Intravenous Theophylline Therapy: Nomogram Guidelines WILLIAM J. JUSKO, Ph.D.; JEFFREY R. KOUP, Pharm.D.; JOHN W. VANCE, M.D.; JEROME J. SCHENTAG, Pharm.D.; and PAUL KURITZKY, M.D.; Buffalo, New York
We evolved a nomogram for guiding and standardizing intravenous theophylline therapy in hospitalized patients. It provides rapid calculation of a loading dose based on body weight and previous therapy and a maintenance infusion rate related to three categories of expected metabolic activity. The guidelines were prospectively used in the treatment of 72 patients, mainly in a respiratory care unit. The nomogram was successfully used to attain near-steady-state serum concentrations in the therapeutic range of 8 to 20 mg/litre in 7 2 % of patients, with only two patients outside of the range of 5 to 25 mg/litre. These guidelines facilitate initial theophylline dosage in older patients with liver and cardiac disease and provide a rational basis for interpreting serum concentration measurements and adjustment of drug therapy.
T H E USE OF THEOPHYLLINE as a bronchodilator is fre-
quently associated with clinical difficulties ranging from inadequate response to serious adverse reactions caused by overdosage. Many of these problems can be traced to the confusion generated by the plethora of dosage and salt forms containing variable quantities of anhydrous theophylline ( 1 ) , the appreciable variability in rates of metabolism of theophylline among typical patients (2, 3 ) , and the low therapeutic index of the drug (2, 4 ) . Measurements of serum concentrations of theophylline have become useful in managing patient therapy, since optimum bronchodilation with minimum adverse effects is usually achieved within a serum concentration range of 8 to 20 mg/litre (2, 4 ) . However, the availability of serum level measurements of theophylline is limited and, even where used, is accompanied by collection, analytic, and interpretive lag-times. Thus improvement in dosage regimen guidelines is of practical clinical importance. This report relates our experience in the prospective use of a "second-generation" dosage regimen protocol for intravenous administration of theophylline. Our therapeutic guidelines are based partly on loading and maintenance dose recommendations published previously ( 4 ) . In addition, they incorporate reductions in maintenance dosage related to age and hepatic and cardiac status, use a nomogram format for rapid clinical application, and specify • From the Departments of Pharmaceutics and Medicine, Schools of Pharmacy and Medicine, State University of New York at Buffalo, and Millard Fillmore Hospital; Buffalo, New York.
400
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blood collection intervals for use and interpretation of serum theophylline concentrations. Methods NOMOGRAM
Mitenko and Ogilvie (4) examined the pulmonary effects and disposition rate of theophylline in nine patients with asthma. Their dosage recommendation for aminophylline was an intravenous loading dose of 5.6 mg/kg (given over 20 minutes) and a maintenance infusion of 0.9 mg/kg • h. This was a conservative dose expected to produce a target serum concentration of about 10 mg/litre within 1 h. At our first use of this schedule, it became apparent that many older or seriously ill patients experienced elevated serum concentrations of theophylline with adverse effects. This suggested that the dosing rate of theophylline should be reduced on the basis of diminished metabolic capacity in older patients and in patients with congestive heart failure or liver disease. A nomogram for rapid and standardized clinical use of theophylline was deemed desirable. The loading and maintenance dosage of aminophylline is shown in Figure 1 along with instructions for use of the nomogram. In essence, the system allows rapid selection of a loading dose of aminophylline based on body weight and the possibility of previous ingestion of theophylline; and selection of a maintenance infusion of aminophylline based on body weight, age, and cardiac and hepatic function. The dosage for young patients expected to be rapid metabolizers is that recommended by Mitenko and Ogilvie (4) (0.9 mg/kg h ) , while older patients receive a 25% reduction in infusion rate (0.68 mg/kg • h) and patients with congestive heart failure or liver disease receive 50% of the normal dose (0.45 mg/kg-h). About 90% of the dose of theophylline is biotransformed by the liver (5), and the reduction in dosage was based on the general expectations of the effects of age (6) and organ function on metabolic drug disposition. Preliminary examination of theophylline clearances in several hospital patients indicated that a reduction in recommended dosage by 25% to 50% was needed, and these values were retained for tentative use of the nomogram. Theophylline was always used in the form of the aminophylline salt, and the designated amounts of drug on the nomogram are in terms of total aminophylline content (4). Administration of the drug was usually carried out using a Saga Model 355 infusion pump (Saga Instruments; Cambridge, Massachusetts), occassionally with an IVAC large volume infusion pump (McGaw Laboratories; Glendale, California), and rarely by means of a pediatric drip set. The theophylline nomogram was disseminated to the medical staff of the Millard Fillmore Hospital in Buffalo in February 1975 for its optional use in the management of patients requiring theophylline treatment. No specific age or disease criteria were specified, to allow the clinicians maximum flexibility in selecting dosages. These dosing guidelines were most frequently used in the Respiratory Care Unit and Emergency Room, and the survey primarily reflects patients with moderate to severe respiratory impairment. The Clinical Pharmacokinetics Laboratory at the Millard Fillmore Hospital was usually alerted to the use of the nomogram for a particular patient upon the Annals of Internal Medicine 86:400-404, 1977
arrival of blood samples collected at the specified time intervals (1, 12, and 24 h). Data from 72 patients were obtained over 12 months.
The time-course (t) of serum theophylline concentrations (C„) can be characterized by the equation
VD Cp = C V e
SERUM THEOPHYLLINE ASSAY
Theophylline concentrations in serum were measured by high-performance liquid chromatography (7). Samples of 0.5-ml serum were deproteinized with 0.15 ml of trichloracetic acid, and the supernatant was injected onto a Dupont SCX column (DuPont Instruments; Wilmington, Delaware). The mobile phase was 0.66% acetic acid, column pressure was 1200 psi, and the instrument was a Dupont Model 841 Liquid Chromatograph with a UV detector using the 254-nm wavelength. This analytic procedure is specific for theophylline and is not affected by the presence of four of its major metabolites, caffeine, theobromine, or by various drugs commonly received by asthmatic patients, including phenobarbital and corticosteroids. PHARMACOKINETICS
Theophylline has a half-life usually ranging from 3 to 10 h, and a steady-state would require at least four half-lives (12 to 40 h) to elapse providing no loading dose was administered. Measurement times of 1, 12, and 24 h were thus selected to allow for the examination of the approach to the steady-state level and for convenient appraisal of serum drug concentrations during the first day of therapy.
I + ^ \ l -
VD e
l
j ,
/
where C°P is the initial serum concentration, C1B is the body clearance (volume of plasma cleared of drug per unit time), VD is the apparent volume of distribution, and kG is the infusion rate of the drug. The expected steady-state serum concentration (CpSs) is Cpss = ko/ClB. It was possible to fit the Cp values of each patient to the first equation by nonlinear least-squares regression (6) assuming that VD = 0.45 litres/kg (2,3) and using either dose/VD or the 1-h Cp value as C°P. This yielded estimates of C1B. As defined in the above equations, body clearance is the proportionality factor between drug dosing rate and steady-state serum concentration as well as a reflection of the total rate of disposition of theophylline. Results
Serum theophylline concentrations found in 10 typical patients during the infusion process are shown in Figure 2. Most patients either received a loading dose of amino-
Figure 1. Guidelines for intravenous aminophylline therapy. Mark patient's weight in kg on Lines B and H. Use a ruler to connect these points. Loading Dose: Line C provides a loading dose of 5.6 mg/kg. Give concentrated solution at a rate not exceeding 50 mg/min. Give 0 to Vi of this dose if patients have received theophylline within 12 h. Maintenance Dose: The infusion rate (in mg/h) is obtained from the intersection on the following lines. Normal: Young patients expected to be rapid metabolizers. Reduced: Typical older patients (over 50 years). Low: Patients with congestive heart failure or liver disease. Begin infusion soon after injection of the bolus. The rate of infusion is critical and must be checked frequently by nursing personnel. Blood: Collect 5-ml blood samples at 1, 12, and 24 h after starting infusion. Most patients will be near steady-state by 24 h.
Jusko et al. • Intravenous Theophylline Therapy
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Figure 2. Serum theophylline concentrations at various time intervals after beginning therapy in 10 typical hospitalized patients. The curves were fitted to the data using the first equation (see text).
phylline or were earlier recipients of the drug and thus had achieved a reasonably high serum concentration of the bronchodilator by 1 h. The first equation provides a good fit to the data. Comparing the expected steady-state serum concentration values (calculated with the second equation) with the measured 24-h serum concentration indicated that the 24-h value was usually near the steadystate level. Eighty-four percent of the patients had 24-h serum concentrations that were within 20% of the anticipated steady-state level. Thus the 24-h value was used for further evaluation of the nomogram's usefulness because of its closeness to steady-state and because it reflects the end-point of a full day of theophylline therapy. The serum concentration of theophylline found at or nearest to 24 h from the onset of therapy in each of the patients is shown in Figure 3. Overall, 72% of all patients attained 24-h serum concentrations values in the usual therapeutic range. Only two of the 72 patients were outside of the range of 5 to 25 mg/litre, indicating that the nomogram allows extremely safe use of theophylline during the first day of therapy. The distribution of patients and the achieved 24-h serum concentration values in the three dosage categories are listed in Table 1. Forty patients were assigned to the "reduced dose" category, which constituted the largest patient group. There was a tendency for the "predictability" of 24-h serum concentrations to diminish with the use of smaller maintenance doses—83% of patients in the "normal dose" category attained the therapeutic range while only 57% of those in the "low dose" category were in the 402
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8 to 20 mg/litre range. A summary of the patient characteristics and the average body clearances calculated with the first equation are also provided in Table 1. The patient population consisted of persons ranging in age from 19 to 85 years. There were 33 male and 39 female patients. Only two patients had overt liver impairment as indicated by elevated serum bilirubin and lowered serum albumin concentrations. The presence of congestive heart failure was usually indicated by history and physical findings including edema and elevated central venous pressure. The mean body clearances in the reduced dose and low dose categories were significantly smaller (P < 0.05) than the value in the normal dose category. The data for patients with congestive heart failure or liver disease are of particular interest because these patients have the lowest body clearances and are at greatest risk from accumulation of theophylline. It is estimated (second equation) that 11 of 14 of these patients would have attained steady-state serum concentrations exceeding 20 mg/litre had they received the "normal dose" (assuming that the full dosage was administered and evidence of adverse effects did not cause therapeutic adjustments). Similarly, 17 of 40 patients in the reduced dose group might have attained steady-state serum levels in excess of 20 mg/litre if given the normal dose. Patients in the low dose category require additional caution in the use of theophylline and more prolonged monitoring of serum theophylline concentrations. These patients are expected to have the longest half-life values and thus may require more than 24 h to achieve a true steady-state. Discussion
Considerable improvement in the clinical use of theophylline for bronchodilation has been achieved since the relation between steady-state serum concentrations of theophylline and improvement of pulmonary function has been defined in adults (2, 4) and children ( 6 ) . Despite the knowledge of the target serum concentration range (8 to 20 mg/litre) and the means of assuring its achievement by serum analysis, pharmacokinetic guidelines are needed for optimal initial dosing with theophylline. Serum level monitoring has limited clinical availability and, when accesible, is accompanied by a moderate to appreciable turn-
Table 1. Patient Characteristics and Theophylline Serum Concentrations Dosage Group
Aminophylline maintenance dose, mg/kg • h Sex (M/F) Age (SD), yrs Patients studied, no. Patients in therapeutic range*, no. Body clearance (SD), ml/h - kg
Normal
Reduced
0.9 5/13 44.5(13.4) 18
0.68 22/18 60.2(13.4) 40
15
Low
0.45 6/8 63.1 (7.6) 14
29
63.4 (34.7) 48.6 (33.0) f
8 31.8(14.8)1
* Serum concentrations in the: range of 8 to 20 mg/litre at 24 h t Significantly different from '"normal dose" group at P < 0.05.
Figure 3. Serum theophylline concentrations at 24 h after beginning therapy in 72 hospital patients prospectively placed into three metabolic categories by physicians. The broken lines designate the usual therapeutic range of 8 to 20 mg/litre.
over time even with the advent of rapid assay methods. As our results show, there are certain limitations inherent in previously recommended dosages of theophylline. Mitenko and Ogilvie (4) derived their guidelines after examining only nine patients who were not suffering an asthma attack at the time of the study and who did not appear to be otherwise seriously ill. Also, no patient was more than 51 years old. Piafsky and Ogilvie (8) later modified their recommendations, suggesting that the maintenance infusion rate be "reduced by one-third of the usual dose in the presence of congestive heart failure and reduced by half the usual dose in patients with severe liver impairment." Our study has tested similar guidelines in a large number of hospitalized adult patients receiving intravenous aminophylline. The nomogram format facilitates dosage computations by clinicians, and the blood collection protocol permits the nomogram to be tested and provides for rapid adjustment of the infusion rate in patients whose metabolic rate is unusually rapid or slow. We believe that the nomogram, used with clinical judgment, is a valuable means of deciding initial theophylline therapy. It reduces the chance for computational error and speeds the process of initiating the proper dosage regimen for patients with serious organ impairment. Care is particu-
larly needed in selecting the loading dose because many patients may have previously received the drug. In addition, it is not certain whether all types of patients should receive a common loading dose. One measure of the usefulness of the nomogram is the relative safety with which aminophylline was used. Besides yielding serum concentrations in the range of 5 to 25 mg/litre in 70 of 72 patients, the drug caused no moderate or serious adverse reactions that we observed. However, this study did not include close monitoring of efficacy and toxicity by "blind" observers in addition to typical respiratory care unit procedures, and the occurrence of mild adverse effects may have been missed. The relative success of the nomogram guidelines may be examined by comparing the measured serum concentrations achieved in our 72 patients to those obtained in two recent studies where theophylline therapy was monitored in hospitalized adults. Jacobs, Senior, and Kessler (9) found that of 47 patients receiving the drug by various routes, 12 had serum concentrations above 25 mg/litre, and 11 had serum concentrations below 8 mg/litre—a total of 4 9 % of the patients who were decidedly out of the therapeutic range. Weinberger and associates (10) examined data from 15 adult patients who received aminophylline infusions. Six had apparent steady-state serum concentrations above 25 mg/litre while one was below 8 mg/litre. In these two earlier studies, 30 of 62 ( 4 8 % ) patients were outside the 8 to 25 mg/litre serum concentration range. Using our guidelines, only 13 of 72 ( 1 8 % ) patients missed the range of 8 to 25 mg/litre. Both previous reports concluded that the initial dosage recommendations of Mitenko and Ogilvie (4) were not sufficiently flexible to account for the effects of old age and serious associated illnesses on theophylline metabolism, and that serum concentration monitoring is important clinically in guiding effective and safe use of theophylline. Our investigation confirms these findings but further indicates that modification of the dosage guidelines of Mitenko and Ogilvie, based on knowledge of the primary factors affecting drug metabolism, may provide more reliable achievement of the therapeutic range for hospitalized patients. This should be of particular value for patients who cannot be monitored with frequent serum concentration measurements. ACKNOWLEDGMENTS: The authors thank Mrs. Anna Poliszczuk for her technical assistance; and the house staff and nurses of the Millard Fillmore Hospital for their cooperation in the implementation of the nomogram procedures. Grant support: in part by Grant No. 20852 from the National Institutes of General Medical Sciences, National Institutes of Health. Received 9 August 1976; revision accepted 14 December 1976. • Requests for reprints should be addressed to William J. Jusko, Ph.D.; Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital; Buffalo, NY 14209. References 1. ELLIS EF, EDDY ED: Anhydrous theophylline equivalence of
commercial theophylline formulations. / Allergy Clin Immunol 53:116-118, 1974 2. JENNE JW, WYZE E, ROOD FS, et al: Pharmacokinetics of theo-
phylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 13:349-360, 1972 3. MITENKO PA, OGILVIE RI:
Pharmacokinetics
of
intravenous
theophylline. Clin Pharmacol Ther 14:509-513, 1973 Jusko et a/. • Intravenous Theophylline Therapy
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4. MITENKO PA, OGILVIE RI: Rational intravenous doses of theophylline. N Engl J Med 289:600-603, 1973
and spectrophotometric assays for theophylline in biological fluids. Am J Hosp Pharm 33:1193-1196, 1976
5. THOMPSON RD, NAGASAWA HT, JENNE JW: Determination of
8. PIAFSKY KM, OGILVIE RI: Dosage of theophylline in bronchial
theophylline and its metabolites in human urine and serum by high-pressure liquid chromatography. / Lab Clin Med 84:584593, 1974 6. MASELLI R, CASAL GL, ELLIS EF: Pharmacologic effects of in-
travenously administered aminophylline in asthmatic children. J Pediatr 76:777-782, 1970 7. JUSKO WJ, POLISZCZUK A: High pressure liquid chromatographic
asthma. N Engl J Med 292:1218-1222, 1975 9. JACOBS MH, SENIOR RM, KESSLER G: Clinical experience with
theophylline. Relationships between dosage, serum concentration, and toxicity. JAMA 235:1983-1986, 1976 10. WEINBERGER MW, MATTHAY RA, GINCHANSKY EJ, et al: Intra-
venous aminophylline dosage: use of serum theophylline measurement for guidance. JAMA 235:2110-2113, 1976
A Reminder American Board of Internal Medicine Recertification Examination The American Board of Internal Medicine is offering the second voluntary Recertification Examination on Saturday, 29 October 1977. Applications for the examination are available now. As in the 1974 examination, by which more than 3500 Diplomates were recertified, the 1977 examination will be closely linked to the Medical Knowledge Self-Assessment Program (MKSAP IV), which is now available from the American College of Physicians. The examination will be given in as many centers across the country as demand requires. The morning section will consist of multiple choice questions that relate to recent advances in internal medicine as described in the MKSAP syllabus, considered relevant to current practice and also to other medical information deemed important in general internal medicine. The afternoon section will consist of Patient Management Problems (PMPs) that are sequential, feedback patient simulations designed to assess clinical problem solving. The format of these questions is the same as that used and critiqued in MKSAP IV, which will be distributed in May 1977. In the PMP section of the examination the internist will have the opportunity to select some cases that reflect the individual nature of his or her practice. Internists successful on the examination will be issued a Certificate, and notation of their recertification will appear in the Directory of Medical Specialists. Unsuccessful candidates will not lose their primary certification, and individual results will be kept confidential. You are eligible for the 1977 examination if you were certified in internal medicine in 1971 or earlier and were not recertified by the 1974 examination. The fee for the examination is $100 and is payable upon submission of the completed application. The closing date for registration has been extended to 1 July 1977. To apply request an application form from: The American Board of Internal Medicine 3930 Chestnut Street Philadelphia, Pennsylvania 19104
404-
April 1977 • Annals of Internal Medicine • Volume 86 • Number 4
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We evolved a nomogram for guiding and standardizing intravenous theophylline therapy in hospitalized patients. It provides rapid calculation of a loading dose based on body weight and previous therapy and a maintenance infusion rate related to three categories of expected metabolic activity. The guidelines were prospectively used in the treatment of 72 patients, mainly in a respiratory care unit. The nomogram was successfully used to attain near-steady-state serum concentrations in the therapeutic range of 8 to 20 mg/litre in 7 2 % of patients, with only two patients outside of the range of 5 to 25 mg/litre. These guidelines facilitate initial theophylline dosage in older patients with liver and cardiac disease and provide a rational basis for interpreting serum concentration measurements and adjustment of drug therapy.
T H E USE OF THEOPHYLLINE as a bronchodilator is fre-
quently associated with clinical difficulties ranging from inadequate response to serious adverse reactions caused by overdosage. Many of these problems can be traced to the confusion generated by the plethora of dosage and salt forms containing variable quantities of anhydrous theophylline ( 1 ) , the appreciable variability in rates of metabolism of theophylline among typical patients (2, 3 ) , and the low therapeutic index of the drug (2, 4 ) . Measurements of serum concentrations of theophylline have become useful in managing patient therapy, since optimum bronchodilation with minimum adverse effects is usually achieved within a serum concentration range of 8 to 20 mg/litre (2, 4 ) . However, the availability of serum level measurements of theophylline is limited and, even where used, is accompanied by collection, analytic, and interpretive lag-times. Thus improvement in dosage regimen guidelines is of practical clinical importance. This report relates our experience in the prospective use of a "second-generation" dosage regimen protocol for intravenous administration of theophylline. Our therapeutic guidelines are based partly on loading and maintenance dose recommendations published previously ( 4 ) . In addition, they incorporate reductions in maintenance dosage related to age and hepatic and cardiac status, use a nomogram format for rapid clinical application, and specify • From the Departments of Pharmaceutics and Medicine, Schools of Pharmacy and Medicine, State University of New York at Buffalo, and Millard Fillmore Hospital; Buffalo, New York.
400
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blood collection intervals for use and interpretation of serum theophylline concentrations. Methods NOMOGRAM
Mitenko and Ogilvie (4) examined the pulmonary effects and disposition rate of theophylline in nine patients with asthma. Their dosage recommendation for aminophylline was an intravenous loading dose of 5.6 mg/kg (given over 20 minutes) and a maintenance infusion of 0.9 mg/kg • h. This was a conservative dose expected to produce a target serum concentration of about 10 mg/litre within 1 h. At our first use of this schedule, it became apparent that many older or seriously ill patients experienced elevated serum concentrations of theophylline with adverse effects. This suggested that the dosing rate of theophylline should be reduced on the basis of diminished metabolic capacity in older patients and in patients with congestive heart failure or liver disease. A nomogram for rapid and standardized clinical use of theophylline was deemed desirable. The loading and maintenance dosage of aminophylline is shown in Figure 1 along with instructions for use of the nomogram. In essence, the system allows rapid selection of a loading dose of aminophylline based on body weight and the possibility of previous ingestion of theophylline; and selection of a maintenance infusion of aminophylline based on body weight, age, and cardiac and hepatic function. The dosage for young patients expected to be rapid metabolizers is that recommended by Mitenko and Ogilvie (4) (0.9 mg/kg h ) , while older patients receive a 25% reduction in infusion rate (0.68 mg/kg • h) and patients with congestive heart failure or liver disease receive 50% of the normal dose (0.45 mg/kg-h). About 90% of the dose of theophylline is biotransformed by the liver (5), and the reduction in dosage was based on the general expectations of the effects of age (6) and organ function on metabolic drug disposition. Preliminary examination of theophylline clearances in several hospital patients indicated that a reduction in recommended dosage by 25% to 50% was needed, and these values were retained for tentative use of the nomogram. Theophylline was always used in the form of the aminophylline salt, and the designated amounts of drug on the nomogram are in terms of total aminophylline content (4). Administration of the drug was usually carried out using a Saga Model 355 infusion pump (Saga Instruments; Cambridge, Massachusetts), occassionally with an IVAC large volume infusion pump (McGaw Laboratories; Glendale, California), and rarely by means of a pediatric drip set. The theophylline nomogram was disseminated to the medical staff of the Millard Fillmore Hospital in Buffalo in February 1975 for its optional use in the management of patients requiring theophylline treatment. No specific age or disease criteria were specified, to allow the clinicians maximum flexibility in selecting dosages. These dosing guidelines were most frequently used in the Respiratory Care Unit and Emergency Room, and the survey primarily reflects patients with moderate to severe respiratory impairment. The Clinical Pharmacokinetics Laboratory at the Millard Fillmore Hospital was usually alerted to the use of the nomogram for a particular patient upon the Annals of Internal Medicine 86:400-404, 1977
arrival of blood samples collected at the specified time intervals (1, 12, and 24 h). Data from 72 patients were obtained over 12 months.
The time-course (t) of serum theophylline concentrations (C„) can be characterized by the equation
VD Cp = C V e
SERUM THEOPHYLLINE ASSAY
Theophylline concentrations in serum were measured by high-performance liquid chromatography (7). Samples of 0.5-ml serum were deproteinized with 0.15 ml of trichloracetic acid, and the supernatant was injected onto a Dupont SCX column (DuPont Instruments; Wilmington, Delaware). The mobile phase was 0.66% acetic acid, column pressure was 1200 psi, and the instrument was a Dupont Model 841 Liquid Chromatograph with a UV detector using the 254-nm wavelength. This analytic procedure is specific for theophylline and is not affected by the presence of four of its major metabolites, caffeine, theobromine, or by various drugs commonly received by asthmatic patients, including phenobarbital and corticosteroids. PHARMACOKINETICS
Theophylline has a half-life usually ranging from 3 to 10 h, and a steady-state would require at least four half-lives (12 to 40 h) to elapse providing no loading dose was administered. Measurement times of 1, 12, and 24 h were thus selected to allow for the examination of the approach to the steady-state level and for convenient appraisal of serum drug concentrations during the first day of therapy.
I + ^ \ l -
VD e
l
j ,
/
where C°P is the initial serum concentration, C1B is the body clearance (volume of plasma cleared of drug per unit time), VD is the apparent volume of distribution, and kG is the infusion rate of the drug. The expected steady-state serum concentration (CpSs) is Cpss = ko/ClB. It was possible to fit the Cp values of each patient to the first equation by nonlinear least-squares regression (6) assuming that VD = 0.45 litres/kg (2,3) and using either dose/VD or the 1-h Cp value as C°P. This yielded estimates of C1B. As defined in the above equations, body clearance is the proportionality factor between drug dosing rate and steady-state serum concentration as well as a reflection of the total rate of disposition of theophylline. Results
Serum theophylline concentrations found in 10 typical patients during the infusion process are shown in Figure 2. Most patients either received a loading dose of amino-
Figure 1. Guidelines for intravenous aminophylline therapy. Mark patient's weight in kg on Lines B and H. Use a ruler to connect these points. Loading Dose: Line C provides a loading dose of 5.6 mg/kg. Give concentrated solution at a rate not exceeding 50 mg/min. Give 0 to Vi of this dose if patients have received theophylline within 12 h. Maintenance Dose: The infusion rate (in mg/h) is obtained from the intersection on the following lines. Normal: Young patients expected to be rapid metabolizers. Reduced: Typical older patients (over 50 years). Low: Patients with congestive heart failure or liver disease. Begin infusion soon after injection of the bolus. The rate of infusion is critical and must be checked frequently by nursing personnel. Blood: Collect 5-ml blood samples at 1, 12, and 24 h after starting infusion. Most patients will be near steady-state by 24 h.
Jusko et al. • Intravenous Theophylline Therapy
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401
Figure 2. Serum theophylline concentrations at various time intervals after beginning therapy in 10 typical hospitalized patients. The curves were fitted to the data using the first equation (see text).
phylline or were earlier recipients of the drug and thus had achieved a reasonably high serum concentration of the bronchodilator by 1 h. The first equation provides a good fit to the data. Comparing the expected steady-state serum concentration values (calculated with the second equation) with the measured 24-h serum concentration indicated that the 24-h value was usually near the steadystate level. Eighty-four percent of the patients had 24-h serum concentrations that were within 20% of the anticipated steady-state level. Thus the 24-h value was used for further evaluation of the nomogram's usefulness because of its closeness to steady-state and because it reflects the end-point of a full day of theophylline therapy. The serum concentration of theophylline found at or nearest to 24 h from the onset of therapy in each of the patients is shown in Figure 3. Overall, 72% of all patients attained 24-h serum concentrations values in the usual therapeutic range. Only two of the 72 patients were outside of the range of 5 to 25 mg/litre, indicating that the nomogram allows extremely safe use of theophylline during the first day of therapy. The distribution of patients and the achieved 24-h serum concentration values in the three dosage categories are listed in Table 1. Forty patients were assigned to the "reduced dose" category, which constituted the largest patient group. There was a tendency for the "predictability" of 24-h serum concentrations to diminish with the use of smaller maintenance doses—83% of patients in the "normal dose" category attained the therapeutic range while only 57% of those in the "low dose" category were in the 402
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8 to 20 mg/litre range. A summary of the patient characteristics and the average body clearances calculated with the first equation are also provided in Table 1. The patient population consisted of persons ranging in age from 19 to 85 years. There were 33 male and 39 female patients. Only two patients had overt liver impairment as indicated by elevated serum bilirubin and lowered serum albumin concentrations. The presence of congestive heart failure was usually indicated by history and physical findings including edema and elevated central venous pressure. The mean body clearances in the reduced dose and low dose categories were significantly smaller (P < 0.05) than the value in the normal dose category. The data for patients with congestive heart failure or liver disease are of particular interest because these patients have the lowest body clearances and are at greatest risk from accumulation of theophylline. It is estimated (second equation) that 11 of 14 of these patients would have attained steady-state serum concentrations exceeding 20 mg/litre had they received the "normal dose" (assuming that the full dosage was administered and evidence of adverse effects did not cause therapeutic adjustments). Similarly, 17 of 40 patients in the reduced dose group might have attained steady-state serum levels in excess of 20 mg/litre if given the normal dose. Patients in the low dose category require additional caution in the use of theophylline and more prolonged monitoring of serum theophylline concentrations. These patients are expected to have the longest half-life values and thus may require more than 24 h to achieve a true steady-state. Discussion
Considerable improvement in the clinical use of theophylline for bronchodilation has been achieved since the relation between steady-state serum concentrations of theophylline and improvement of pulmonary function has been defined in adults (2, 4) and children ( 6 ) . Despite the knowledge of the target serum concentration range (8 to 20 mg/litre) and the means of assuring its achievement by serum analysis, pharmacokinetic guidelines are needed for optimal initial dosing with theophylline. Serum level monitoring has limited clinical availability and, when accesible, is accompanied by a moderate to appreciable turn-
Table 1. Patient Characteristics and Theophylline Serum Concentrations Dosage Group
Aminophylline maintenance dose, mg/kg • h Sex (M/F) Age (SD), yrs Patients studied, no. Patients in therapeutic range*, no. Body clearance (SD), ml/h - kg
Normal
Reduced
0.9 5/13 44.5(13.4) 18
0.68 22/18 60.2(13.4) 40
15
Low
0.45 6/8 63.1 (7.6) 14
29
63.4 (34.7) 48.6 (33.0) f
8 31.8(14.8)1
* Serum concentrations in the: range of 8 to 20 mg/litre at 24 h t Significantly different from '"normal dose" group at P < 0.05.
Figure 3. Serum theophylline concentrations at 24 h after beginning therapy in 72 hospital patients prospectively placed into three metabolic categories by physicians. The broken lines designate the usual therapeutic range of 8 to 20 mg/litre.
over time even with the advent of rapid assay methods. As our results show, there are certain limitations inherent in previously recommended dosages of theophylline. Mitenko and Ogilvie (4) derived their guidelines after examining only nine patients who were not suffering an asthma attack at the time of the study and who did not appear to be otherwise seriously ill. Also, no patient was more than 51 years old. Piafsky and Ogilvie (8) later modified their recommendations, suggesting that the maintenance infusion rate be "reduced by one-third of the usual dose in the presence of congestive heart failure and reduced by half the usual dose in patients with severe liver impairment." Our study has tested similar guidelines in a large number of hospitalized adult patients receiving intravenous aminophylline. The nomogram format facilitates dosage computations by clinicians, and the blood collection protocol permits the nomogram to be tested and provides for rapid adjustment of the infusion rate in patients whose metabolic rate is unusually rapid or slow. We believe that the nomogram, used with clinical judgment, is a valuable means of deciding initial theophylline therapy. It reduces the chance for computational error and speeds the process of initiating the proper dosage regimen for patients with serious organ impairment. Care is particu-
larly needed in selecting the loading dose because many patients may have previously received the drug. In addition, it is not certain whether all types of patients should receive a common loading dose. One measure of the usefulness of the nomogram is the relative safety with which aminophylline was used. Besides yielding serum concentrations in the range of 5 to 25 mg/litre in 70 of 72 patients, the drug caused no moderate or serious adverse reactions that we observed. However, this study did not include close monitoring of efficacy and toxicity by "blind" observers in addition to typical respiratory care unit procedures, and the occurrence of mild adverse effects may have been missed. The relative success of the nomogram guidelines may be examined by comparing the measured serum concentrations achieved in our 72 patients to those obtained in two recent studies where theophylline therapy was monitored in hospitalized adults. Jacobs, Senior, and Kessler (9) found that of 47 patients receiving the drug by various routes, 12 had serum concentrations above 25 mg/litre, and 11 had serum concentrations below 8 mg/litre—a total of 4 9 % of the patients who were decidedly out of the therapeutic range. Weinberger and associates (10) examined data from 15 adult patients who received aminophylline infusions. Six had apparent steady-state serum concentrations above 25 mg/litre while one was below 8 mg/litre. In these two earlier studies, 30 of 62 ( 4 8 % ) patients were outside the 8 to 25 mg/litre serum concentration range. Using our guidelines, only 13 of 72 ( 1 8 % ) patients missed the range of 8 to 25 mg/litre. Both previous reports concluded that the initial dosage recommendations of Mitenko and Ogilvie (4) were not sufficiently flexible to account for the effects of old age and serious associated illnesses on theophylline metabolism, and that serum concentration monitoring is important clinically in guiding effective and safe use of theophylline. Our investigation confirms these findings but further indicates that modification of the dosage guidelines of Mitenko and Ogilvie, based on knowledge of the primary factors affecting drug metabolism, may provide more reliable achievement of the therapeutic range for hospitalized patients. This should be of particular value for patients who cannot be monitored with frequent serum concentration measurements. ACKNOWLEDGMENTS: The authors thank Mrs. Anna Poliszczuk for her technical assistance; and the house staff and nurses of the Millard Fillmore Hospital for their cooperation in the implementation of the nomogram procedures. Grant support: in part by Grant No. 20852 from the National Institutes of General Medical Sciences, National Institutes of Health. Received 9 August 1976; revision accepted 14 December 1976. • Requests for reprints should be addressed to William J. Jusko, Ph.D.; Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital; Buffalo, NY 14209. References 1. ELLIS EF, EDDY ED: Anhydrous theophylline equivalence of
commercial theophylline formulations. / Allergy Clin Immunol 53:116-118, 1974 2. JENNE JW, WYZE E, ROOD FS, et al: Pharmacokinetics of theo-
phylline. Application to adjustment of the clinical dose of aminophylline. Clin Pharmacol Ther 13:349-360, 1972 3. MITENKO PA, OGILVIE RI:
Pharmacokinetics
of
intravenous
theophylline. Clin Pharmacol Ther 14:509-513, 1973 Jusko et a/. • Intravenous Theophylline Therapy
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4. MITENKO PA, OGILVIE RI: Rational intravenous doses of theophylline. N Engl J Med 289:600-603, 1973
and spectrophotometric assays for theophylline in biological fluids. Am J Hosp Pharm 33:1193-1196, 1976
5. THOMPSON RD, NAGASAWA HT, JENNE JW: Determination of
8. PIAFSKY KM, OGILVIE RI: Dosage of theophylline in bronchial
theophylline and its metabolites in human urine and serum by high-pressure liquid chromatography. / Lab Clin Med 84:584593, 1974 6. MASELLI R, CASAL GL, ELLIS EF: Pharmacologic effects of in-
travenously administered aminophylline in asthmatic children. J Pediatr 76:777-782, 1970 7. JUSKO WJ, POLISZCZUK A: High pressure liquid chromatographic
asthma. N Engl J Med 292:1218-1222, 1975 9. JACOBS MH, SENIOR RM, KESSLER G: Clinical experience with
theophylline. Relationships between dosage, serum concentration, and toxicity. JAMA 235:1983-1986, 1976 10. WEINBERGER MW, MATTHAY RA, GINCHANSKY EJ, et al: Intra-
venous aminophylline dosage: use of serum theophylline measurement for guidance. JAMA 235:2110-2113, 1976
A Reminder American Board of Internal Medicine Recertification Examination The American Board of Internal Medicine is offering the second voluntary Recertification Examination on Saturday, 29 October 1977. Applications for the examination are available now. As in the 1974 examination, by which more than 3500 Diplomates were recertified, the 1977 examination will be closely linked to the Medical Knowledge Self-Assessment Program (MKSAP IV), which is now available from the American College of Physicians. The examination will be given in as many centers across the country as demand requires. The morning section will consist of multiple choice questions that relate to recent advances in internal medicine as described in the MKSAP syllabus, considered relevant to current practice and also to other medical information deemed important in general internal medicine. The afternoon section will consist of Patient Management Problems (PMPs) that are sequential, feedback patient simulations designed to assess clinical problem solving. The format of these questions is the same as that used and critiqued in MKSAP IV, which will be distributed in May 1977. In the PMP section of the examination the internist will have the opportunity to select some cases that reflect the individual nature of his or her practice. Internists successful on the examination will be issued a Certificate, and notation of their recertification will appear in the Directory of Medical Specialists. Unsuccessful candidates will not lose their primary certification, and individual results will be kept confidential. You are eligible for the 1977 examination if you were certified in internal medicine in 1971 or earlier and were not recertified by the 1974 examination. The fee for the examination is $100 and is payable upon submission of the completed application. The closing date for registration has been extended to 1 July 1977. To apply request an application form from: The American Board of Internal Medicine 3930 Chestnut Street Philadelphia, Pennsylvania 19104
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April 1977 • Annals of Internal Medicine • Volume 86 • Number 4
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