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Lactic acidosis in theophylline overdose
lactic Acidosis in Theophylline Overdose LAWRENCE J. LEVENTHAL, MD,* GURPREET KOCHAR, MD,t NEIL H. FELDMAN, DO,t SHERMAN M. PODOLSKY, MD,* MARJORIE S. STANEK, MD+ An ll-year-old man with theophylline overdose developed an increased anion gap metabolic acidosis. Serum lactate levels were markedly elevated. A direct correlation was found between the increasing theophylline level, clinical hyperadrenergicstate, and the worsening acidosis. Early hemoperfusion reversed the acidosis, the elevated serum theophylline level, and the hyperadrenergic state. This case substantiates the role of lactate accumulation in the metabolic acidosis associated with isolated theophylline toxicity. (Am J Emerg Med 1989;7:417-418. 01989 by W.8. Saunders Company.)
Acute theophylline overdose caused by intentional or accidental ingestion has been reported with increasing frequency. ‘-3 Associated metabolic abnormalities such as hypokalemia, hypophosphatemia, hypomagnesemia, and respiratory alkalosis have been described. ’ T4*5However, metabolic acidosis from isolated theophylline toxicity without concurrent drugs or in the absence of shock has not been noted as frequently. Although previous reports postulate that the mechanism for the acidosis involves lactate accumulation,‘+4*5 this has never been firmly established. We report a case of acute theophylline intoxication, with documented elevated serum lactate, causing an increased anion gap metabolic acidosis. CASE REPORT An l&year-old male presented to the emergency department two hours after ingesting 9 g of a sustained-release theophylline preparation in a suicide attempt. He denied taking any other medications. On arrival he complained only of nausea. On physical examination he was awake and alert, From the ‘Rheumatology Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia; and the Departments of *Medicine and *Emergency Medicine, Albert Einstein Medical Center, Temple University School of Medicine, Philadelphia. Manuscript received August 29, 1988; revision accepted October 19, 1988. Address reprint requests to Dr Leventhal: Maloney 570, Hospital of the University of Pennsylvania, 3800 Spruce St, Philadelphia, PA 19104-4283. Key Words: Theophylline,
toxicity, lactate, acidosis.
01989 by W.B. Saunders Company. 0735-6757/89/0704-0016$5.00/O
although restless and irritable. BP was 160/90 mmHg, pulse was regular at 116 beats/min, and respirations were 20/min. Examination of the heart, lungs, abdomen, and central nervous system was normal. Results of the complete blood count, electrolytes, BUN, serum creatinine, urinalysis, and chest x-ray were all normal. An ECG showed a sinus tachycardia. Toxicological analyses of blood and urine were negative for ethanol, salicylates, ethylene glycol, methanol, benzodiazepines, barbiturates, opiates, and amphetamines. Initial serum theophylline level was 8 mg/L. Syrup of ipecac, magnesium citrate, and oral activated charcoal were administered immediately. Over the subsequent 12 hours, the patient became more restless and tremulous, with the heart rate increasing to 180 to 200 beats/min. He did not experience any ventricular ectopy, hypotension, or seizure activity. Theophylline levels continued to increase, reaching 83 mg/L. Along with the increase in the theophylline level, hyperglycemia, hypokalemia, and worsening increased anion gap metabolic acidosis were also noted (Table 1). An arterial blood gas on 2 L of oxygen revealed a pure metabolic acidosis; pH, 7.32; PO,, 141 mmHg; Pco,, 25 mmHg; and HCO,, 13 mEq/L. Serum lactate level measured at this time was 52 mg/dL (five times the normal). BUN, serum creatinine, and serum phosphorus remained within normal limits. At this stage, with an increasing theophylline level, increasing acidosis, and the profound hyperadrenergic state, charcoal hemoperfusion was performed and continued for 90 minutes. Shortly thereafter, restlessness and tremors improved and the heart rate decreased to 117 beats/min. Within one hour of hemopertusion, theophylline levels decreased to 37 mg/L; ten hours later the level had dropped to zero. The decrease in theophylline level was associated with corresponding decreases in the anion gap and increases in serum CO, (Table 2). The patient was transferred to the psychiatric service the following day with theophylline levels remaining at zero and metabolic status returning to normal.
DISCUSSION Metabolic acidosis from isolated theophylline toxicity, without concurrent drugs or in the absence of shock, has been described infrequently.1*4*5 Review of the literature reveals metabolic acidosis associated with theophylline occurring more commonly in instances in which additional drugs, such as acetylsalicylic acid or ethanol, were ingested.4.5 These drugs are well-known causes of increased anion gap acidosis.6V7 In our patient, only theophylline was involved, as demonstrated by the negative toxicology screen. 417
AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 7, Number 4 n July 1989
TABLE1. Association Between Increasing Theophylline and Increasing Gap Metabolic Acidosis
Levels
TABLE2. Association Between Declining Theophylline and Improvement in Acidosis
Time After Ingestion of Theophylline (h) 2
4
6
8
8.0 23.1 45.2 70.5 Serum theophylline (mg/L)* 89 186 226 184 Glucose (mg/dL) 4.0 2.4 Serum potassium (mEq/L) 3.0 3.3 140 135 136 140 Serum sodium (mEq/L) 104 102 102 104 Serum chloride (mEq/L) 23 16 15 14 Serum COP (mEq/L) 13 17 19 22 Anion gap Serum lactate (mg/dL) Arterial blood gas (2 Umin 0,) PH _ Pcop (mm/Hg) PO, (mm/Hg) HCO, (mEq/L)
Hours After Hemoperfusion 10
83.0 196 3.5 142 106 12 24 52.0
7.32 25 141 13
*Normal, 10 to 20 mg/L.
Toxic levels of theophylline have been shown to be associated with markedly elevated levels of norepinephrine and epinephrine in experimental animals5 Theophylline increases the release of catecholamines from the sympathoadrenal medullary system, increases cyclic adenosine monophosphate levels, and inhibits nonneuronal uptake and metabolism of catecholamines.5,7 These effects on the sympathetic nervous system may collectively result in a hyperadrenergic state, especially with toxic theophylline levels.8*9 The catecholamines stimulate betaadrenergic receptors, which activate gluconeogenesis and glycogenolysis, resulting in an increased serum lactate concentration.5,‘0 The other mechanisms of the increased lactate levels are peripheral action of catecholamines causing tissue hypoxia and diminished excretion of lactate from decreased perfusion of the liver and kidneys.‘07” We believe this report substantiates the role of lactate accumulation in the metabolic acidosis associated with isolated theophylline toxicity. Increase in the serum lactate level was documented in association with worsening acidosis. The acidosis improved with the decrease in theophylline and lactate levels immediately after hemoperfusion. We suggest that with an increased number of persons admitted to the hospital with theophylline overdose, physicians should be aware of lactic acidosis as a potential complication, in addition to the better-known complications. Whether
418
Levels
Serum theophylline (mg/L)* Glucose (mg/dL) Serum potassium (mEq/L) Serum sodium (mEq/L) Serum chloride (mEq/L) Serum COP (mEq/L) Anion gap Serum lactate (mg/dL) Arterial blood gas (room air) PH Pcop (mm/Hg) PO, (mm/Hg) HCO, (mEq/L)
1
4
9
37.6 80 3.9 139 105 19 15 -
27.4 83 4.1 140 106 21 13 0
13.0 -
-
-
-
11
0 97 4.0 137 102 23 12 7.41 38 98 23
‘Normal, 10 to 20 mg/L.
the presence of lactic acidosis is a clue to a poor outcome, and therefore an early indication for hemoperfusion, needs to be studied further. REFERENCES 1. Biberstein MP, Zeigler MG, Ward DM: Use of beta blockade and hemoperfusion for acute theophylline poisoning. West J Med 1984;141:485-490 2. Helliwell M, Beny D: Theophylline poisoning in adults. Br Med J 1979;2:1114 3. Greenberg A, Piraino BA, Kroboth PD, et al: Severe theophylline toxicity. Am J Med 1984;76:854-860 4. Hall KW, Dobson KE, Dalton JG. et al: Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-462 5. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and beta-adrenergic system. Ann Intern Med 1985;102:766-769 6. Anderson RJ, Potts DE, Gabow PA, et al: Unrecognized adult salicylate intoxication. Ann Intern Med 1976;85:745748 7. lsselbacher KJ: Metabolic and hepatic effects of alcohol. N Engl J Med 1977;296:612-616 8. Higbee MD, Kumar M, Galant SP: Stimulation of endogenous catecholamine release by theophylline: A proposed additional mechanism of action for theophylline effects. J Allergy Clin lmmuno 1982;70:377-382 9. Vestel RE, Eiriksson CE, Musser B, et al: Effects of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67:162-171 10. Huckabee WE: Abnormal resting blood lactate. Am J Med 1961;30:833 11. Kolendorf K, Moller BB: Lactic acidosis in epinephrine poisoning. Acta Med Stand 1974;196:465-466
Acute theophylline overdose caused by intentional or accidental ingestion has been reported with increasing frequency. ‘-3 Associated metabolic abnormalities such as hypokalemia, hypophosphatemia, hypomagnesemia, and respiratory alkalosis have been described. ’ T4*5However, metabolic acidosis from isolated theophylline toxicity without concurrent drugs or in the absence of shock has not been noted as frequently. Although previous reports postulate that the mechanism for the acidosis involves lactate accumulation,‘+4*5 this has never been firmly established. We report a case of acute theophylline intoxication, with documented elevated serum lactate, causing an increased anion gap metabolic acidosis. CASE REPORT An l&year-old male presented to the emergency department two hours after ingesting 9 g of a sustained-release theophylline preparation in a suicide attempt. He denied taking any other medications. On arrival he complained only of nausea. On physical examination he was awake and alert, From the ‘Rheumatology Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia; and the Departments of *Medicine and *Emergency Medicine, Albert Einstein Medical Center, Temple University School of Medicine, Philadelphia. Manuscript received August 29, 1988; revision accepted October 19, 1988. Address reprint requests to Dr Leventhal: Maloney 570, Hospital of the University of Pennsylvania, 3800 Spruce St, Philadelphia, PA 19104-4283. Key Words: Theophylline,
toxicity, lactate, acidosis.
01989 by W.B. Saunders Company. 0735-6757/89/0704-0016$5.00/O
although restless and irritable. BP was 160/90 mmHg, pulse was regular at 116 beats/min, and respirations were 20/min. Examination of the heart, lungs, abdomen, and central nervous system was normal. Results of the complete blood count, electrolytes, BUN, serum creatinine, urinalysis, and chest x-ray were all normal. An ECG showed a sinus tachycardia. Toxicological analyses of blood and urine were negative for ethanol, salicylates, ethylene glycol, methanol, benzodiazepines, barbiturates, opiates, and amphetamines. Initial serum theophylline level was 8 mg/L. Syrup of ipecac, magnesium citrate, and oral activated charcoal were administered immediately. Over the subsequent 12 hours, the patient became more restless and tremulous, with the heart rate increasing to 180 to 200 beats/min. He did not experience any ventricular ectopy, hypotension, or seizure activity. Theophylline levels continued to increase, reaching 83 mg/L. Along with the increase in the theophylline level, hyperglycemia, hypokalemia, and worsening increased anion gap metabolic acidosis were also noted (Table 1). An arterial blood gas on 2 L of oxygen revealed a pure metabolic acidosis; pH, 7.32; PO,, 141 mmHg; Pco,, 25 mmHg; and HCO,, 13 mEq/L. Serum lactate level measured at this time was 52 mg/dL (five times the normal). BUN, serum creatinine, and serum phosphorus remained within normal limits. At this stage, with an increasing theophylline level, increasing acidosis, and the profound hyperadrenergic state, charcoal hemoperfusion was performed and continued for 90 minutes. Shortly thereafter, restlessness and tremors improved and the heart rate decreased to 117 beats/min. Within one hour of hemopertusion, theophylline levels decreased to 37 mg/L; ten hours later the level had dropped to zero. The decrease in theophylline level was associated with corresponding decreases in the anion gap and increases in serum CO, (Table 2). The patient was transferred to the psychiatric service the following day with theophylline levels remaining at zero and metabolic status returning to normal.
DISCUSSION Metabolic acidosis from isolated theophylline toxicity, without concurrent drugs or in the absence of shock, has been described infrequently.1*4*5 Review of the literature reveals metabolic acidosis associated with theophylline occurring more commonly in instances in which additional drugs, such as acetylsalicylic acid or ethanol, were ingested.4.5 These drugs are well-known causes of increased anion gap acidosis.6V7 In our patient, only theophylline was involved, as demonstrated by the negative toxicology screen. 417
AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 7, Number 4 n July 1989
TABLE1. Association Between Increasing Theophylline and Increasing Gap Metabolic Acidosis
Levels
TABLE2. Association Between Declining Theophylline and Improvement in Acidosis
Time After Ingestion of Theophylline (h) 2
4
6
8
8.0 23.1 45.2 70.5 Serum theophylline (mg/L)* 89 186 226 184 Glucose (mg/dL) 4.0 2.4 Serum potassium (mEq/L) 3.0 3.3 140 135 136 140 Serum sodium (mEq/L) 104 102 102 104 Serum chloride (mEq/L) 23 16 15 14 Serum COP (mEq/L) 13 17 19 22 Anion gap Serum lactate (mg/dL) Arterial blood gas (2 Umin 0,) PH _ Pcop (mm/Hg) PO, (mm/Hg) HCO, (mEq/L)
Hours After Hemoperfusion 10
83.0 196 3.5 142 106 12 24 52.0
7.32 25 141 13
*Normal, 10 to 20 mg/L.
Toxic levels of theophylline have been shown to be associated with markedly elevated levels of norepinephrine and epinephrine in experimental animals5 Theophylline increases the release of catecholamines from the sympathoadrenal medullary system, increases cyclic adenosine monophosphate levels, and inhibits nonneuronal uptake and metabolism of catecholamines.5,7 These effects on the sympathetic nervous system may collectively result in a hyperadrenergic state, especially with toxic theophylline levels.8*9 The catecholamines stimulate betaadrenergic receptors, which activate gluconeogenesis and glycogenolysis, resulting in an increased serum lactate concentration.5,‘0 The other mechanisms of the increased lactate levels are peripheral action of catecholamines causing tissue hypoxia and diminished excretion of lactate from decreased perfusion of the liver and kidneys.‘07” We believe this report substantiates the role of lactate accumulation in the metabolic acidosis associated with isolated theophylline toxicity. Increase in the serum lactate level was documented in association with worsening acidosis. The acidosis improved with the decrease in theophylline and lactate levels immediately after hemoperfusion. We suggest that with an increased number of persons admitted to the hospital with theophylline overdose, physicians should be aware of lactic acidosis as a potential complication, in addition to the better-known complications. Whether
418
Levels
Serum theophylline (mg/L)* Glucose (mg/dL) Serum potassium (mEq/L) Serum sodium (mEq/L) Serum chloride (mEq/L) Serum COP (mEq/L) Anion gap Serum lactate (mg/dL) Arterial blood gas (room air) PH Pcop (mm/Hg) PO, (mm/Hg) HCO, (mEq/L)
1
4
9
37.6 80 3.9 139 105 19 15 -
27.4 83 4.1 140 106 21 13 0
13.0 -
-
-
-
11
0 97 4.0 137 102 23 12 7.41 38 98 23
‘Normal, 10 to 20 mg/L.
the presence of lactic acidosis is a clue to a poor outcome, and therefore an early indication for hemoperfusion, needs to be studied further. REFERENCES 1. Biberstein MP, Zeigler MG, Ward DM: Use of beta blockade and hemoperfusion for acute theophylline poisoning. West J Med 1984;141:485-490 2. Helliwell M, Beny D: Theophylline poisoning in adults. Br Med J 1979;2:1114 3. Greenberg A, Piraino BA, Kroboth PD, et al: Severe theophylline toxicity. Am J Med 1984;76:854-860 4. Hall KW, Dobson KE, Dalton JG. et al: Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-462 5. Kearney TE, Manoguerra AS, Curtis GP, et al: Theophylline toxicity and beta-adrenergic system. Ann Intern Med 1985;102:766-769 6. Anderson RJ, Potts DE, Gabow PA, et al: Unrecognized adult salicylate intoxication. Ann Intern Med 1976;85:745748 7. lsselbacher KJ: Metabolic and hepatic effects of alcohol. N Engl J Med 1977;296:612-616 8. Higbee MD, Kumar M, Galant SP: Stimulation of endogenous catecholamine release by theophylline: A proposed additional mechanism of action for theophylline effects. J Allergy Clin lmmuno 1982;70:377-382 9. Vestel RE, Eiriksson CE, Musser B, et al: Effects of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67:162-171 10. Huckabee WE: Abnormal resting blood lactate. Am J Med 1961;30:833 11. Kolendorf K, Moller BB: Lactic acidosis in epinephrine poisoning. Acta Med Stand 1974;196:465-466