Peak Serum Theophylline Concentration Research Articles

Life-threatening events after theophylline overdose: a 10-year prospective analysis.

Despite the declining use of theophylline, episodes of intoxication continue to occur, producing seizures, arrhythmias, and death. To further characterize major toxic effects and to examine the efficacy of existing interventions. We conducted a longitudinal cohort study of patients with theophylline overdose. For a 125-month period, all patients referred to the Massachusetts Poison Control System in Boston with a serum theophylline concentration of 167 micromol/L (> or =30 microg/mL) or more were followed up prospectively. Recommended management by the poison center was uniform and protocol based. Three hundred fifty-six patients were enrolled. Mean age was 34.5 years (range, 3 days to 98 years). Mean peak serum theophylline concentration was 336 micromol/L (60 microg/mL) (range, 167-1360 micromol/L [30-245 microg/mL]). One hundred sixty-two patients (45.5%) had acute, 144 (40.4%) had chronic, and 50 (14.0%) had acute-on-therapeutic poisoning. Seventy-four patients (20.8%) developed cardiac arrhythmias, and 29 (8.2%) developed seizures. Fifteen patients (4.2%) died, 11 (73%) of whom had chronic overmedication. Arrhythmias were significantly more common after chronic overmedication than after acute intoxication (35% vs. 10%; odds ratio, 4.97; 95% confidence interval, 2.68-9.23; P<.001). Eight percent of patients with chronic overmedication died compared with 2.5% of those with acute intoxication (odds ratio, 3.20; 95% confidence interval, 1.01-10.39; P = .04). There was no significant difference in the rate of major toxic effects (25.9% vs. 30.0%) or death (4.6% vs. 3.7%) among patients referred from 1986 to 1991 and from 1992 to 1996. Theophylline intoxication results in substantial morbidity and mortality, particularly in those with chronic overmedication. Treatment strategies fail to improve clinical outcome. With safer alternative options available, the current indications for theophylline should be rigorously evaluated with a goal toward minimal use of this agent.

Significance of the Therapeutic Range of Serum Theophylline Concentration in the Treatment of an Attack of Bronchial Asthma.

The purpose of this study was to evaluate the accuracy of the recommended theophylline therapeutic range in the treatment of acute airway obstruction. Twenty seven patients (20 to 64 years) with acute asthma attack were given aminophylline intravenously to obtain a theophylline concentration between 10 and 20 micrograms/ml. Peak expiratory flow rates (PEFR) and serum theophylline concentrations were measured before and after aminophylline injection. When a marked improvement was not seen after aminophylline injection, the treatment was followed by inhalation of a beta-agonist and intravenously administered hydrocortisone. In order to clarify the relationship between theophylline efficacy at a therapeutic level and PEFR, as measured before aminophylline administration, the patients were classified into four groups. Group A (n = 7): asthma attack persisted regardless of treatment with aminophylline, beta-agonist and hydrocortisone, group B (n = 7): asthma attack improved by aminophylline, beta-agonist and hydrocortisone, group C (n = 6): asthma attack improved by both aminophylline and beta-agonist, group D (n = 7): asthma attack improved by intravenous aminophylline alone. The means (+/- S.E.) PEFR before aminophylline administration were 94.3 +/- 11.31/min in group A, 114.3 +/- 10.01/min in group B, 196.7 +/- 22.21/min in group C, and 220.0 +/- 12.51/min in group D, respectively. There were significant differences in PEFR between the A and C, A and D, B and C, and B and D groups. These findings suggest that theophylline efficacy is not expected in patients with low PEFR (less than 2001/min) at the time of treatment of an attack, even if a therapeutic theophylline concentration was obtained.

Conversion from Twice-to Once-Daily Extended-Release Theophylline Treatment in Patients with Reversible Airway Obstruction

This multicenter, randomized, investigator-blinded, parallel group study compared the effects of converting patients from a q12h extended-release theophylline preparation (Theo-Dur) to a q24h extended-release product (Uni-Dur). Patients (n = 133) first received open-label Theo-Dur treatment with dosage titrated to achieve peak serum theophylline concentrations of 10-20 micrograms/ml. Patients then were randomized to continue Theo-Dur (n = 64) or to convert to Uni-Dur (n = 60) with peak serum theophylline concentrations maintained in the desired range. Pulmonary function tests were performed during the open-label and blinded periods; patients maintained diaries and performed peak flow measurements before each dose of study treatment. Adverse events were recorded throughout the study. Respiratory status during blinded treatment was rated as the same or improved compared with open-label treatment by > 87% of evaluable patients and physicians, regardless of treatment group. There were no significant differences in mean peak serum theophylline concentrations at baseline, at the final evaluation, or at any point during the study. Few dosage adjustments were necessary (5/52, Uni-Dur; 9/57, Theo-Dur). There were no significant changes in pulmonary function test results or patient diary entries between the open-label and blinded periods. Headache and nausea were the most commonly reported adverse events. In conclusion, converting patients from twice- to once-daily theophylline treatment resulted in no significant changes in any measures of pulmonary function, and there were no significant differences between the groups during the blinded treatment period.

Plasma levels and therapeutic response: the relevance to community pharmacy.

An assessment of 26 patients, taking theophylline for COAD or asthma, was undertaken in a Belfast Community pharmacy. Patients had peak flow rate and serum theophylline concentration monitored. Based on these findings patients were counselled and, where appropriate, theophylline dosage was adjusted using a pharmacokinetic computer program. A statistically significant improvement was found between the number of patients who had a serum theophylline concentration in the therapeutic range at the initial assessment and at 3 months and 12 months. This was accompanied by a statistically significant improvement in peak expiratory flow rates.

Hypokalemia, Hyperglycemia and Plasma Catecholamine Activity After Severe Theophylline Intoxication

To determine if differences in the rate of hypokalemia and hyperglycemia between victims of acute versus chronic theophylline intoxication relate to alterations in plasma catecholamine activity, we evaluated plasma catechols in three groups of patients: victims of acute theophylline intoxication (n = 10), chronic theophylline overmedication (n = 3), and healthy controls (n = 6). There were no differences in peak serum theophylline concentration between acute and chronic groups (86.6 vs 73.0 mcg/mL, p = NS). Among those with acute intoxication mean (+/- SEM) serum potassium was 2.80 +/- .16 mEq/L while mean serum glucose was 208 +/- 26 mg/dL. In contrast, those with chronic intoxication had a mean serum potassium of 4.10 +/- .70 mEq/L with a mean serum glucose of 139 mg/dL (p < .0001 and p < .04 for between-group potassium and glucose, respectively). Potassium and glucose concentrations of those with chronic theophylline intoxication were similar to those of controls. Plasma epinephrine was higher in those with acute theophylline intoxication than in victims of chronic overmedication and controls (282 vs 133 vs 58 pg/mL, p < .003). Plasma norepinephrine and dopamine in contrast were significantly higher in those with chronic overmedication than in those with acute intoxication and controls (norepinephrine 1395 vs 965 vs 268 pg/mL, p < .008; dopamine 198 vs 148 vs 39 pg/mL, p < .009). These data suggest that the pattern of glucose and potassium disturbances after acute theophylline intoxication parallel differences in plasma epinephrine concentrations. This supports theories that hypokalemia is the result of enhanced beta-2 receptor stimulation.

Predictors of major toxicity after theophylline overdose.

To identify patients at high risk for major toxicity after theophylline intoxication who might benefit from early charcoal hemoperfusion. A 67-month prospective study. Massachusetts Poison Control System. 249 consecutive patients referred after theophylline intoxication (defined by a peak serum theophylline concentration > or = 167 mumol/L [30 mg/L]). Uniform, protocol-directed management recommendations. Identification of risk factors for major toxicity. 119 patients (48%) not receiving theophylline therapy had acute intoxication; among those receiving such therapy, 92 (37%) had theophylline intoxication because of chronic overmedication and 38 (15%) had acute intoxication. Major toxicity developed in 62 patients (25%); 13 patients (5%) died. Major toxicity was more common in patients with intoxication due to chronic overmedication than in those with acute intoxication who were not receiving theophylline therapy (49% compared with 10%, risk ratio, 4.85; 95% CI, 2.96 to 7.94), even though the former group had lower peak serum theophylline concentrations (283 mumol/L compared with 777 mumol/L, P = 0.001). Logistic regression analysis identified two major factors associated with the development of major toxicity: 1) peak serum theophylline concentrations in cases of acute intoxication and 2) patient age in cases of chronic overmedication. Receiver-operating characteristic curve analysis indicated that major toxicity occurred in patients with a peak serum theophylline concentration of greater than 555 mumol/L (100 mg/L) after acute intoxication and in patients older than 60 years (regardless of peak serum theophylline concentration) after chronic overmedication. Predictors for major toxicity after theophylline intoxication differ by type of overdose.

Computer assisted design of a theophylline dosing regimen in acute bronchospasm: Serum concentrations and clinical outcome

The effect of intravenous theophylline on the outcome of inhospital treatment of acute bronchospasm has been assessed, comparing the results achieved by computer-assisted dosing, designed to achieve and maintain a serum theophylline level of 16 micrograms.ml-1 (10 patients) with those of unaided physicians (15 control patients). The outcome measures compared were clinical improvement, peak expiratory flow rate and serum theophylline concentration. Loading doses of theophylline in the control and computer groups were: 167 and 437 mg, respectively. Initial serum theophylline concentrations, measured 20 min after the loading dose, were 13.6 and 17.0 micrograms.ml-1 in the control and computer groups, respectively. In patients who had not received theophylline prior to admission, loading doses and initial concentrations were: 200 mg and 9.4 micrograms.ml-1 in the control group (n = 5) versus 613 mg and 15.7 micrograms.ml-1 in the computer group (n = 4), respectively. During maintenance therapy, serum theophylline concentrations were kept in the therapeutic range (10-20 micrograms.ml-1) throughout 51% and 77% of the hospitalisation period, in the control and computer groups, respectively. There were no differences between the two groups in the rate or extent of clinical improvement or in change in peak expiratory flow rate. The computer assisted theophylline dosing regimen outperformed that of the unaided physicians in achieving and maintaining therapeutic serum theophylline concentrations in acute bronchospasm. There was no correlation between clinical outcome and serum theophylline concentration, but this may have been due to the small sample size and modest difference in serum theophylline between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The Influence of Age vs Peak Serum Concentration on Life-Threatening Events After Chronic Theophylline Intoxication

To identify risk factors for the development of seizures and cardiac arrhythmias after chronic, unintentional theophylline intoxication we monitored the clinical course of 72 consecutive patients referred to a regional poison center with chronic theophylline intoxication (serum theophylline concentration, greater than or equal to 167 mumol/L after protracted use). The median age of the sample was 47.5 years (range, 4 days to 91 years). Median peak theophylline concentration was 239 mumol/L, with a range of 167 to 722 mumol/L. A life-threatening event (LTE) occurred in 28 patients (39%) that included seizures in eight and a major cardiac arrhythmia in 22. The median peak (theophylline) of patients who had an LTE vs those who did not was 235.8 vs 238.7 mumol/L. However, the median age of patients with an LTE compared with those without an LTE was significantly greater (70.5 vs 18.0 years). Stratification of data by chronologic age revealed a stepwise increase in the frequency of LTE with advancing years: patients more than 75 years old had a 16.7-fold greater risk of LTE than patients less than 25 years old (95% confidence interval, 3.56, 77.5) despite comparable intergroup median serum (theophylline). These data suggest the primary determinant of LTEs after chronic theophylline intoxication is chronologic age. Elderly patients have an inordinately greater risk of LTE than younger patients. Peak serum theophylline concentration cannot predict which patients with chronic theophylline intoxication will have an LTE. Finally, these data indicate that theophylline should be used cautiously and with frequent monitoring of serum theophylline concentrations in elderly patients.

Comparison of a New Sustained-Release Theophylline Formulation (Theotrim) with a Reference Drug (Theodur) in the Steady State in Asthmatic Children

The bioequivalency of two sustained-release theophylline formulations (SRT), Theotrim and Theodur, was studied in the steady state in asthmatic children, using a double-blind crossover design. Ten children, aged 7–14 (mean 10.2) years, were treated for 2 weeks, with identical doses (mean 16 mg/kg•day) of either Theotrim or Theodur tablets. Each drug was given for 1 week in a randomized sequence. At the end of each week, a 12-hour serum theophylline concentration (STC) profile was performed and pharmacokinetic data of both drugs were compared. Peak STCs with Theotrim and Theodur were 17.1 ± 1.4 μg/ml (M ± SEM) and 16 ± 1 μg/ml (M ± SEM), respectively. Through STC were 8.9 ± 0.8 μg/ml (M ± SEM) with Theotrim compared with 9.4 ± 0.8 μg/ml (M ± SEM) with Theodur. Six patients had % fluctuation of STC < 100% with both Theotrim and Theodur, while the mean (±SEM) % fluctuation was 99(±17)% and 79(±15)% with Theotrim and Theodur, respectively. The area under the concentration curve (AUC) for 0–12 hours was 158.9 ± 13 (M ± SEM) μg/hr•ml for Theotrim, compared with 153.0 ± 10 (M ± SEM) μg/hr·ml for Theodur. The differences between all these pharmacokinetic parameters showed no statistical significance (p > 0.1). Likewise, there were no differences in the frequency of symptoms of asthma, requirement for additional bronchodilator medication, and theophylline side effects in the patients during the week of treatment with Theotrim compared with the other week when treated with Theodur. We conclude that in this group of asthmatic children, Theotrim proved to be bioequivalent to Theodur in the steady state and equally effective in the treatment of asthma.

Hypokalemia in acute theophylline poisoning

The frequency, severity, and time of occurrence of hypokalemia and their relationship with vomiting was studied in 40 patients with acute theophylline poisoning. The mean peak theophylline concentration was 58 μg/mL (range, 21 to 115), and the mean nadir of serum potassium was 3.0 mEq/L (range, 2.1 to 3.9). In 85% of the patients, the nadir of serum potassium was less than 3.5 mEq/L; 45% had potassium concentrations of less than 3 mEq/L. The severity of hypokalemia correlated with peak serum theophylline concentrations ( p < 0.001). Hypokalemia was observed early in the course of the overdose (mean, 5 hours after ingestion or administration of theophylline). The nadir in serum potassium concentrations was more severe among 25 patients who presented to the emergency department within 6 hours of the overdose than among 13 patients who presented later (mean ± SE, 3.0 ± 0.1 mEq/L vs 3.4 ± 0.1 mEq/L, p < 0.01), despite similar admission serum theophylline concentrations in both groups (49 ± 5 and 55 ± 5 μg/mL, respectively; p = not significant). Spontaneous or ipecac-induced emesis occurred in 95% of the patients; however, hypokalemia preceded vomiting in 13 patients. Its severity was similar whether patients did or did not vomit before its occurrence. Hypoklaemia is a frequent manifestation of acute theophylline poisoning, has a very early onset, and occurs independently of vomiting, suggesting an intracellular shift of potassium.

Characteristics of vomiting associated with acute sustained release theophylline poisoning: implications for management with oral activated charcoal.

Vomiting in acute theophylline toxicity has assumed increased clinical importance since the introduction of multiple dose activated charcoal therapy. We performed a prospective study of 26 patients with acute overdose of sustained release theophylline to characterize vomiting, and its possible interference with the acceptance of activated charcoal. Twenty five of 26 patients vomited. The duration of vomiting correlated with both peak serum theophylline concentrations (p less than 0.001) and the duration of theophylline toxicity (p less than 0.001). Vomiting extended over 63% of the drug's absorptive phase (the time interval between ingestion and the peak level) and 49% of the elimination phase (the time interval between the peak level and decrease of theophylline level to less than 20 mcg/ml). Patients with peak serum theophylline concentrations less than 70 mcg/ml were able to accept larger amounts of activated charcoal than patients with serum theophylline concentrations greater than 70 mcg/ml (113 +/- 15 gms vs. 57 +/- 24 gms, p less than 0.05). Vomiting in acute sustained release theophylline toxicity is protracted, and limits the use of activated charcoal especially in patients with severe acute theophylline poisoning.

Comparison of intravenous and oral routes of theophylline loading in acute asthma

In a prospective, randomized clinical trial, 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV (n = 10) or oral route (n = 9) of administration following treatment with epinephrine. Plasma concentrations of theophylline were measured prior to giving the loading dose, and one, two, three, and 24 to 48 hours later. Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose, and one, three, and 24 to 48 hours later. Side effects also were recorded. In the IV group, the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading, and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading. There was no correlation between theophylline concentrations and normalized change in spirometric values. There was no significant difference in spirometric values between the IV and oral groups. Nausea was slightly more common in the IV group. We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine.

Clinical and bronchodilating efficacy of controlled-release theophylline as a function of its serum concentrations in preschool children

To evaluate the dose-effect relationship of a controlled-release theophylline in preschool children, 20 patients with asthma (mean age 4.8 years, range 2 1/2 to 7 years) were given three different dose levels (13.4 +/- 1.4, 18.4 +/- 1.6, and 23.5 +/- 2.0 mg/kg/day, mean +/- SD) at 12-hour intervals for 2 weeks. Subjective variables, peak expiratory flow rate, and co-medications were recorded daily; clinical condition, serum theophylline levels, and lung function measured with a multiple forced oscillation technique were assessed at the end of each period. The morning predose (through) and 4-hour postdose (peak) serum theophylline concentrations increased in an approximately linear fashion with increasing dose. In the majority of patients, dose levels of 20 to 25 mg/kg/day maintained serum concentrations within a clinically effective range, with an acceptable level of fluctuation. However, wide interindividual variations in serum theophylline concentrations were observed, indicating that for optimal treatment individualization of dosage is preferable. Efficacy was related to serum concentration and, less closely, to the dose administered. Symptom scores for night cough, wheeze, and activity showed small improvements between 5 and 10 mg X 1(-1) and marked improvements above 10 mg X 1(-1), whereas lung function values improved in a linear fashion across the serum concentration range. The serum theophylline concentration-response curves varied in an approximately parallel manner between individuals.

Inhibition of exercise-induced asthma by theophylline

Although an association between exercise and provocation of asthma has been recognized for 300 yr, Jones et al., ’ pediatricians at Alder Hey Children’s Hospital in Liverpool, appear to have been the first to attempt to assess the effect of drugs as modulators of the exercise-induced bronchoconstriction phenomenon. Among the drugs they investigated was the choline salt of theophylline, a formulation that contains 64% anhydrous theophylline. In a single-dose study in which the subjects were administered anhydrous theophylline of the equivalent of between 4.5 and 5.8 mg/kg body weight several hours before exercise challenge, the postexercise fall in FEV, was completely or partially prevented in eight of nine subjects, and Jones et al. concluded that theophylline was protective against exercise-induced wheezing. In retrospect, it appears that the FEV, was measured before drug administration and not immediately before exercise and thus one does not know how much of the putative inhibition of exercise-induced asthma (EIA) was due to the bronchodilator effect of theophylline. Anderson et al.’ have emphasized the importance of measuring expiratory flow rate immediately before exercise so that the bronchodilating effect of the drug and its inhibitory effect on EIA can be considered separately. Nonetheless, in the study of Jones et al., the maximal FEV, after exercise was observed at a mean of 90 min after drug administration, which would coincide with the time of the peak serum theophylline concentration after administration of a rapidly absorbed product such as the one used. This was the first suggestion of a pharmacodynamic effect of theophylline in asthma. During the past decade there have been 10 additional studies2-” in which the efficacy of theophylline in the prevention of EIA has been investigated (Table I). While these studies are not strictly comparable because of a number of differences in experimental design and particularly in dose of theophylline, there are some generalizations that can be made. First, the results of these studies have uniformly shown that the-

Influenza Vaccination in Asthmatic Children on Maintenance Theophylline Therapy

Reports of toxic serum theophylline concentrations in adults following influenza vaccination prompted this study. Peak and trough serum theophylline concentrations were measured in eight severely asthmatic children before and after vaccination against influenza. All eight chil dren had been treated with chronic theophylline therapy for at least one year prior to joining the study. No significant alteration of theophylline levels were seen up to 52 hours after vac cination. No clinical evidence of drug toxicity developed.

Conversion from intravenous to oral dosing using sustained-release theophylline tablets.

Theophylline total body clearance was determined in asthmatic patients, from steady-state serum theophylline concentrations, measured during a constant-rate, intravenous aminophylline infusion. Theo-Dur dosing rates were calculated from the product of theophylline total body clearance and the desired steady-state theophylline concentration. After stopping the aminophylline infusion, oral doses of Theo-Dur were given every 12 hours. Blood samples were obtained 1, 3, 6,9, and 12 hours after the first oral dose and 12 hours after the second oral dose. Patients were evaluated for compliance and theophylline toxicity after receiving Theo-Dur for one week. Total body clearances and theophylline dosing rates varied more than threefold. The difference between the intravenous steady-state serum concentration and the average oral serum concentration was 1.2 micrograms/ml in patients with similar oral and intravenous dosing rates. The difference between peak and trough serum theophylline concentrations after the first oral dose averaged 7.8 micrograms/ml. Eight of nine patients evaluated after leaving the hospital were compliant, as determined from a tablet count during a clinic visit. Serum theophylline concentrations, determined 12 hours after the last Theo-Dur dose, averaged 10.4 micrograms/ml for the compliant patients.