Pharmacologic effects of intravenously administered aminophylline in asthmatic children

May, 1970 T h e J o u r n a l o[ P E D I A T R I C S

777

Pharmacologic effects o/intravenously admim'stered aminophylline in asthmatic children The effects o[ intravenously administered aminophylline were studied in 49 asthmatic children while they were symptomatic. The drug was administered in a dose o[ 4 rag. per kilograr~,d[ body weight either rapidly over a'4 to 5 minute period or slowly over an 8 hour period. Blood theophylline concentrations and FEVI were determined at 15 and 30 minutes and l, 2, 4, 6, and 8 hours a#er administration o[ the drug was begun. The sa[ety of both methods o[ intravenous administration o[ aminophylline was documented by absence o/ adverse effects. The superiority o[ giving aminophylline relatively rapidly was clearly demonstrated on clinical grounds, by rapid improvement in FEV1, and by prompt attainment o[ therapeutic plasma concentrations o[ theophylline. A control group o[ 10 patients who were treated with bed rest and intravenous fluids alone showed only minimal transient improvement in FEVI.

Roberto Maselli, M.D., German L. Casal, B.A., and Elliot F. Ellis, M.D. * DENVER,

COLO.

A ~a I N o P H Y L L I N E (theophylline ethylenediamine) is widely used in asthma for its potent bronchodilating property. It is especially valuable in the epinephrine-resistant asthmatic patient since its pharmacologic mechanism of action differs from that of epinephrine. Although both drugs act on the effector cell to increase the intracellular concentrations of cyclic 3',5'-adenosine mono-

From the Pediatric Allergy Division, National Jewish Hospital, and the Department o[ Pediatrics, The University of Colorado. This work was supported in part by United States Public Health Service Grant No. A I 08428. *Address: Pediatric Altergy Div{sion, National Jewish Hospital, 3800 E. Col[ax Ave., Denver, Colo. 80206.

phosphate (cyclic 3',5'-AMP), epinephrine and certain other catecholamines achieve this by increasing the activity of adenyl cyclase, while theophylline and other methylxanthines inhibit the action of phosphodiesterase, the enzyme which degrades cyclic 3',5'-AMP to 5P-adenosine monophosphate (5'-AMP) 1 -(Fig. 1). Some physicians avoid the use of theophylline compounds in children because of several reports of adverse reactions, including death, following their administration to pediatric patients. 2-4 This study was designed to investigate the pharmacologic effects of intravenously administered amlnophylline in a group of asthmatic children and to evaluate the safety of the drug given by this route. Vol. 76, No. 5, pp. 777-782

778

Maselli, Casal, and Ellis

The Journal of Pediatrics May 1970

CATECHOLAMINES

1

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METHYLXANTHI NES

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Fig. 1. Relationship of catecholamines and rnethylxanthines to the metabolism of cyclic 3',5'adenosine monophosphate (cyclic 3',5'-AMP).

Table I. Comparison of the subjects and methods of administration of aminophylline

Subjects Method of administration Group I (I.V. injection) Group II (I.V. infusion) Group III (control)

PATIENTS

AND

Male 21 5 8

I Female 17 6 2

METHODS

T h e subjects were 59 children (49 who received aminophylline and 10 controls) with severe, intractable asthma, receiving residential care in the Pediatric Allergy Division of the National Jewish Hospital and Research Center in Denver, Colorado. T h e ages~df the children ranged from 4 to 15 years ~(Table I ) . T h e majority of the children h a d significant asthmatic symptoms at the time 'they were studied. They had not received any medication containing theophylline, caffeine, or barbiturates for at least 12 hours prior to study (the latter two drugs interfere with the spectrophotometric assay for theophylline). The children were randomly assigned to one of three groups. All of them were receiving maintenance doses of bronchodilators a n d / o r corticosteroids. Inhaled bronchodilators (isoproterenol) were withheld for at least 8 hours prior to the beginning of the study. The first group of 38 subjects received aminophylline, 4 mg. per kilogram of body weight intravenously over a 4 t% 5 minute interval. Five per cent dextrose in 0.2 per cent saline in a dose

Total 38 11 10

Age (yr.) 10 (4-15) 11 (7-14) 10 (7-15)

t

Weight (Kg.) 32 (17-66) 33 (18-61) 29 (22-40)

of 1,500 c.c. per square meter per 24 hours was continued over 8 hours. In the second group of 11 patients the same dose of aminophylline was given in the same volume of fluids as used in group I, as a slow intravenous infusion over an 8 hour period. A third control group of 10 children received the same type .and amount of intravenous fluids but were given an injection of isotonic saline instead of aminophylline in order to evaluate the effect of hydration alone on asthma. Forced expiratory volume in the first second (FEV1), pulse, respiratory rate, blood pressure, and the plasma concentration of theophylline were determined at time 0, 15, and 30 minutes and 1, 2, 4, 6, and 8 hours. T h e FEV1 was measured with a Pulmonor (Jones Medical Inst. Co., Chicago) spirometer familiar to all of the children in the study. Plasma levels of theophylline were determined by a modification of the method of Schack and Waxler. s Two milliliters of heparinized plasma were extracted twice with

Volume 76 Number 5

Effects o[ intravenous aminophylline

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Time (hours) Fig. 2. Effect on FEV1 of the same dose of aminophylline given by two different methods.

successive 50 ml. aliquots of a freshly prepared 20:1 mixture of chloroform and isopropanol. After five minutes of the second extraction the two aliquots of organic solvent were combined in another separatory funnel and back extracted into 4 ml. of 0.1N N a O H , in a mechanical shaker for 5 minutes. The aqueous phase, containing the extracted theophylline, was collected and its optical density measured in a Beckman Model D U spectrophotometer at 274 m/~. Recovery of theophylline from plasma in our hands by this method was approximately 87 per cent. The plasma concentration of theophylline was calculated as follows: O.D. sample minus O.D. blank 100 4 O.D. theoghylline STD x ~ x --2 ~--#g theophylline/ml, of plasma RESULTS Evaluation of the effect of aminophylline on pulmonary functions was made only in those children whose base-line FEV~ values were under 80 per cent of the predicted. Of the 59 patients studied, only 21 in group I, 7 in group I I , and 10 in group I I I met this criterion. With the exception of 3 children, all in group I had an immediate clinical improvement and an increase in the FEV~

(Fig. 2). The mean improvement in the F E V 1 at 15 minutes was 65 per cent over the initial value. During the next 1 ~ hours the FEV1 values continued to increase; a maximum improvement of 78 per cent was reached at the end of this time. At the end of 3 hours the improvement had declined to 57 per cent. The FEV1 values then remained fairly stable until the end of the 8 hour period, when they declined markedly. In contrast to the rapid improvement in the FEV1 noted in this first group, the patients in group I I who received aminophylline as a slow intravenous infusion over an 8 hour period had minimal improvement in the FEV1 until 2 hours after the infusion was begun. I m p r o v e m e n t in the F E V I approximating that observed in group I patients was not-attained until near the end of the 8 hour infusion. T h e control group of 10 children had maximal improvement in the FEV1 of 17 per cent over the initial value at 30 minutes. However, after this interval their clinical condition worsened tO the extent that bronchodilator therapy (isoproterenol by inhalation) had to be given. By the end of 3 hours half of the children required bronchodilator treatment; all required treatment by 6 hours. Comparison of mean plasma concentrations

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Maselli, Casal, and Ellis

The Journal o[ Pediatrics May 1970

of theophylline showed a marked difference between the two study groupst(Table I I ) . Administration of aminophylline over a 4 to 5 minute period resulted in high initial values with a mean theophylline concentration of 8.58 _+ 0.74 /zg per milliliter of plasma at 15 minutes. During the next 8 hours there was'" an exponential disappearance of the-

ophylline from the plasma (Fig. 3). A theophylline concentration of only 0.95 /~g _+ 0.04/zg per milliliter remained at the end of the 8 hour period. In the group receiving a constant infusion of aminophylline, the plasma theophylline concentration rose very slowly to a peak value of 3.77 + 0.71 /xg per milliliter at the end of the 8 hour period. Measurements of heart rate, respiratory rate, and blood pressure during the study showed no significant change. Central nervous system stimulation was not observed; nor were there signs or symptoms of disturbance of the gastrointestinal tract. Diuresis was noted in some of the children, but its magnitude was not quantified.

Table II. Comparison of plasma theophylline concentrations (micrograms per mil!iliter) according to method of administration

Time

15 min. 30 min. 1 hr. 2 hr. 4 hr. 6 hr. 8 hr.

Plasma theophylline concentrations (mean + standard error) (micrograms per milliliter) Aminophylline, Aminophylline, 4- mg./Kg. 4 mg./Kg. I.V. injection I.V. in[usion (4 to 5 rain.) (8 hr.) 8.58 + 0.74 0 7.17 -+0.69 0.50 -+0.08 6.II +0.60 0.62+0.08 4.86+0.58 0.79+0.10 3.05 -+0.54 1.79 + 0.43 1.91 + 0.44 3.23 -+0~49 0.95 + 0.04 3.77 -+0.71

DISCUSSION The results of this investigation establish that aminophylline is a rapid, effective, and safe bronchodilator in asthmatic children when the total calculated 8 hour dose (4 mg. per kilogram of body weight) is administered intravenously over a 4 to 5 minute period. A therapeutic plasma concentration of theophylline is obtained almost immediately

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Time (hours) Fig. 3. Comparison of mean plasma theophylline concentrations attained following administration of aminophylline by two different methods.

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Effects o/ intravenous arninophylline

following rapid infusion of the drug and results in prompt subjective and objective improvement. A marked increase in FEV1 occurs within 15 minutes and is sustained for 7 hours. In contrast, slow infusion of the same dosage over an 8 hour period yields considerably lower plasma theophylline levels and a delayed clinical response. A 20 per cent increase in FEV~ does not occur until approximately 2 hours after the infusion is begun. This delayed response makes this method of administration undesirable in the management of the asthmatic child with significant respiratory distress. The correlation between clinical improvement and plasma theophylline concentration" in the two treatment groups supports the observation that the effect of theophylline is related to its plasma concentrationY Although this study was not designed to determine the minimal plasma concentration necessary for a therapeutic bronchodilator effect, the data from group I I suggest that the concentration required may be less than the generally accepted value of 5/xg per milliliter of plasma7 Figs. 2 and 3 show that children who received aminophylline by slow infusion had significant i m p r o v e m e n t in FEV1 values, though plasma theophylline concentration remained below 5 t~g per milliliter. Despite a mean plasma theophylline concentration at 8 hours

of only 3.77 + 0.71 /zg per milliliter, the improvement in mean FEV1 was comparable to that observed with significantly higher plasma theophylline concentrations in group I. The reason for the difference is difficult to interpret because the observations were made at different points in time and other factors may have been involved. It is possible that lower initial plasma concentrations than those achieved with the 4 mg. per kilogram dose would have given an equivalent improvement of FEV1. The inability of children in the control group to tolerate the 8 hour study period without medication suggests that bed rest and intravenous hydration alone were not sufficient to account for the improvement observed in the two study groups. No adverse reactions were noted either during or following intravenous administration of aminophylline. Although in group I patients the total calculated 8 hour dose was given over a 4 to 5 minute period, it would seem reasonable to extend the period to 15 or 20 minutes in clinical practice. Manifestations of theophylline toxicity in order of frequency are irritability, dehydration, severe vomiting, hematemesis, albuminutia, stupor, and convulsions, s While idiosyncratic reactions to theophylline may occa-

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Fig. 4. Dose of theophyltine preparations (milligrams per kilogram of body weight) given to children in reported toxic reactions. The figure in the parentheses indicates the number of times the dose was given. The t indicates that death occurred. Source data from references 2, 4, 9, 10.

78 1

782

Maselli, Casal, and Ellis

sionally occur, review of the "toxic" reactions attributed to theophylline which are reported in the medical literature indicates that in most such instances a grossly excessive dose of the drug was administered (Fig. 4). Prior to the administration of aminophylline intravenously, a careful history should be taken of~drug therapy during the previous 24 hours. If th~ child has received no more than the usually recommended oral dosage of theophylline-containing preparations, it is safe to administer additional aminophylline by the intravenous route because of the low plasma theophylline concentration which results from oral, t h e r a p y y -1~ We acknowledge the valuable heIp of Miss Sally Winkler, R.N., who was in constant attendance with the subjects during, the experimental period. Annette DeTuerk did the plasma theophylline determinations. We are indebted to Mayer Goren, Ph.D., for advice concerning the theophylline assay, to Sumio Go, M.D., for assistance, and to Harry Shirkey, M.D., for his critical reading of the manuscript. REFERENCES

1. Butcher, R. W., and Sutherland, E. W.: Adenosine 3',5'-monophosphate in biological materials, J. Biol. Chem. 237: 1244, 1962. 2. Rounds, V. J.: Aminophylline poisoning, Pediatrics 14: 528, 1954.

The Journal o[ Pediatrics May 1970

3. Love, F. M., and Corrado, A. G.: Aminophylline overdosage in children, Amer. J. Dis. Child. 89: 468, 1955. 4. Soifer, H.: Aminophylline toxicity, J. P~mAT. 50: 657, 1957. 5. Schack, J. A., and Waxler, S. R.: An ultraviolet spectrophotometrlc method for the determination of theophylline and theobromine in blood and tissues, J. Pharmacol. Exp. Thor. 97: 283, 1949. 6. Turner-Warwick, T.: Study of theophylline plasma levels after oral administration of new theophylline compounds, Brit. Med. J. 2: 67, 1957. 7. Truitt, E. B., Jr., MeKusick, V. A., and Krantz, J. C.: Theophylline blood levels after oral, rectal, and intravenous administration, and-correlation with diuretic action, J. Pharmaeol. Exp. Ther. 100" 309, 1950. 8. McKee, M., and Haggerty, R. J.: Aminophytline poisoning, New Eng. J. Med. 256: 956, 1957. 9. Baeal, H. L., Linegar, K., Denton, R. L., and Gourdeau, R.: Aminophylline poisoning, Canad. Med. J. 80: 6, 1959. 10. Nolke, A. C.: Severe toxic effects from aminophylline and theophylline suppositories in children, J. A. M. A. 161: 693, 1956. 11. Calesniek, B., Munch, J. C., Di Palma, J. R., and Altarelli, V. R.: Bioassay of theophylline preparations using human subjects, Brit. Med. J. 2" 33, 1960. 12. tteimlich, E. M., and Siegel, S. C.: Clinical and laboratory evaluation of an antiasthmatic preparation with proIonged action, J. Allerg. 35: 27, 1964.