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CLIN. CHEM. 36/2, 398-399 (1990)
Massive Theophylline Overdose with Atypical Metabolic Abnormalities
Susan H. Shakln Eshleman and LeslIe M. Shaw1
We report a case of fatal theophylline overdose in a 16year-old asthmatic boy who presented with seizures, respiratory arrest, and a theophylline concentration of 117 mg/L in
serum. His hospital course was complicated by refractory
hypotension and severe ischemic necrosis of skeletal muscle, bowel, and liver. The metabolic abnormalities observed
early in his hospital course included severe hyperkalemia,
hyperphosphatemia, hypermagnesemia, hypocalcemia, and
profound metabolic acidosis. These metabolic abnormalities
differ from those previously reported in cases of massive
theophylline overdose. The metabolic abnormalities observed in this patient probably reflected his extensive ischemic tissue damage with release of intracellular ions and
associated acidemia. Markedly increased catalytic activities
of creatine kinase, aspartate aminotransferase, and alanine
aminotransferase in serum were also noted.
Case Report
The patient, a 16-year-old boy with a history of asthma,
was transferred to the Hospital of the University of Pennsylvania (H.U.P.) after theophylline overdose. His usual
theophylline dose was 400 mg (‘Theo-Dur”; Key Pharmaceuticals, Inc.) orally twice daily.
His past medical history was remarkable
only for
asthma, celiac disease, and meningitis as an infant. He was
taking no other prescribed medications. Three days before
admission, the patient experienced worsening asthma and
reportedly took his theophylline
tablets with increasing
frequency, taking an estimated 8 g (20 tablets) during the
three
days, despite nausea and vomiting.
The morning of admission, he experienced agrand mal
seizure and respiratory arrest. He was found unresponsive
and wheezing with sluggish dilated pupils and was treated
with epinephrine, naloxone, dextrose, and metaproterenol
sulfate with no change. He was intubated and brought to
an outside hospital. On presentation there, his serum
theophylline
concentration
was 117 mgfL (therapeutic
range = 10-20 mg/L) with an arterial pH of 6.88 (normal
range = 7.35-7.45). A computer tomographic scan of the
head reportedly showed no significant abnormality. He was
treated with oral charcoal, diazepam, and a neuromuscular
blocking agent and was transferred to H.U.P. On arrival at
H.U.P., his heart rate was 150/mn, and his systolic blood
pressure was 80 mmHg, despite intravenous
presser
agents, and he was afebrile. He was unresponsive, with
sluggish dilated pupils and with hand, jaw, and eye twitching. Results of the rest of the physical exam were unremarkable. Urine was tea-colored. An electrocardiogram
showed sinus tachycardia with no other arrhythmia.
A
chest roentgenogram showed no abnormality. An electroencephalogram
showed probable status epilepticus, and he
Department of Pathology and Laboratory Medicine, Hospital of
the University ofPennsylvania, 3400 Spruce St., Philadelphia, PA
19104.
1 To whom correspondence
shouldbe addressed.
Received September 25, 1989; accepted October 27, 1989.
398
CLINICAL CHEMISTRY, Vol. 36, No. 2, 1990
received lorazepam, phenytoin, and a phenobarbital load.
Continuous arterial/venous hemoperfusion with charcoal
was initiated in the intensive care unit. The patient was
maintained in phenobarbital coma, with his electroencephalographic trace being consistent with burst suppression.
The patient’s initial laboratory values on transfer to
H.U.P., 3-4 h after respiratory arrest, were as follows.
Serum drug analyses revealed theophylline, 87.9 mgIL, and
a positive screen result for benzodiazepines. Urine drug
analyses were positive for ben.zodiazepines, caffeine, ephedrine, lidocaine, and theophylline. Other test results were
as follows: serum Na 138 mmol/L, K 6.2 mmollL, C1
107 mmolJL, CO2 9 mmol/L, glucose 1.01 gIL, urea nitrogen
230 mgfL, creatinine 13 mg/L, PO43 142 mgIL, Ca2 46
mg/L, Mg
50 mg/L, creatine kinase 90 048 UIL (reference
interval 20-315), alanine aminotransferase 162 UIL (040), aspartate
aminotransferase
1141 UIL (0-36), gammaglutamyltransferase
19 U/L (0-40), total bilirubin
6 g/L
(0-12), alkaline phosphatase 113 U/L (35-125), hemoglobin
169 gIL, hematocrit
49%, leukocyte count 33 500/giL, and
platelets 457 000 /.iL.
After 4 h of hemoperf’usion, the patient’s theophylline
concentration
in serum was 14 mg/L. Over the next 24 h,
his creatine kinase rose to 1 548 800 U/L; serum K increased to 7.1 mmol!L, requiring
dialysis. Glucose decreased to 0.31 g/L and uric acid increased to 212 mgIL. His
urine output ceased, consistent with acute tubular necrosis
secondary to rhabdomyolysis,
and his urea nitrogen and
creatinine
concentrations in serum steadily increased. He
remained markedly acidotic and hypotensive despite aggressive management. Two days after admission
he underwent extensive emergent bowel resection for ischemic
bowel syndrome; three days after admission he died. On
autopsy, there was marked ischemic necrosis of skeletal
muscle and liver.
Materials and Methods
Theophylline was measured with the EMIT procedure in a
Hitachi 704 automated analyzer, according to the manufacturer’s instructions (Syva Co., Palo Alto, CA 94304). The
urine drug screen was done with the ToxiLab system as
described by the manufacturer (Marion Laboratories, KanMs City, MO 641 14). To confirm positive results, we used a
gas chromatographic-mass
spectrometric procedure (1).
Discussion
Theophylline, one of three naturally occurring methylxanthine derivatives, is widely used in the treatment of
acute and chronic asthma and chronic obstructive pUImOnary disease because ofits ability to relax bronchial smooth
muscle (2). The therapeutic range of theophylline, 10-20
mg/L, is very narrow; most patients begin to experience
adverse effects at concentrations >20 mgfL (3). The severity of these adverse effects is generally but not always
correlated with the concentration ofthe drug in plasma (3).
Among patients with theophylline
overdose, those who
develop seizures have the worst prognosis, the estimated
mortality rate being 50% (4).
Several clinical factors may have contributed to the
severity of the complications of overdose in this case.
Ordinarily, about 40% of theophylline is bound to plasma
proteins (5); the remaining free (active) drug distributes in
all tissues except fat, the volume of distribution
being
approximately
0.45 11kg (range = 0.3-0.7 11kg) (3). The
proportion of free theophylline
can increase in patients
with uncorrected acidemia (6). In the present case, the
patient’s severe acidemia may have resulted in higher
plasma concentrations of active theophylline in the presence of his already massive total plasma theophylline
concentration (117 mgfL). Correction of acidemia in this
setting may have been clinically beneficial by reducing the
amount of active drug in the circulation.
Another factor that may have affected the severity of
adverse reactions in this case was that the toxic concentration of theophylline were most probably attained over a
period of several days. Severe adverse effects of theophylline (i.e., serious cardiac arrhythmias
and seizures) have
generally been observed at lower plasma concentrations in
patients who attain toxic concentrations ofthe drug over a
period of several days than in patients with acute drug
overdose (7-9). Patients receiving theophylline chronically
before overdose often develop excessively high concentrations in plasma because of inappropriate dosing or because
of a decrease in drug clearance (e.g., worsening hepatic or
cardiac function) (7). In acute overdose, it is uncommon to
see severe reactions at concentrations <100 mg/L; in patients taking toxic doses of theophylline over several days,
severe reactions have been reported at concentrations as
low as 28 mg/L (8, 9). The reason for this difference is not
theophylline
in serum is essential in patients who are
receiving theophylline. First, in a large proportion of patients with serious complications of theophylline toxicity
(e.g., seizure), no other symptoms were noted before the
serious complications arose (4); therefore, mild or moderate
adverse effects cannot be relied upon to predict a patient’s
risk for severe complications of toxicity. Monitoring theophylline therapy is also particularly
important because
many factors can substantially alter the rate of theophylline clearance and therefore lead to increased concentrations of the drug in serum with no change in dosing (3).
These factors include changes in cardiac or hepatic function, viral illnesses, smoking history, diet, and concurrent
administration
ofa wide variety ofother drugs (3). Finally,
it is also important to note that relatively small increases
in dose, such as in this case, can lead to clinically significant toxicity because ofthe narrow therapeutic “window” of
the drug. For example, in this case, we can estimate the
total dose required to achieve a peak plasma concentration
of 117 mg/L by using the following equation: minimum
dose taken
(volume of distribution in LIkg) x (weight in
kg) x (peak concentration
in mg/L). This equation is
derived from the equation used for the calculation of the
peak concentration of a drug in plasma after a single dose
(13). In the case of this patient, this equals 0.45 kg/L x 70
kg x 117 mg/L = 3700 mg, or only 9-10 of the patient’s
400-mg tablets. For these reasons, close therapeutic drug
monitoring and extensive patient education are essential to
avoid serious complications in patients receiving theophylline.
known.
1. Remaley AT, Hicks DO, Kane MD, Shaw LM. Laboratory
assessment of poisoning with a carbamate insecticide. Clin Chem
In addition to the above-mentioned factors, administration of other drugs with adrenergic effects may have exacerbated the toxicity ofthe theophylline. Caffeine and ephedrine were detected in the patient’s urine at initial presentation. Ephedrine, most likely obtained by the patient in an
over-the-counter
preparation,
is known to act synergistically with theophylline to increase the frequency of adverse
effects (10). Epinephrine,
given to this patient in the
setting ofrespiratory arrest, may have further exacerbated
the adverse effects of theophylline.
Various metabolic effects have been reported with therapeutic and supratherapeutic doses oftheophylline,
including: hyperglycemia
(11), hypokalemia (11, 12), hypophosphatemia (11, 12), hypomagnesemia (11), respiratory alkalosis (11), and, less commonly, metabolic acidosis (11, 12).
Some ofthese metabolic abnormalities may be secondary to
increased concentrations ofcirculating
catecholamines (11,
12). The metabolic abnormalities noted in this patientmarked hyperkalemia,
hyperphosphatemia,
hypermagnesemia,
hypocalcemia,
and profound metabolic acidosisare not typical. These findings and several other dramatic
laboratory
me kinase,
abnormalities
in this case (e.g., increased creataminotransferases,
and uric acid) most proba-
bly reflected the unusual degree oftissue damage resulting
from the seizures and decreased tissue perfusion. The
finding of atypical metabolic abnormalities in a case such
as this should alert the medical staff to consider secondary
complications of theophylline overdose, as well as other
possibly unrelated concomitant clinical problems.
For several reasons, close monitoring of concentrations of
-
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