BRIEF COMMUNICATIONS
Theophylline-lnduced Seizures in Adults Correlation with Serum Concentrations CLIFFORD W. ZWILLICH, M.D., FRANK D. SUTTON, Jr., M.D., THOMAS A. NEFF, M.D., WARREN M. COHN, M.D., RICHARD A. MATTHAY, M.D., and MILES M. WEINBERGER, M.D., Denver, Colorado, and Birmingham, Alabama
Eight patients developed grand mal seizures during intravenous theophylline therapy. None had a history of neurologic disorder, and all were acutely ill with severe pulmonary or cardiovascular disease, or both. Serum theophylline concentrations obtained within 1 hour of the seizure ranged from 25 /xg/ml to 70 /zg/ml, with a mean value (53 ± 4.8 Mg/ml) more than twice the upper limit of the recommended therapeutic concentration. This serum theophylline concentration was greater than the concentration found in a group of patients with less severe drug-related symptoms (35 ± 1.8 /ug/ml, P < 0.01). A third group of patients without drug-related symptoms had a mean theophylline serum concentration of 19 ± 2.0 /*g/ml, which was less than that found in either group with toxicity symptoms (P < 0.05). Factors predisposing to the high serum concentrations in the patients with seizures were both higher drug dosage, compared with the other groups (P < 0.01), and hepatic dysfunction, which was more common in both groups with drug-related symptoms.
THEOPHYLLINE is used in the treatment of bronchospasm associated both with asthma and chronic obstructive lung disease. Intravenous aminophylline (theophylline ethylenediamine) is the preparation of theophylline most commonly used in seriously ill patients. Serious toxic effects of theophylline have been described previously, but serum levels have not been reported in most of these cases (1-9). Only the less serious and more common adverse effects of anorexia, nausea, and vomiting have been shown to relate to serum theophylline concentrations (8, 10, 11). Seizures have been reported in two adults receiving aminophylline (8, 12), but serum theophylline concentrations were quantified only in the latter case. This report describes generalized convulsions in eight adults receiving intravenous aminophylline associated with serum theophylline con• From the Divisions of Pulmonary Medicine and Clinical Pharmacology, Department of Medicine, University of Colorado Medical Center, and affiliated hospitals, Denver, Colorado.
784
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centrations well in excess of those seen in a similar group of patients without adverse medication effects. Patients and Methods During a 10-month period, 8 patients with no seizure history were observed to have major motor seizures while receiving intravenous aminophylline and had serum theophylline concentrations determined from blood drawn within 1 hour of the convulsion. Serum theophylline concentrations were subsequently monitored in 15 other patients receiving intravenous aminophylline who did not have serious adverse effects associated with their treatment. Tests of arterial blood gases and routine laboratory tests for renal and hepatic function were done in all patients. Serum theophylline concentrations in the eight patients with seizures were measured by the classic method using solvent extraction from serum and measurement of ultraviolet absorbance (13). Serum theophylline concentrations in the patients who did not have seizures were monitored by a newly developed method using high-pressure ion exchange chromatography (14). These two methods have been shown to give similar results*. The advantage of the latter method lies in its speed and ease of measurement, thereby allowing adjustment of dosage based on serial assays. Differences in clinical and laboratory data found between the groups were assessed using the analysis of variance. Results The patients were grouped by presence and type of adverse effects (Table 1). Patients in all three groups had similar diseases of similar severity. The ages of the patients with seizures averaged somewhat higher but were not statistically greater than in the other two groups. Arterial blood gas tensions and pH were similar in the three groups. Urea nitrogen and creatinine also did not differ significantly. Seven of the 8 patients in the seizure group, however, had abnormalities in hepatic function, as did all four patients in the group with adverse effects other than seizures. Only 4 of the 11 patients without adverse effects had laboratory evidence of hepatic dysfunction. Mean serum theophylline concentration of 53 fig/ml * WEINBERGER M, CHIDSEY C: Rapid analysis of theophylline in serum by high-pressure ion exchange chromatography. Unpublished. Annals of Internal Medicine 82:784-787, 1975
Table 1 . Clinical and Laboratory Data in Patients Treated with Intravenous Aminophylline*
Patient
Age
Sex
Weight
Clinical Diagnosis
Duration of Dose/ Total Dose
mg/kg bodyweight • day
kg Patients with seizures 1 58 M
Dose
Highest Serum Concentration f tig/ml
2§
64
F
39
3§ 4
69 71
M M
54 65
Chronic obstructive lung disease, bronchogenic carcinoma Chronic obstructive lung disease, alcoholism Chronic obstructive lung disease Asthma
5§ 6§
72 76
F F
49 50
Chronic obstructive lung disease Congestive heart failure
31 20
48 h/3 g 48h/2g
61 25
7
74
F
46
43
48 h/4 g
55
8
58
M
58
Chronic obstructive lung disease, congestive heart failure Chronic obstructive lung disease, congestive heart failure
34
48 h/4 g
54
Mean SEM
Range
68 ±2.4 58-76
72
54 ± 3.8 39-72
Pvalue||- NS P < 0.05 Patients with adverse effects other than seizures Chronic obstructive lung disease, 9 51 F 68 congestive heart failure Chronic obstructive lung disease, 10 56 M 70 congestive heart failure Chronic obstructive lung disease, 11 59 F 83 cor pulmonale, congestive heart failure 12 54 F 58 Asthma, congestive heart failure Mean SEM
Range
55 ± 1.7 51-59
70 ±5.0 58-83
Patients with no adverse effects 13 22 F 59 14 52 M 71 15
29
M
71
16
57
F
71
17
68
M
100
18
68
F
47
19 20 21
66 54 77
M M M
75 87 67
22
81
M
63
23
50
M
59
51
48 h/7.5 g
70
31
156h/7.8g
48
37 27
288 h/24 g 72h/5.3g
62 47
34 ± 3.4 20-51
Hepatic Function Abnormalites %
92 h/7.2 g 24-288 h/ 2-24 g
P < 0.01
Prothrombin time, 19/10s Alkaline phosphatase, 133IU;SGOT, 58 U No abnormality Alkaline phosphatase, 93 IU; SGOT, 128 U SGOT, 113 U Bilirubin, 3.3 mg/100 ml; prothrombin time, 29/13 s; alkaline phosphatase, 109 IU; SGOT, 190 U Alkaline phosphatase, 89 IU; SGOT, 60 U Bilirubin, 1.2 mg/100 ml; SGOT, 240 U; alkaline phosphatase, 100 IU
53 ±4.8 25-70 P < 0.01
17
48 h/2.3 g
33
10
72 h/2.2 g
31
Prothrombin time, 21/12s Bilirubin, 2.5 mg/100 ml
14
72h/3.6g
38
Bilirubin, 1.5 mg/100 ml
19
33h/2.6g
38
Alkaline phosphatase, 152 IU
15 ± 2.0 10-19
56 h/2.7 g
35 ± 1.8 31-38
33-72 h/ 2.2-3.6 g
Asthma Asthma
20 20
6h/0.3g 37 h/2.2 g
19 16
Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, Cor pulmonale Chronic obstructive lung disease Asthma Myocardial infarction, congestive heart failure Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale
27
60 h/5.3 g
22
No abnormality Alkaline phosphatase, 113 IU No abnormality
20
18h/l.lg
13
No abnormality
22
48 h/4.3 g
15
20
216h/8.6g
19
Alkaline phosphatase, 94 IU No abnormality
22 21 18
48h/3.2g 96 h/7.2 g 60 h/3.0 g
7 28 18
19
24h/1.2g
31
No abnormality SGOT, 34 U Alkaline phosphatase, 129 IU No abnormality
20
72 h/3.6 g
22
No abnormality
[Table 1 Continued on p. 786] Zwillich et al. • Theophylline and Seizures
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
785
Table 1. (Continued)
Patient
Age
Sex
Weight
Clinical Diagnosis
kg 56 ± 5.4 22-81
Mean SEM
Range
70 ±4.3 47-100
Dose
mg/kg body weight • day 21 ± 0.7 18-27
Duration of Dose/ Total Dose
Highest Serum Concentration f
Hepatic Function Abnormalities %
iig/ml
62 h/3.6 g 6-216 h/ 0.3-8.6 g
19 ± 2.0 7-31
* Normal values: alkaline phosphatase, < 85 IU; serum glutamic oxalic transferase (SGOT), < 25 U; total bilirubin, =^1.0 mg/100 ml. t Therapeutic level, 10-20 /ig/ml (See References 8, 11, 15, 16). t Prothrombin time is given as patient over control value. § Patient died. || P signifies differences between the group with seizures compared with other groups. NS = not significant.
found in those patients with seizures was significantly greater (P < 0.01) than the value found in the group with adverse effects other than seizures (35 /xg/ml). A mean serum theophylline concentration of 19 /xg/ml was found in the group without adverse effects, a value significantly less (P < 0.05) than the 35 //g/ml found in the group with adverse effects other than seizures. Two patients tolerated serum theophylline concentrations greater than 25 /xg/ml without adverse effects, although one seizure occurred associated with a level of 25 /xg/ml. The daily dose of aminophylline adjusted for weight was higher in the patients who had seizures than that observed in the other two groups (P < 0.05), but a consistent relation between dose and serum concentration was not present. Three of the four patients with adverse medication effects other than seizures suffered from nausea, and one also experienced epigastric pain. The fourth suffered from severe headache. Relief of these symptoms occurred with dose reduction. Among the patients with seizures, only one complained of prior nausea. Seizures were often relatively intractable and refractory to intravenous diazepam, diphenylhydantoin, and phenobarbital in four of the eight patients even though theophylline administration was immediately stopped in each case. Four patients who had seizures never regained consciousness and died. Three were autopsied, showing hepatic pathology including micronodular cirrhosis, hepatic congestion, and generalized congestion and fatty metamorphosis, respectively. In Patient 3, a nonocclusive frontal lobe infarction was found at autopsy. Brain pathology was not found at the other two autopsies. All of the patients who did not have seizures survived their acute episode of respiratory failure. Discussion
The therapeutic range for serum theophylline concentrations has become generally accepted as being roughly between 10 and 20 /xg/ml (8, 11, 15, 16). Lower serum concentrations are commonly not as efficacious, whereas toxicity has been commonly, although not always, associated with serum concentrations greater than 20 /xg/ml. The current data support the relative safety of theophylline concentrations under 20 /xg/ml because no patient 786
June 1975 • Annals of Internal Medicine • Volume 82 • Number 6
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with levels below that value experienced adverse effects. Twelve of 14 patients with theophylline concentrations of 25 /xg/ml and greater, however, experienced adverse medication effects, including seizures in 8 and death in 4. Although this does not necessarily express a true estimate of the incidence of seizures or death at high serum concentrations, a clinically important risk is suggested. Identifiable clinical factors other than serum theophylline concentrations did not present a reasonable explanation for the toxic reactions or unfortunate outcomes. Dosage recommendation for intravenous aminophylline remains controversial despite many years of use. Even a very recent review (17) still suggests toxicity as a valid end point for therapy and assumes that gastrointestinal symptoms will invariably precede more serious signs of toxicity. The current data do not support this recommendation because prior adverse effects were not recognized in 7 of the 8 patients who experienced seizures. An attempt has been made to base dosage on mean pharmacokinetic data in an attempt to achieve therapeutic effect with a low risk for toxicity (18). The data from this latter study, however, were obtained from 6 asthmatic and 10 normal volunteers. The patients reported in our study are probably more representative of adults hospitalized for conditions warranting intravenous aminophylline therapy. Most of these 23 patients had medical complications other than simple reversible obstructive airway disease (asthma). Frequent diagnoses of cor pulmonale and congestive heart failure along with liver dysfunction suggest that these factors combined with the higher dosage may have played a role in the unusually high serum concentrations of the seizure group. The dose in this group, although higher than in the other groups, generally did not exceed recent recommendations ( 7 ) . Since theophylline undergoes what is probably primarily hepatic metabolism, hemodynamic and hepatic dysfunction in these patients could have slowed the rate of theophylline clearance. Previous case reports of prolonged theophylline degradation in association with hepatitis (8), heart failure (19, 20), and chronic obstructive pulmonary disease (9) support this hypothesis. Considerable variability of theophylline metabolism has been documented, even in patients with uncomplicated asthma. Dosage for intravenous aminophylline is therefore more complex than has been previously thought. Both
"pushing" to tolerance and fixed dose recommendations based on mean pharmacokinetics present risks of serious toxicity in some patients, but overly conservative doses may minimize the potential for benefit. Further data are needed on the value of routinely monitoring serum theophylline concentrations to individualize intravenous aminophylline dosage. ACKNOWLEDGMENTS: Received 24 September 1974; revision accepted 4 February 1975. • Requests for reprints should be addressed to Clifford W. Zwillich, M.D., Box C 272, Pulmonary Division, University of Colorado Medical Center, 4200 E. Ninth Ave., Denver, CO 80220. References
8. JENNE JW, WYZE E, ROOD FS, et al: Pharmacokinetics of
theophylline: application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 13:349-360, 1972 9. JACOBS MH, SENIOR RM: Theophylline toxicity due to impaired theophylline degradation. Am Rev Resp Dis 110:342-345, 1974 10. JACOBS MH, SENIOR RM, KESSLER G: Clinical experience with
theophylline: relationships between dosage, serum concentration, and toxicity. Am Rev Resp Dis 109:715, 1974 11. WEINBERGER MM, BRONSKY EA: Evaluation of oral bronchodilator therapy in asthmatic children. J Pediatr 84:421-427, 1974 12. NICHOLSON DP, CHICK TW: A re-evaluation of parenteral
aminophylline. Am Rev Resp Dis 108:241-247, 1973 13. SCHACK J A, WAXLER SH: An ultraviolet spectrophotometric
method for the determination of theophylline and theobromine in blood and tissues. / Pharmacol Exp Ther 97:283-291, 1949 14. WEINBERGER M, CHIDSEY C: Rapid specific measurement of theophylline. / Allergy Clin Immunol, in press 15. WEINBERGER MM, RIEGELMAN S: Rational use of theophylline
1. BRESNICK E, WOODARD WK, SAGEMAN CB: Fatal reactions to
intravenous administration of aminophylline. / Am Med Assoc 136:397-398, 1948 2. ROUNDS VJ: Aminophylline poisoning. Pediatrics 14:528-531, 1954 3. NOLKE AC: Severe toxic effects from aminophylline in children. J Am Med Assoc 161:693-697, 1956 4. WHITE
7. FEITELSON AA: Another reaction to aminophylline. N Engl J Med 285:1327, 1971
BH, DAESCHNER
CW: Aminophylline
(theophylline
ethylenediamine) poisoning in children. / Pediatr 1956 5. BACAL HL, LINEGAR K, DENTON RL, et al:
W'.lbl-lll.
Aminophylline
poisoning in children. Can Med Assoc J 80:6-9, 1959 6. DAVIDSON MB: Reaction to intravenous aminophylline. N Engl J Med 285:689, 1971
for bronchodilatation. N Engl J Med 291:151-153, 1974 16. TURNER-WARWICK M: Study of theophylline plasma levels after oral administration of new theophylline compounds. Br Med J 2:67, 1957 17. FRANKLIN W: Treatment of severe asthma. N Engl J Med 290:1469-1472, 1974 18. MITENKO PA, OGILVIE RI: Rational intravenous doses of theophylline. N Engl J Med 289:600-603, 1973 19. JENNE JW, CHICK TW, MILLER BA, et al: Effect of congestive
heart failure on the elimination of theophylline. / Allergy Clin Immunol 53:80, 1974 20. PIAFSKY KM, SITAR DS, RANGNO RE, et al: Disposition of
theophylline in acute pulmonary edema (abstract). Clin Res 22:726A, 1974
Zwllllch et a/. • Theophylline and Seizures
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Theophylline-lnduced Seizures in Adults Correlation with Serum Concentrations CLIFFORD W. ZWILLICH, M.D., FRANK D. SUTTON, Jr., M.D., THOMAS A. NEFF, M.D., WARREN M. COHN, M.D., RICHARD A. MATTHAY, M.D., and MILES M. WEINBERGER, M.D., Denver, Colorado, and Birmingham, Alabama
Eight patients developed grand mal seizures during intravenous theophylline therapy. None had a history of neurologic disorder, and all were acutely ill with severe pulmonary or cardiovascular disease, or both. Serum theophylline concentrations obtained within 1 hour of the seizure ranged from 25 /xg/ml to 70 /zg/ml, with a mean value (53 ± 4.8 Mg/ml) more than twice the upper limit of the recommended therapeutic concentration. This serum theophylline concentration was greater than the concentration found in a group of patients with less severe drug-related symptoms (35 ± 1.8 /ug/ml, P < 0.01). A third group of patients without drug-related symptoms had a mean theophylline serum concentration of 19 ± 2.0 /*g/ml, which was less than that found in either group with toxicity symptoms (P < 0.05). Factors predisposing to the high serum concentrations in the patients with seizures were both higher drug dosage, compared with the other groups (P < 0.01), and hepatic dysfunction, which was more common in both groups with drug-related symptoms.
THEOPHYLLINE is used in the treatment of bronchospasm associated both with asthma and chronic obstructive lung disease. Intravenous aminophylline (theophylline ethylenediamine) is the preparation of theophylline most commonly used in seriously ill patients. Serious toxic effects of theophylline have been described previously, but serum levels have not been reported in most of these cases (1-9). Only the less serious and more common adverse effects of anorexia, nausea, and vomiting have been shown to relate to serum theophylline concentrations (8, 10, 11). Seizures have been reported in two adults receiving aminophylline (8, 12), but serum theophylline concentrations were quantified only in the latter case. This report describes generalized convulsions in eight adults receiving intravenous aminophylline associated with serum theophylline con• From the Divisions of Pulmonary Medicine and Clinical Pharmacology, Department of Medicine, University of Colorado Medical Center, and affiliated hospitals, Denver, Colorado.
784
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centrations well in excess of those seen in a similar group of patients without adverse medication effects. Patients and Methods During a 10-month period, 8 patients with no seizure history were observed to have major motor seizures while receiving intravenous aminophylline and had serum theophylline concentrations determined from blood drawn within 1 hour of the convulsion. Serum theophylline concentrations were subsequently monitored in 15 other patients receiving intravenous aminophylline who did not have serious adverse effects associated with their treatment. Tests of arterial blood gases and routine laboratory tests for renal and hepatic function were done in all patients. Serum theophylline concentrations in the eight patients with seizures were measured by the classic method using solvent extraction from serum and measurement of ultraviolet absorbance (13). Serum theophylline concentrations in the patients who did not have seizures were monitored by a newly developed method using high-pressure ion exchange chromatography (14). These two methods have been shown to give similar results*. The advantage of the latter method lies in its speed and ease of measurement, thereby allowing adjustment of dosage based on serial assays. Differences in clinical and laboratory data found between the groups were assessed using the analysis of variance. Results The patients were grouped by presence and type of adverse effects (Table 1). Patients in all three groups had similar diseases of similar severity. The ages of the patients with seizures averaged somewhat higher but were not statistically greater than in the other two groups. Arterial blood gas tensions and pH were similar in the three groups. Urea nitrogen and creatinine also did not differ significantly. Seven of the 8 patients in the seizure group, however, had abnormalities in hepatic function, as did all four patients in the group with adverse effects other than seizures. Only 4 of the 11 patients without adverse effects had laboratory evidence of hepatic dysfunction. Mean serum theophylline concentration of 53 fig/ml * WEINBERGER M, CHIDSEY C: Rapid analysis of theophylline in serum by high-pressure ion exchange chromatography. Unpublished. Annals of Internal Medicine 82:784-787, 1975
Table 1 . Clinical and Laboratory Data in Patients Treated with Intravenous Aminophylline*
Patient
Age
Sex
Weight
Clinical Diagnosis
Duration of Dose/ Total Dose
mg/kg bodyweight • day
kg Patients with seizures 1 58 M
Dose
Highest Serum Concentration f tig/ml
2§
64
F
39
3§ 4
69 71
M M
54 65
Chronic obstructive lung disease, bronchogenic carcinoma Chronic obstructive lung disease, alcoholism Chronic obstructive lung disease Asthma
5§ 6§
72 76
F F
49 50
Chronic obstructive lung disease Congestive heart failure
31 20
48 h/3 g 48h/2g
61 25
7
74
F
46
43
48 h/4 g
55
8
58
M
58
Chronic obstructive lung disease, congestive heart failure Chronic obstructive lung disease, congestive heart failure
34
48 h/4 g
54
Mean SEM
Range
68 ±2.4 58-76
72
54 ± 3.8 39-72
Pvalue||- NS P < 0.05 Patients with adverse effects other than seizures Chronic obstructive lung disease, 9 51 F 68 congestive heart failure Chronic obstructive lung disease, 10 56 M 70 congestive heart failure Chronic obstructive lung disease, 11 59 F 83 cor pulmonale, congestive heart failure 12 54 F 58 Asthma, congestive heart failure Mean SEM
Range
55 ± 1.7 51-59
70 ±5.0 58-83
Patients with no adverse effects 13 22 F 59 14 52 M 71 15
29
M
71
16
57
F
71
17
68
M
100
18
68
F
47
19 20 21
66 54 77
M M M
75 87 67
22
81
M
63
23
50
M
59
51
48 h/7.5 g
70
31
156h/7.8g
48
37 27
288 h/24 g 72h/5.3g
62 47
34 ± 3.4 20-51
Hepatic Function Abnormalites %
92 h/7.2 g 24-288 h/ 2-24 g
P < 0.01
Prothrombin time, 19/10s Alkaline phosphatase, 133IU;SGOT, 58 U No abnormality Alkaline phosphatase, 93 IU; SGOT, 128 U SGOT, 113 U Bilirubin, 3.3 mg/100 ml; prothrombin time, 29/13 s; alkaline phosphatase, 109 IU; SGOT, 190 U Alkaline phosphatase, 89 IU; SGOT, 60 U Bilirubin, 1.2 mg/100 ml; SGOT, 240 U; alkaline phosphatase, 100 IU
53 ±4.8 25-70 P < 0.01
17
48 h/2.3 g
33
10
72 h/2.2 g
31
Prothrombin time, 21/12s Bilirubin, 2.5 mg/100 ml
14
72h/3.6g
38
Bilirubin, 1.5 mg/100 ml
19
33h/2.6g
38
Alkaline phosphatase, 152 IU
15 ± 2.0 10-19
56 h/2.7 g
35 ± 1.8 31-38
33-72 h/ 2.2-3.6 g
Asthma Asthma
20 20
6h/0.3g 37 h/2.2 g
19 16
Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, Cor pulmonale Chronic obstructive lung disease Asthma Myocardial infarction, congestive heart failure Chronic obstructive lung disease, cor pulmonale Chronic obstructive lung disease, cor pulmonale
27
60 h/5.3 g
22
No abnormality Alkaline phosphatase, 113 IU No abnormality
20
18h/l.lg
13
No abnormality
22
48 h/4.3 g
15
20
216h/8.6g
19
Alkaline phosphatase, 94 IU No abnormality
22 21 18
48h/3.2g 96 h/7.2 g 60 h/3.0 g
7 28 18
19
24h/1.2g
31
No abnormality SGOT, 34 U Alkaline phosphatase, 129 IU No abnormality
20
72 h/3.6 g
22
No abnormality
[Table 1 Continued on p. 786] Zwillich et al. • Theophylline and Seizures
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
785
Table 1. (Continued)
Patient
Age
Sex
Weight
Clinical Diagnosis
kg 56 ± 5.4 22-81
Mean SEM
Range
70 ±4.3 47-100
Dose
mg/kg body weight • day 21 ± 0.7 18-27
Duration of Dose/ Total Dose
Highest Serum Concentration f
Hepatic Function Abnormalities %
iig/ml
62 h/3.6 g 6-216 h/ 0.3-8.6 g
19 ± 2.0 7-31
* Normal values: alkaline phosphatase, < 85 IU; serum glutamic oxalic transferase (SGOT), < 25 U; total bilirubin, =^1.0 mg/100 ml. t Therapeutic level, 10-20 /ig/ml (See References 8, 11, 15, 16). t Prothrombin time is given as patient over control value. § Patient died. || P signifies differences between the group with seizures compared with other groups. NS = not significant.
found in those patients with seizures was significantly greater (P < 0.01) than the value found in the group with adverse effects other than seizures (35 /xg/ml). A mean serum theophylline concentration of 19 /xg/ml was found in the group without adverse effects, a value significantly less (P < 0.05) than the 35 //g/ml found in the group with adverse effects other than seizures. Two patients tolerated serum theophylline concentrations greater than 25 /xg/ml without adverse effects, although one seizure occurred associated with a level of 25 /xg/ml. The daily dose of aminophylline adjusted for weight was higher in the patients who had seizures than that observed in the other two groups (P < 0.05), but a consistent relation between dose and serum concentration was not present. Three of the four patients with adverse medication effects other than seizures suffered from nausea, and one also experienced epigastric pain. The fourth suffered from severe headache. Relief of these symptoms occurred with dose reduction. Among the patients with seizures, only one complained of prior nausea. Seizures were often relatively intractable and refractory to intravenous diazepam, diphenylhydantoin, and phenobarbital in four of the eight patients even though theophylline administration was immediately stopped in each case. Four patients who had seizures never regained consciousness and died. Three were autopsied, showing hepatic pathology including micronodular cirrhosis, hepatic congestion, and generalized congestion and fatty metamorphosis, respectively. In Patient 3, a nonocclusive frontal lobe infarction was found at autopsy. Brain pathology was not found at the other two autopsies. All of the patients who did not have seizures survived their acute episode of respiratory failure. Discussion
The therapeutic range for serum theophylline concentrations has become generally accepted as being roughly between 10 and 20 /xg/ml (8, 11, 15, 16). Lower serum concentrations are commonly not as efficacious, whereas toxicity has been commonly, although not always, associated with serum concentrations greater than 20 /xg/ml. The current data support the relative safety of theophylline concentrations under 20 /xg/ml because no patient 786
June 1975 • Annals of Internal Medicine • Volume 82 • Number 6
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
with levels below that value experienced adverse effects. Twelve of 14 patients with theophylline concentrations of 25 /xg/ml and greater, however, experienced adverse medication effects, including seizures in 8 and death in 4. Although this does not necessarily express a true estimate of the incidence of seizures or death at high serum concentrations, a clinically important risk is suggested. Identifiable clinical factors other than serum theophylline concentrations did not present a reasonable explanation for the toxic reactions or unfortunate outcomes. Dosage recommendation for intravenous aminophylline remains controversial despite many years of use. Even a very recent review (17) still suggests toxicity as a valid end point for therapy and assumes that gastrointestinal symptoms will invariably precede more serious signs of toxicity. The current data do not support this recommendation because prior adverse effects were not recognized in 7 of the 8 patients who experienced seizures. An attempt has been made to base dosage on mean pharmacokinetic data in an attempt to achieve therapeutic effect with a low risk for toxicity (18). The data from this latter study, however, were obtained from 6 asthmatic and 10 normal volunteers. The patients reported in our study are probably more representative of adults hospitalized for conditions warranting intravenous aminophylline therapy. Most of these 23 patients had medical complications other than simple reversible obstructive airway disease (asthma). Frequent diagnoses of cor pulmonale and congestive heart failure along with liver dysfunction suggest that these factors combined with the higher dosage may have played a role in the unusually high serum concentrations of the seizure group. The dose in this group, although higher than in the other groups, generally did not exceed recent recommendations ( 7 ) . Since theophylline undergoes what is probably primarily hepatic metabolism, hemodynamic and hepatic dysfunction in these patients could have slowed the rate of theophylline clearance. Previous case reports of prolonged theophylline degradation in association with hepatitis (8), heart failure (19, 20), and chronic obstructive pulmonary disease (9) support this hypothesis. Considerable variability of theophylline metabolism has been documented, even in patients with uncomplicated asthma. Dosage for intravenous aminophylline is therefore more complex than has been previously thought. Both
"pushing" to tolerance and fixed dose recommendations based on mean pharmacokinetics present risks of serious toxicity in some patients, but overly conservative doses may minimize the potential for benefit. Further data are needed on the value of routinely monitoring serum theophylline concentrations to individualize intravenous aminophylline dosage. ACKNOWLEDGMENTS: Received 24 September 1974; revision accepted 4 February 1975. • Requests for reprints should be addressed to Clifford W. Zwillich, M.D., Box C 272, Pulmonary Division, University of Colorado Medical Center, 4200 E. Ninth Ave., Denver, CO 80220. References
8. JENNE JW, WYZE E, ROOD FS, et al: Pharmacokinetics of
theophylline: application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 13:349-360, 1972 9. JACOBS MH, SENIOR RM: Theophylline toxicity due to impaired theophylline degradation. Am Rev Resp Dis 110:342-345, 1974 10. JACOBS MH, SENIOR RM, KESSLER G: Clinical experience with
theophylline: relationships between dosage, serum concentration, and toxicity. Am Rev Resp Dis 109:715, 1974 11. WEINBERGER MM, BRONSKY EA: Evaluation of oral bronchodilator therapy in asthmatic children. J Pediatr 84:421-427, 1974 12. NICHOLSON DP, CHICK TW: A re-evaluation of parenteral
aminophylline. Am Rev Resp Dis 108:241-247, 1973 13. SCHACK J A, WAXLER SH: An ultraviolet spectrophotometric
method for the determination of theophylline and theobromine in blood and tissues. / Pharmacol Exp Ther 97:283-291, 1949 14. WEINBERGER M, CHIDSEY C: Rapid specific measurement of theophylline. / Allergy Clin Immunol, in press 15. WEINBERGER MM, RIEGELMAN S: Rational use of theophylline
1. BRESNICK E, WOODARD WK, SAGEMAN CB: Fatal reactions to
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