin in the serum can aid in the diagnosis even before any significant renal insufficiency occurs.
Knowledge of the pathogenetic relationships makes an adequate treatment possible. The case study
reveals that a purposeful initiation of a targeted treatment can avoid a progression of rhabdomyolysis
and the complications involved.
We like to thank Mrs. Christine Stahr for her comprehensive support in the documentation of this case.
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Contact address
Stefan Teweleit
Institut für Klinische Pharmakologie
der Universität
Dornburger Straße 159
D-07740 Jena
Telefon (+49/3641) 937-770,
Fax -788,
E-Mail: stefan.teweleit@med uni-jena.de