CASE REPORT theophylline, overdose
Acute Theophylline Intoxication We describe a case of intentional acute theophyIline intoxication with cardiac, cerebral, and gastrointestinal features of moderate-to-severe toxicity. The unusual metabolic and hematologic sequelae included hypokalemia, hyperglycemia, metabolic acidosis, extreme neutrophilia, increased creatinine levels attributed to muscle damage, and hematuria. The implications of these unusual findings for the management of acute theophylline intoxication include the recognition that these effects can be due to intoxication per se and do not necessarily indicate a primary endocrine disorder or infection. [Anderson W, Youl B, Mackay IR: Acute theophylline intoxication. Ann Emerg Med October 1991;20:1143-1145.]
INTRODUCTION Theophylline is useful in the maintenance treatment of asthma. Although chronic and acute intoxications are well recognized, conventional doses rarely result in toxic blood levels. We describe the consequences of an intentional acute theophylline overdose, including some previously rarely reported metabolic and hematologic effects attributed to this commonly prescribed medication.
Warwick Anderson, MB BS, BMedSci, MA Bryan Youl, MB BS, BMedSci, FRACP lan R Mackay, MD, FRCP, FRACP, FRCPA Melbourne, Australia From the Clinical Research Unit of the Walter and Eliza Hall Institute for Medical Research, and the Royal Melbourne Hospital, Melbourne, Australia. Received for publication November 14, 1990. Revision received April 5, 1991. Accepted for publication May 17, 1991. Address for reprints: Warwick Anderson, MB BS, BMedSci, MA, HSS Department, University of Pennsylvania, 215 South 34th Street, Philadelphia, Pennsylvania 19104-6310.
CASE REPORT A 19-year-old asthmatic man presented to the Royal Melbourne Hospital after a deliberate overdose of theophylline. He was a nonsmoker, drank alcohol only occasionally, and was not addicted to any drugs. He had used salbutamol inhalers and theophylline but no corticosteroids regularly for five years for mild exacerbations of asthma. On this occasion, four hours before presentation, he had taken approximately 20 slow-release 300 mg theophylline tablets in a suicide attempt. He complained of headache, nausea, severe thirst, and frequency of micturition. During the previous two hours, he had vomited frequently. While in the emergency department, he had two hematemeses of a total of approximately 150 mL. On examination, he was lethargic and confused, with a mildly exaggerated physiologic tremor of both hands. His blood pressure was 105/50 m m Hg; pulse, 120 and regular; oral temperature, 36 C; and respirations, 32. Breath sounds were normal. There was a right ventricular heave and a loud pulmonary component of the second heart sound. An ECG showed sinus tachycardia and changes consistent with hypokalemia and right ventricular hypertrophy. Chest radiograph was normal. Arterial blood gases on 2 L O 2 by mask were pH 7.42; Pco2, 21 m m Hg; Po2, 117 m m Hg; and HCO3, 18 m m Hg. Electrolyte concentrations were sodium of 137 mmol/L; potassium, 2.0 mmol/L; chloride, 103 mmol/L; and bicarbonate, 15 mmol/L. The creatinine concentration was elevated (0.24 retool/L), with urea of 5.3 mmol/L. Random blood glucose on admission was raised (15.2 mmol/L; normal range, 3.6 to 5.2 mmol/L). There was marked leukocytosis (47.8 x 10-9/L), with neutrophilia of 34.8 x 10-9/L and mild monocytosis of 1.43 x 10-9/L but a normal lymphocyte count {Table). The aspartate transaminase level was slightly increased, to 54 IU/L. There were microscopic hematuria and glycosuria present. A midstream urine examination contained 4,000 glomerular RBCs/mL but no leukocytes. The urine culture was negative. A general toxicologic screen was not
20:10 October 1991
Annals of Emergency Medicine
1143/131
T H E O P H Y L L I N E INTOXICATION A n d e r s o n , Youl & M a c k a y
available. Preliminary assessment showed that the patient had the indications of theophylline intoxication of confusion, hematemesis, hyperventilation, tachycardia, hypotension, hypokalemia, hyperglycemia with polydipsia and polyuria, and leukocytosis. A theophylline level six hours after the overdose was 269 Fmol/L (therapeutic range, 55 to 110 ~mol/L). Initial t r e a t m e n t consisted of IV rehydration, subcutaneous insulin, potassium supplementation, and oral antacids. The patient's condition returned to normal over the following 24 hours, with restoration of blood pressure to 120/80 m m Hg. The potassium level increased to 3.8 mmol/L, and the creatinine level decreased to within the normal range. An ECG on the second day after admission was normal. After three days, insulin was no longer required. The WBC count was within normal limits by the fifth day. Microscopic hematuria was still present at discharge from the hospital on day five, but on review one month later the urine examination waS n o r m a l .
DISCUSSION The frequency and severity of cerebral, cardiac, and gastrointestinal expressions of theophylline toxicity are known to correlate well with serum concentrations. 1-3 Most signs and symptoms of theophylline intoxication can be attributed to ~3-adrenergic and direct central nervous system stimulation. 4 Cerebral expressions commonly include headache, hyperventilation, restlessness, lethargy, stupor, and focal and generalized seizures. 2 Cardiac expressions range from sinus tachycardia, which has been reported in 89% of toxic patients, 5 to h y p o t e n s i o n and lifethreatening arrhythmias.6, 7 Gastrointestinal expressions usually include nausea and vomiting and occasionally include hematemesis. 8 Metabolic expressions, in particular, hypokalemia, hyperglycemia, hypercalcemia, h y p o p h o s p h a t e m i a , and lactic acidosis, have been reported recently in acute poisoning. 9-13 The high mortality associated with acute theophylline toxicity is accounted for by cardiovascular collapse and intractable seizure activity. ~4 Our case exemplifies some rarely emphasized or novel metabolic and 132/1144
TABLE. Full blood counts 24 Hours
Time 48 Hours
4 Days
RBC count (3.8 to 6,4 x 10 WL)
5.57
4.89
5.39
Pratelet count (130 to 400 x 10-9/L)
353
288
261
WBC count (4.5 to 11.0 x 10-9/L) Differential: Polymorphonuclear ]eukocytes (3.00 to 6.00 x 10-9/L) Metamyelocytes (0.30 to 0.5 x 10 9/L) Monocytes (0.35 to 0.50 x 10 9/L) Lymphocytes (1.50 to 2.70 x 10 9/L)
47.8
29.0
8.0
34.8
24.0
*
10.0
1.74
*
1.43
1.16
*
1.60
2.03
1.50
• Differential not done (normal total WBC counl)
hematologic features. Hypokalemia was particularly profound; in view of the potential contribution of hypokalemia to cardiac arrhythmias, this finding is obviously pertinent. The occurrence of hypokalemia after theophylline intoxication requires consideration, especially when the overdose is acute, is We treated this with cautious IV potassium supplementation, I6 while recognizing that the low serum level would not necessarily reflect total body depletion, lz H y p e r g l y c e m i a has been n o t e d only occasionally in other cases.l 1,16 Hall and associates reported an increased blood glucose level in most of the 22 patients with theophylline intoxication in whom laboratory data were analyzed retrospectively, is In their series, hyperglycemia was seldom high enough to have required treatment. Leukocytosis (47.8 x 10-9/L) was a striking feature of our case. This lasted four days and occurred in the absence of fever or signs of inflamm a t i o n , a l t h o u g h blood c u l t u r e s were not done. Hall and associates also reported leukocytosis, the highest level being 37.4 x ] 0 - 9 / L . 19 They suggested that an increase in plasma catecholamines induced by theophylline led to demargination of leukocytes, a theory supported by normal differential leukocyte counts in four of the five patients for whom data were available. 16 The leukocytosis in our case was considerably greater than any previously reported; it c o n s i s t e d p r i n c i p a l l y of pron o u n c e d n e u t r o p h i l i a , w i t h mild Annals of Emergency Medicine
monocytosis and normal lymphocyte concentrations (Table). The absence of lymphocytosis is difficult to reconcile with the hypothesis of a shift within the circulation from the marginal to the circulating pool. Neutrophilia can occur by several other mechanisms: an increase in cell production, an accelerated release of cells from the marrow to the blood, or a reduced use of cells. Lithium salts, for example, increase the bone marrow production of neutrophils by enhancing the release of c o l o n y - s t i m u l a t i n g activity. 2o But any such increase in the production of neutrophils occurs over a number of days 21 and therefore cannot explain the early onset of neutrophilia observed in our case. The acute neutrophilia seen in c a s e s of i n f e c t i o n is p r o d u c e d through the release of neutrophils from the marrow storage pool. Although this may occur within a few hours, it is not a convincing explanation of the neutrophilia in the present case for two reasons: there was no clinical evidence of infection or inflammation, and the blood counts do not present a typical picture of i n f e c t i o n . In p a r t i c u l a r , m e t a myelocytes are found in the peripheral blood only in extreme circumstances. 19 Thus, we argue that alt h o u g h the t i m e c o u r s e of the neutrophilia and the previously identified association between theophylline and increased plasma catecholamine levels imply that demargination was the most likely cause of the leukocytosis in this case, the pres20:10 October 1991
THEOPHYLLINE INTOXICATION Anderson, Youl & Mackay
ence of a normal l y m p h o c y t e concentration nevertheless suggests the need for further investigation of this m a n i f e s t a t i o n of t h e o p h y l l i n e toxicity. Elevation of serum creatinine during the first 24 hours and prolonged microscopic hematuria were novel features of the present case. We note that increased creatine kinase levels in the absence of seizures have been reported previously 22 and that rhabdomyolysis can occur as a complication of theophylline overdose and induce acute renal failure.28, 24 H o w ever, there was no myoglobinuria in our patient, nor any significant oliguria. T h e s y s t e m i c d i s t u r b a n c e s , such as hypotension, were not severe enough to account for any renal impairment. Little information is available regarding the direct effect of theophylline on renal function. A m i n o phylline has been shown to increase renal blood flow and cause a direct tubular blockade of sodium readsorption w h e n administered in l o w doses to dogs. 25 SUMMARY We describe a case of intentional acute theophylline intoxication that illustrates s o m e previously rarely reported metabolic and hematologic sequelae, including an unusual leuko-
20:10 October 1991
cytosis. Recognition of the range of m a n i f e s t a t i o n s of t h e o p h y l l i n e toxi c i t y w i l l assist in the a s s e s s m e n t and m a n a g e m e n t of this not u n c o m m o n problem. REFERENCES 1. Jacobs MH, Senior RM, Kessler G: Clinical experience with theophylline: Relationships between dosage, serum concentration and toxicity. JAMA 1976;235: 1983-1986. 2. Zwillich CW, Sutton FD, Neff TA, et ah Theophylline-induced seizures in adults: Correlation with serum c o n c e n t r a t i o n s . A n n I n t e r n M e d 1975;82:784787.
poisoning {letter). Lancet 1983;2:618. 12. Amitai Y, Lovejoy FH: Hypokalemia in acute theophylline poisoning. A m J Emerg Mecl 1988;6:214-218. 13. Sawyer WT, Caravati M, Ellison MJ, et al: Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose. Am J Emerg Med 1985;3:408-411. 14. Paloucek FP, Rodvold KA: Evaluation of theophylline overdoses and toxicities. Ann Ernerg Med 1988; 17:135 144. 15. Shannon M, Lovejoy FH: Hypokalemia after theophylline intoxication: The effects of acute vs chronic poi soning. Arch Intern Med 1989;149:2725-2729. 16. Hall KW, Dobson KE, Dalton JG, et al: Theophylline overdose and metabolic abnormalities [letter/. Ann Intern Med 1985;102:562.
3. Dawson AH, Whyte IM: The assessment and treatm e n t of theophylline poisoning. Med J Aust 1989; 151:689-693.
17. D'Angio R, Sabatelli ]a: Management considerations in treating metabolic abnormalities associated with theo p h y l l i n e overdose. Arch Intern Med 1987;147: 1837 1838.
4. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and the beta adrenergie system. Ann Intern Med 1985;102:766-769.
18. Hall KW, Dobson KE, Dalton JG, et ah Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med i984;101:457-462.
5. Hendeles L, Bighley L, Richardson RH, et al: Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intell Clin Pharmacoi 1977~11: 12q8.
19. Dale DC: Nentrophilia, in Williams WJ, Beutler B, Erslev AJ, et al {edsJ: Helnatology, ed 4. N e w York, McGraw-Hill Book Co, 1990, p 816-820.
6. Horowitz LN, Spear JF, Moore EN, et al: Effects of aminophylline on the threshold for initiating ventricu lar fibrillation during respiratory failure. A m ] CardioI 1975;35:376-379.
20. Rothstein G, Clarkson DR, Larsen W, et al: Effect of lithium on neutrophil mass and production. N Engl f Med 1978;298:178-180. 21. Joyce RA: Sequential effects of lithium on haematopoiesis. Br J Haernatol 1984;56:307-321.
7. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose: Acute single ingestion versus chronic repeated overmedieation. Arn J Emerg Med 1985;3: 386-394.
22. Ng RH, Roe C, ]aunt D, et al: Increased activity of creatine kinase isoenzyme MB in a theophylline-intoxicated patient. Clin Chem 1985~31:1741-1742.
8. Amitai Y, Lovejoy FH: Characteristics of vomiting associated with acute sustained release theophylline poisoning. Clin Toxicoi 1987;25:539-554.
23. Robertson NJ: Fatal overdose from a sustained-release theophyliine preparation. Ann Emerg Med 1985; 14:154-158.
9. Halliwell M, Berry D: Theophylline poisoning in adults. Br Med J 1979;2:1114.
24. MacDonald JB, Jones HM, Cowan RA: Rhahdomyolysis and acute renal failure after theophylline overdose {letter). Lancet 1985;1:932-933.
10. Rose C: T h e o p h y l l i n e 1979;130:466-467.
t o x i c i t y . West ] Med
11. Buckley BM, Braithwaite RA, Vale JA: Theophylline
Annals of Emergency Medicine
25. Ludens JH, Willis LR, Williamson HE: The effect of aminophylline on renal hemodynamics and sodium excretion. Arch Int Pharmacodyn 1970;185:274-286.
1145/133
Acute Theophylline Intoxication We describe a case of intentional acute theophyIline intoxication with cardiac, cerebral, and gastrointestinal features of moderate-to-severe toxicity. The unusual metabolic and hematologic sequelae included hypokalemia, hyperglycemia, metabolic acidosis, extreme neutrophilia, increased creatinine levels attributed to muscle damage, and hematuria. The implications of these unusual findings for the management of acute theophylline intoxication include the recognition that these effects can be due to intoxication per se and do not necessarily indicate a primary endocrine disorder or infection. [Anderson W, Youl B, Mackay IR: Acute theophylline intoxication. Ann Emerg Med October 1991;20:1143-1145.]
INTRODUCTION Theophylline is useful in the maintenance treatment of asthma. Although chronic and acute intoxications are well recognized, conventional doses rarely result in toxic blood levels. We describe the consequences of an intentional acute theophylline overdose, including some previously rarely reported metabolic and hematologic effects attributed to this commonly prescribed medication.
Warwick Anderson, MB BS, BMedSci, MA Bryan Youl, MB BS, BMedSci, FRACP lan R Mackay, MD, FRCP, FRACP, FRCPA Melbourne, Australia From the Clinical Research Unit of the Walter and Eliza Hall Institute for Medical Research, and the Royal Melbourne Hospital, Melbourne, Australia. Received for publication November 14, 1990. Revision received April 5, 1991. Accepted for publication May 17, 1991. Address for reprints: Warwick Anderson, MB BS, BMedSci, MA, HSS Department, University of Pennsylvania, 215 South 34th Street, Philadelphia, Pennsylvania 19104-6310.
CASE REPORT A 19-year-old asthmatic man presented to the Royal Melbourne Hospital after a deliberate overdose of theophylline. He was a nonsmoker, drank alcohol only occasionally, and was not addicted to any drugs. He had used salbutamol inhalers and theophylline but no corticosteroids regularly for five years for mild exacerbations of asthma. On this occasion, four hours before presentation, he had taken approximately 20 slow-release 300 mg theophylline tablets in a suicide attempt. He complained of headache, nausea, severe thirst, and frequency of micturition. During the previous two hours, he had vomited frequently. While in the emergency department, he had two hematemeses of a total of approximately 150 mL. On examination, he was lethargic and confused, with a mildly exaggerated physiologic tremor of both hands. His blood pressure was 105/50 m m Hg; pulse, 120 and regular; oral temperature, 36 C; and respirations, 32. Breath sounds were normal. There was a right ventricular heave and a loud pulmonary component of the second heart sound. An ECG showed sinus tachycardia and changes consistent with hypokalemia and right ventricular hypertrophy. Chest radiograph was normal. Arterial blood gases on 2 L O 2 by mask were pH 7.42; Pco2, 21 m m Hg; Po2, 117 m m Hg; and HCO3, 18 m m Hg. Electrolyte concentrations were sodium of 137 mmol/L; potassium, 2.0 mmol/L; chloride, 103 mmol/L; and bicarbonate, 15 mmol/L. The creatinine concentration was elevated (0.24 retool/L), with urea of 5.3 mmol/L. Random blood glucose on admission was raised (15.2 mmol/L; normal range, 3.6 to 5.2 mmol/L). There was marked leukocytosis (47.8 x 10-9/L), with neutrophilia of 34.8 x 10-9/L and mild monocytosis of 1.43 x 10-9/L but a normal lymphocyte count {Table). The aspartate transaminase level was slightly increased, to 54 IU/L. There were microscopic hematuria and glycosuria present. A midstream urine examination contained 4,000 glomerular RBCs/mL but no leukocytes. The urine culture was negative. A general toxicologic screen was not
20:10 October 1991
Annals of Emergency Medicine
1143/131
T H E O P H Y L L I N E INTOXICATION A n d e r s o n , Youl & M a c k a y
available. Preliminary assessment showed that the patient had the indications of theophylline intoxication of confusion, hematemesis, hyperventilation, tachycardia, hypotension, hypokalemia, hyperglycemia with polydipsia and polyuria, and leukocytosis. A theophylline level six hours after the overdose was 269 Fmol/L (therapeutic range, 55 to 110 ~mol/L). Initial t r e a t m e n t consisted of IV rehydration, subcutaneous insulin, potassium supplementation, and oral antacids. The patient's condition returned to normal over the following 24 hours, with restoration of blood pressure to 120/80 m m Hg. The potassium level increased to 3.8 mmol/L, and the creatinine level decreased to within the normal range. An ECG on the second day after admission was normal. After three days, insulin was no longer required. The WBC count was within normal limits by the fifth day. Microscopic hematuria was still present at discharge from the hospital on day five, but on review one month later the urine examination waS n o r m a l .
DISCUSSION The frequency and severity of cerebral, cardiac, and gastrointestinal expressions of theophylline toxicity are known to correlate well with serum concentrations. 1-3 Most signs and symptoms of theophylline intoxication can be attributed to ~3-adrenergic and direct central nervous system stimulation. 4 Cerebral expressions commonly include headache, hyperventilation, restlessness, lethargy, stupor, and focal and generalized seizures. 2 Cardiac expressions range from sinus tachycardia, which has been reported in 89% of toxic patients, 5 to h y p o t e n s i o n and lifethreatening arrhythmias.6, 7 Gastrointestinal expressions usually include nausea and vomiting and occasionally include hematemesis. 8 Metabolic expressions, in particular, hypokalemia, hyperglycemia, hypercalcemia, h y p o p h o s p h a t e m i a , and lactic acidosis, have been reported recently in acute poisoning. 9-13 The high mortality associated with acute theophylline toxicity is accounted for by cardiovascular collapse and intractable seizure activity. ~4 Our case exemplifies some rarely emphasized or novel metabolic and 132/1144
TABLE. Full blood counts 24 Hours
Time 48 Hours
4 Days
RBC count (3.8 to 6,4 x 10 WL)
5.57
4.89
5.39
Pratelet count (130 to 400 x 10-9/L)
353
288
261
WBC count (4.5 to 11.0 x 10-9/L) Differential: Polymorphonuclear ]eukocytes (3.00 to 6.00 x 10-9/L) Metamyelocytes (0.30 to 0.5 x 10 9/L) Monocytes (0.35 to 0.50 x 10 9/L) Lymphocytes (1.50 to 2.70 x 10 9/L)
47.8
29.0
8.0
34.8
24.0
*
10.0
1.74
*
1.43
1.16
*
1.60
2.03
1.50
• Differential not done (normal total WBC counl)
hematologic features. Hypokalemia was particularly profound; in view of the potential contribution of hypokalemia to cardiac arrhythmias, this finding is obviously pertinent. The occurrence of hypokalemia after theophylline intoxication requires consideration, especially when the overdose is acute, is We treated this with cautious IV potassium supplementation, I6 while recognizing that the low serum level would not necessarily reflect total body depletion, lz H y p e r g l y c e m i a has been n o t e d only occasionally in other cases.l 1,16 Hall and associates reported an increased blood glucose level in most of the 22 patients with theophylline intoxication in whom laboratory data were analyzed retrospectively, is In their series, hyperglycemia was seldom high enough to have required treatment. Leukocytosis (47.8 x 10-9/L) was a striking feature of our case. This lasted four days and occurred in the absence of fever or signs of inflamm a t i o n , a l t h o u g h blood c u l t u r e s were not done. Hall and associates also reported leukocytosis, the highest level being 37.4 x ] 0 - 9 / L . 19 They suggested that an increase in plasma catecholamines induced by theophylline led to demargination of leukocytes, a theory supported by normal differential leukocyte counts in four of the five patients for whom data were available. 16 The leukocytosis in our case was considerably greater than any previously reported; it c o n s i s t e d p r i n c i p a l l y of pron o u n c e d n e u t r o p h i l i a , w i t h mild Annals of Emergency Medicine
monocytosis and normal lymphocyte concentrations (Table). The absence of lymphocytosis is difficult to reconcile with the hypothesis of a shift within the circulation from the marginal to the circulating pool. Neutrophilia can occur by several other mechanisms: an increase in cell production, an accelerated release of cells from the marrow to the blood, or a reduced use of cells. Lithium salts, for example, increase the bone marrow production of neutrophils by enhancing the release of c o l o n y - s t i m u l a t i n g activity. 2o But any such increase in the production of neutrophils occurs over a number of days 21 and therefore cannot explain the early onset of neutrophilia observed in our case. The acute neutrophilia seen in c a s e s of i n f e c t i o n is p r o d u c e d through the release of neutrophils from the marrow storage pool. Although this may occur within a few hours, it is not a convincing explanation of the neutrophilia in the present case for two reasons: there was no clinical evidence of infection or inflammation, and the blood counts do not present a typical picture of i n f e c t i o n . In p a r t i c u l a r , m e t a myelocytes are found in the peripheral blood only in extreme circumstances. 19 Thus, we argue that alt h o u g h the t i m e c o u r s e of the neutrophilia and the previously identified association between theophylline and increased plasma catecholamine levels imply that demargination was the most likely cause of the leukocytosis in this case, the pres20:10 October 1991
THEOPHYLLINE INTOXICATION Anderson, Youl & Mackay
ence of a normal l y m p h o c y t e concentration nevertheless suggests the need for further investigation of this m a n i f e s t a t i o n of t h e o p h y l l i n e toxicity. Elevation of serum creatinine during the first 24 hours and prolonged microscopic hematuria were novel features of the present case. We note that increased creatine kinase levels in the absence of seizures have been reported previously 22 and that rhabdomyolysis can occur as a complication of theophylline overdose and induce acute renal failure.28, 24 H o w ever, there was no myoglobinuria in our patient, nor any significant oliguria. T h e s y s t e m i c d i s t u r b a n c e s , such as hypotension, were not severe enough to account for any renal impairment. Little information is available regarding the direct effect of theophylline on renal function. A m i n o phylline has been shown to increase renal blood flow and cause a direct tubular blockade of sodium readsorption w h e n administered in l o w doses to dogs. 25 SUMMARY We describe a case of intentional acute theophylline intoxication that illustrates s o m e previously rarely reported metabolic and hematologic sequelae, including an unusual leuko-
20:10 October 1991
cytosis. Recognition of the range of m a n i f e s t a t i o n s of t h e o p h y l l i n e toxi c i t y w i l l assist in the a s s e s s m e n t and m a n a g e m e n t of this not u n c o m m o n problem. REFERENCES 1. Jacobs MH, Senior RM, Kessler G: Clinical experience with theophylline: Relationships between dosage, serum concentration and toxicity. JAMA 1976;235: 1983-1986. 2. Zwillich CW, Sutton FD, Neff TA, et ah Theophylline-induced seizures in adults: Correlation with serum c o n c e n t r a t i o n s . A n n I n t e r n M e d 1975;82:784787.
poisoning {letter). Lancet 1983;2:618. 12. Amitai Y, Lovejoy FH: Hypokalemia in acute theophylline poisoning. A m J Emerg Mecl 1988;6:214-218. 13. Sawyer WT, Caravati M, Ellison MJ, et al: Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose. Am J Emerg Med 1985;3:408-411. 14. Paloucek FP, Rodvold KA: Evaluation of theophylline overdoses and toxicities. Ann Ernerg Med 1988; 17:135 144. 15. Shannon M, Lovejoy FH: Hypokalemia after theophylline intoxication: The effects of acute vs chronic poi soning. Arch Intern Med 1989;149:2725-2729. 16. Hall KW, Dobson KE, Dalton JG, et al: Theophylline overdose and metabolic abnormalities [letter/. Ann Intern Med 1985;102:562.
3. Dawson AH, Whyte IM: The assessment and treatm e n t of theophylline poisoning. Med J Aust 1989; 151:689-693.
17. D'Angio R, Sabatelli ]a: Management considerations in treating metabolic abnormalities associated with theo p h y l l i n e overdose. Arch Intern Med 1987;147: 1837 1838.
4. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and the beta adrenergie system. Ann Intern Med 1985;102:766-769.
18. Hall KW, Dobson KE, Dalton JG, et ah Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med i984;101:457-462.
5. Hendeles L, Bighley L, Richardson RH, et al: Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intell Clin Pharmacoi 1977~11: 12q8.
19. Dale DC: Nentrophilia, in Williams WJ, Beutler B, Erslev AJ, et al {edsJ: Helnatology, ed 4. N e w York, McGraw-Hill Book Co, 1990, p 816-820.
6. Horowitz LN, Spear JF, Moore EN, et al: Effects of aminophylline on the threshold for initiating ventricu lar fibrillation during respiratory failure. A m ] CardioI 1975;35:376-379.
20. Rothstein G, Clarkson DR, Larsen W, et al: Effect of lithium on neutrophil mass and production. N Engl f Med 1978;298:178-180. 21. Joyce RA: Sequential effects of lithium on haematopoiesis. Br J Haernatol 1984;56:307-321.
7. Olson KR, Benowitz NL, Woo OF, et al: Theophylline overdose: Acute single ingestion versus chronic repeated overmedieation. Arn J Emerg Med 1985;3: 386-394.
22. Ng RH, Roe C, ]aunt D, et al: Increased activity of creatine kinase isoenzyme MB in a theophylline-intoxicated patient. Clin Chem 1985~31:1741-1742.
8. Amitai Y, Lovejoy FH: Characteristics of vomiting associated with acute sustained release theophylline poisoning. Clin Toxicoi 1987;25:539-554.
23. Robertson NJ: Fatal overdose from a sustained-release theophyliine preparation. Ann Emerg Med 1985; 14:154-158.
9. Halliwell M, Berry D: Theophylline poisoning in adults. Br Med J 1979;2:1114.
24. MacDonald JB, Jones HM, Cowan RA: Rhahdomyolysis and acute renal failure after theophylline overdose {letter). Lancet 1985;1:932-933.
10. Rose C: T h e o p h y l l i n e 1979;130:466-467.
t o x i c i t y . West ] Med
11. Buckley BM, Braithwaite RA, Vale JA: Theophylline
Annals of Emergency Medicine
25. Ludens JH, Willis LR, Williamson HE: The effect of aminophylline on renal hemodynamics and sodium excretion. Arch Int Pharmacodyn 1970;185:274-286.
1145/133
