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Paroxysmal supraventricular tachycardia during theophylline therapy in a premature infant
1016
June 1978 The Journal of P E D I A T R I C S
Paroxysmal supraventricular tachycardia during theophylline therapy in a premature infant An episode of supraventricular tachycardia occurred in an infant born at 31 weeks" gestation after three days of therapy with theophylline 3.5 mg/kg every six hours. The infant had a plasma theophylline halflife of 24. 7 hours and a low plasma theophylline clearance of 12. 7 ml/kg/hour. The plasma theophylline concentration at the time of the arrhythmia was about 42 mg/l. The extent of drug accumulation with these kinetic characteristics is emphasized. Serious adverse effects due to theophylline may occur with few signs or symptoms of impending toxicity. Plasma theophylline concentration measurements are valuable in avoiding such toxicity.
P. M. Loughnan, M.B.B.S., M.R.A.C.P.,* a n d John M. Me Namara, M.B.B.S., F.R.A.C.P., Melbourne, Australia
T H E O P H Y L L I N E is currently used in the therapy of apneic episodes in premature infants?-,2 Serious toxicity with excessive theophylline dosage has occurred in children and adults, especially i n association with impaired hepatic function, a' .4 The drug is eliminated largely by the hepatic microsomal mixed function oxidase system in adults. This metaboiic degradation is complex; xanthine oxidase is not involved while oxidative processes, both 1and 3- demethylation and hydroxylation, are i m p o r t a n t ? It may be anticipated that theophylline clearance will be impaired and highly variable in the premature newborn infant, as has been shown for other drugs, such as phenytoin metabolized by this enzyme system.~ Limited pharmacokinetic information is available regarding theophylline in the newborn infant but the reported data are consistent with this prediction. 7, 8 We report an infant who developed supraventricular tachycardia during theophylline therapy in association with a high plasma theophylline concentration. It should be emphasized that this serious adverse drug effect occurred while utilizing a theophylline dose which has been recommended, endorsed)' and Widely used. ~ From the Clinical Pharmacology Unit, Royal Children's Hospital, and Special Care Nursery, Mercy Maternity Hospital. *Reprint address: Clinical Phodrmacology Unit, Royal Children's Hospital, Parkvill~e, 3052, Australia.
Vol 92, No. 6, pp. 1016-1018
CASE REPORT A male infant was delivered by cesarean section for fetal distress after spontaneous labor at 31 weeks' gestation. Apgar scores at 1 and 5 minutes were 3 and 8, respectively. Birth weight was 1,420 gm and clinical assessment of maturity was consistent With dates. An umbilical arterial catheter was inserted for 36 hours due to early onset of respiratory distress which abated within 48 hours. Penicillin, 50,000 units, and kanamycin, 10 rag, were given twice daily intramuscularly for five days. Phototherapy was instituted on day 3; the maximum serum bilirubin was 17.1 mg/dl on day 4. Serum electrolytes, glucose, and acidbase studies were within normal limits on repeated occasions during the first four days of life. Apnea commenced at age 10 hours and after five episodes lasting 20 to 30 seconds, theophylline was started at a dose of 5 mg (3.5 mg/kg) orally, every six hours. Five apneic episodes occurred in the 12 hours after institution of theophylline therapy but there was no further apnea. Frequent vomiting (bile stained) occurred from 48 to 96 hours of age. Pulse rate was continuously monitored during theophylline therapy and a moderate sinus tachycardia was noted on the third day of life with a maximum pulse rate 185/minute, leading to cessation of theophylline after the eleventh dose. Three hours later rapid tachycardia was noted and an electrocardiogram showed paroxysmal supraventricular tachycardia at a rate of 320/minute. There was no clinical evidence of cardiac failure. This arrhythmia reverted spontaneously to sinus tachycardia after 10 minutes, but recurred transiently on two occasions over the next hour. Intramuscular digoxin was then commenced, digitalizing dose 60 /~g over 18 hours, maintenance dose 12/~g twice daily. Laboratory studies at
0022-3476/78/0692-1016500.30/0
9 1978 The C. V. Mosby Co.
Volume 92 Number 6
Tachycardia during theophylline therapy
10 17
200 40 "~x
%%
=-"
-40
190
\
E
N%
"\I
\t
180
r
~20 E
.= 17(]
e. o
C~
= 42'3
mg/I
.=
t
tI
16(3 e>, c-
15(~
t
I
"30
2 84
_=
.
~o
~
e-
9
140
to 4 E
LL!LLLIt~ 1
~
2
i
3 Age
_i 4
, 5
i 6
7
tdays ]
Fig. 2. Relationship of mean pulse rate to plasma theophylline concentration. Vertical bars indicate mean • SE of hourly observations of pulse rate over 12-hour periods. Observed (e) and predicted (o) plasma theophylline concentrations are shown. Arrows indicate the time of oral theophylline doses.
2
1 24
48 Time
72
after
last
dose
96
120
(hr.)
_'2 Fig. 1. Semilogarithmic plot of plasma theophylline concentration versus time after the last theophylline dose. the time of the arrhythmia revealed serum sodium 142 mmol/l, potassium 4.7 mmol/l, chloride 107 mmol/l, calcium 6.2 mg/dl, glucose 75 mg/dl, pH 7.35, Paco ~77, and base excess - 2 mmol/1. Chest roentgenogram showed a normal cardiac contour and repeated electrocardiograms were within normal limits. No clinical evidence of cardiac disease was noted in the subsequent hospital course.
E
50
40
0 C 0 0 30 r.c 0 ek-
20
10
E METHODS
O.
Plasma theophylline concentrations were measured by a radioimmunoassay developed by Cook et al? ~ Kinetic constants were derived using the one-compartment o p e n model, ~ assuming rapid and complete absorption of the drug. Predictions of drug accumulation utilized the following equations ~: C% ~ = Xo 9 ( 1 - e " ~ * ) V
(1 - e -kt*)
where Xo and t* are the dose and dosage interval, respectively, C % ~ is t h e peak plasma concentration after the nth dose, k is the elimination rate constant (0.693/t,~), and V the apparent volume of distribution, and C%" = C% x" e -~* where C*'~" is the m i n i m u m plasma concentration after the nth dose.
ILILlll~ll~ Age
(days)
Fig. 3. Predicted accumulation of theophyll{ne in plasma with repeated doses. Solid circles indicate observed plasma theophylline concentrations. Calculated peak (o) and trough (h) plasma theophylline concentrations were derived according to the onecompartment kinetic model. RESULTS In Fig. 1 is shown a semilogarithmic plot o f plasma theophylline concentration measured at intervals after the last dose. T h e p l a s m a theophylline half-life was 24.7 hours. Linear extrapolation of this curve to time zero indicates that shortly after the last dose the plasma theophylline concentration was 42.3 m g / L Slow absorption or zero-order metabolism of theophylline at high p l a s m a concentrations would result in an actual plasma
10 18
Loughnan and M c Namara
concentration somewhat less than that predicted. Nevertheless it is clear, at the time of the arrhythmia, that the plasma theophylline concentration was far in excess of the assumed therapeutic range of 7 to 14 rag/1. 7 Substitution of Cm~ in equation 1 yields the following results: plasma theophylline clearance, kV, 12.7 ml/kg/hour, volume of distribution; 0.45 1/kg. The mean _+ SE of hourly pulse rates plotted for 12hour intervals from birth is shown in Fig. 2. Little change in pulse rate was seen until after the tenth dose. Despite cessation of theophylline a marked tachycardia ensued followed abruptly by the arrhythmia. This occurred when the calculated plasma theophylline concentration was > 40 mg/1. The subsequent sinus tachycardia resolved as plasma theophylline concentrations decreased. The pattern of drug accumulation (Fig. 3) in this patient is predicted using equations 1 and 2. Theophylline was stopped after only about three half-lives, so that steadystate plasma concentrations had not yet been attained. The calculated peak steady-state plasma concentration was 50.2 nag/l, and had theophylline been continued, more serious toxicity would have been likely. DISCUSSION Theophylline, a phospho-diesterase inhibitor, has complex effects on the cardiovascular system and is known to cause tachyarrhythmias. 12 13 There is a good relationship between plasma concentration and adverse effects, :~with minor toxicity occurring above 15 rag/1 and serious toxicity above 30 to 40 mg/1. Supraventricular tachycardia is uncommon in the premature infant, and as no other predisposing factor was observed, it is likely that the arrhythmia was a toxic effect of theophylline. The dose of this drug used in earlier studies in the prematt/re newborn I may produce toxicity, and, more recently, lower doses (2 mg/kg/12 hours) have been recommended based on limited kinetic data in a small number of infants2 ~ The latter dose would have produced a steady state plasma theophylline concentration of about 13 mg/1 in our infant. The use of clinical observation to anticipate and avoid theophylline toxicity has been suggested, 1 but definite clinical manifestations do not always precede serious toxicity in adults. 3 We suggest that this is also true in the newborn infant. Until dosage recommendations for theophylline are more soundly based, plasma theophylline concentrations should be measured in all premature infants receiving this
The Journal of Pediatrics June 1978
drug. We can highlight (Fig. 3) the extent to which drug accumulation may be anticipated when drugs with long half-lives are administered at frequent intervals in the newborn infant. Monitoring of plasma theophylline concentrations is indicated in the early days of therapy when drug accumulation is likely as the steady state is approached. The materials for the radioimmunoassay of theophylline were generously supplied by Dr. C.E. Cook, Research Triangle Institute, North Carolina. The secretarial help of Norma Downey was appreciated. REFERENCES
1. Shannon DC, Gotay F, Stein IM, Rogres MC, Todres ID, and Moylan F: Prevention of apnea and bradycardia in low birthweight infants, Pediatrics 55:589, 1975. 2. Kuzemko JA, and Paala J: Apnoeic attacks in the newborn treated with theophylline, Arch Dis Child 48:404, 1973. 3. ZwillichCW, Sutton FD, Neff TA, Cohn WM, Matthay RA, and Weinberger MM: Theophylline-induced seizures in adults. Correlation with serum concentrations, Ann Intern Med 82:784, 1975. 4. Jacobs M, Senior RM, and Kessler G: Clinical experience with theophylline, JAMA 235:1983, 1976. 5. Jenne JW, Nagasawa HT, and Thompson RD: Relationship or urinary metabolites of theophylline to serum theophylline levels, Clin Pharmacol Ther 19:375, 1976. 6. Loughnan PM, Greenwald A, Purton WW, Watters G, and Neims AH: Pharmacokinetic observations of phenytoin in the newborn and young infant, Arch Dis Child 52:302, 1977. 7. Aranda JV, Sitar DS; Parsons WD, Loughnan PM, and Neims AH: Pharmacokinetic aspects of the0phylline in premature newborns, N Engl J Med 295:413, 1976. 8. GiacoiaG, Jusko WJ, Menke J, and Coup JR: Theophylline pharmacokinetics in premature infants with apnea, J P~r)IA'rR89:829, 1976. 9. Lucey JF: Xanthine treatment of apnea of prematurity, Pediatrics 55:584, 1977. 10. CookCE, Twine ME, Myers M, Amerson E, Kepler JA, and Taylor GF: Theophylline radioimmunoassay, Res Commun Chem Pathol Pharmacol 13:497, 1976. 11. Gibaldi M, and Perrier O: Pharmacokinetics, in Swarbrick J, editor: Drugs and the pharmaceutical sciences, Vo! 1, New York, 1975, Marcel Dekker Inc, p 97. 12. Hendeles E, Bighley L, Richardson RH, Hepler CD, and Carmichael J: Frequent toxicity from IV aminophylline infusions in critically ill patients, Drug Intell Clin Pharm 2:12, 1977. 13. Ritchie JM: Central nervous system stimulants, the xanthines, in Goodman LS and Gilman A, editors: The pharmacologic basis of therapeutics, ed 5, New York, 1975, The Macmillan Co, p 367.
June 1978 The Journal of P E D I A T R I C S
Paroxysmal supraventricular tachycardia during theophylline therapy in a premature infant An episode of supraventricular tachycardia occurred in an infant born at 31 weeks" gestation after three days of therapy with theophylline 3.5 mg/kg every six hours. The infant had a plasma theophylline halflife of 24. 7 hours and a low plasma theophylline clearance of 12. 7 ml/kg/hour. The plasma theophylline concentration at the time of the arrhythmia was about 42 mg/l. The extent of drug accumulation with these kinetic characteristics is emphasized. Serious adverse effects due to theophylline may occur with few signs or symptoms of impending toxicity. Plasma theophylline concentration measurements are valuable in avoiding such toxicity.
P. M. Loughnan, M.B.B.S., M.R.A.C.P.,* a n d John M. Me Namara, M.B.B.S., F.R.A.C.P., Melbourne, Australia
T H E O P H Y L L I N E is currently used in the therapy of apneic episodes in premature infants?-,2 Serious toxicity with excessive theophylline dosage has occurred in children and adults, especially i n association with impaired hepatic function, a' .4 The drug is eliminated largely by the hepatic microsomal mixed function oxidase system in adults. This metaboiic degradation is complex; xanthine oxidase is not involved while oxidative processes, both 1and 3- demethylation and hydroxylation, are i m p o r t a n t ? It may be anticipated that theophylline clearance will be impaired and highly variable in the premature newborn infant, as has been shown for other drugs, such as phenytoin metabolized by this enzyme system.~ Limited pharmacokinetic information is available regarding theophylline in the newborn infant but the reported data are consistent with this prediction. 7, 8 We report an infant who developed supraventricular tachycardia during theophylline therapy in association with a high plasma theophylline concentration. It should be emphasized that this serious adverse drug effect occurred while utilizing a theophylline dose which has been recommended, endorsed)' and Widely used. ~ From the Clinical Pharmacology Unit, Royal Children's Hospital, and Special Care Nursery, Mercy Maternity Hospital. *Reprint address: Clinical Phodrmacology Unit, Royal Children's Hospital, Parkvill~e, 3052, Australia.
Vol 92, No. 6, pp. 1016-1018
CASE REPORT A male infant was delivered by cesarean section for fetal distress after spontaneous labor at 31 weeks' gestation. Apgar scores at 1 and 5 minutes were 3 and 8, respectively. Birth weight was 1,420 gm and clinical assessment of maturity was consistent With dates. An umbilical arterial catheter was inserted for 36 hours due to early onset of respiratory distress which abated within 48 hours. Penicillin, 50,000 units, and kanamycin, 10 rag, were given twice daily intramuscularly for five days. Phototherapy was instituted on day 3; the maximum serum bilirubin was 17.1 mg/dl on day 4. Serum electrolytes, glucose, and acidbase studies were within normal limits on repeated occasions during the first four days of life. Apnea commenced at age 10 hours and after five episodes lasting 20 to 30 seconds, theophylline was started at a dose of 5 mg (3.5 mg/kg) orally, every six hours. Five apneic episodes occurred in the 12 hours after institution of theophylline therapy but there was no further apnea. Frequent vomiting (bile stained) occurred from 48 to 96 hours of age. Pulse rate was continuously monitored during theophylline therapy and a moderate sinus tachycardia was noted on the third day of life with a maximum pulse rate 185/minute, leading to cessation of theophylline after the eleventh dose. Three hours later rapid tachycardia was noted and an electrocardiogram showed paroxysmal supraventricular tachycardia at a rate of 320/minute. There was no clinical evidence of cardiac failure. This arrhythmia reverted spontaneously to sinus tachycardia after 10 minutes, but recurred transiently on two occasions over the next hour. Intramuscular digoxin was then commenced, digitalizing dose 60 /~g over 18 hours, maintenance dose 12/~g twice daily. Laboratory studies at
0022-3476/78/0692-1016500.30/0
9 1978 The C. V. Mosby Co.
Volume 92 Number 6
Tachycardia during theophylline therapy
10 17
200 40 "~x
%%
=-"
-40
190
\
E
N%
"\I
\t
180
r
~20 E
.= 17(]
e. o
C~
= 42'3
mg/I
.=
t
tI
16(3 e>, c-
15(~
t
I
"30
2 84
_=
.
~o
~
e-
9
140
to 4 E
LL!LLLIt~ 1
~
2
i
3 Age
_i 4
, 5
i 6
7
tdays ]
Fig. 2. Relationship of mean pulse rate to plasma theophylline concentration. Vertical bars indicate mean • SE of hourly observations of pulse rate over 12-hour periods. Observed (e) and predicted (o) plasma theophylline concentrations are shown. Arrows indicate the time of oral theophylline doses.
2
1 24
48 Time
72
after
last
dose
96
120
(hr.)
_'2 Fig. 1. Semilogarithmic plot of plasma theophylline concentration versus time after the last theophylline dose. the time of the arrhythmia revealed serum sodium 142 mmol/l, potassium 4.7 mmol/l, chloride 107 mmol/l, calcium 6.2 mg/dl, glucose 75 mg/dl, pH 7.35, Paco ~77, and base excess - 2 mmol/1. Chest roentgenogram showed a normal cardiac contour and repeated electrocardiograms were within normal limits. No clinical evidence of cardiac disease was noted in the subsequent hospital course.
E
50
40
0 C 0 0 30 r.c 0 ek-
20
10
E METHODS
O.
Plasma theophylline concentrations were measured by a radioimmunoassay developed by Cook et al? ~ Kinetic constants were derived using the one-compartment o p e n model, ~ assuming rapid and complete absorption of the drug. Predictions of drug accumulation utilized the following equations ~: C% ~ = Xo 9 ( 1 - e " ~ * ) V
(1 - e -kt*)
where Xo and t* are the dose and dosage interval, respectively, C % ~ is t h e peak plasma concentration after the nth dose, k is the elimination rate constant (0.693/t,~), and V the apparent volume of distribution, and C%" = C% x" e -~* where C*'~" is the m i n i m u m plasma concentration after the nth dose.
ILILlll~ll~ Age
(days)
Fig. 3. Predicted accumulation of theophyll{ne in plasma with repeated doses. Solid circles indicate observed plasma theophylline concentrations. Calculated peak (o) and trough (h) plasma theophylline concentrations were derived according to the onecompartment kinetic model. RESULTS In Fig. 1 is shown a semilogarithmic plot o f plasma theophylline concentration measured at intervals after the last dose. T h e p l a s m a theophylline half-life was 24.7 hours. Linear extrapolation of this curve to time zero indicates that shortly after the last dose the plasma theophylline concentration was 42.3 m g / L Slow absorption or zero-order metabolism of theophylline at high p l a s m a concentrations would result in an actual plasma
10 18
Loughnan and M c Namara
concentration somewhat less than that predicted. Nevertheless it is clear, at the time of the arrhythmia, that the plasma theophylline concentration was far in excess of the assumed therapeutic range of 7 to 14 rag/1. 7 Substitution of Cm~ in equation 1 yields the following results: plasma theophylline clearance, kV, 12.7 ml/kg/hour, volume of distribution; 0.45 1/kg. The mean _+ SE of hourly pulse rates plotted for 12hour intervals from birth is shown in Fig. 2. Little change in pulse rate was seen until after the tenth dose. Despite cessation of theophylline a marked tachycardia ensued followed abruptly by the arrhythmia. This occurred when the calculated plasma theophylline concentration was > 40 mg/1. The subsequent sinus tachycardia resolved as plasma theophylline concentrations decreased. The pattern of drug accumulation (Fig. 3) in this patient is predicted using equations 1 and 2. Theophylline was stopped after only about three half-lives, so that steadystate plasma concentrations had not yet been attained. The calculated peak steady-state plasma concentration was 50.2 nag/l, and had theophylline been continued, more serious toxicity would have been likely. DISCUSSION Theophylline, a phospho-diesterase inhibitor, has complex effects on the cardiovascular system and is known to cause tachyarrhythmias. 12 13 There is a good relationship between plasma concentration and adverse effects, :~with minor toxicity occurring above 15 rag/1 and serious toxicity above 30 to 40 mg/1. Supraventricular tachycardia is uncommon in the premature infant, and as no other predisposing factor was observed, it is likely that the arrhythmia was a toxic effect of theophylline. The dose of this drug used in earlier studies in the prematt/re newborn I may produce toxicity, and, more recently, lower doses (2 mg/kg/12 hours) have been recommended based on limited kinetic data in a small number of infants2 ~ The latter dose would have produced a steady state plasma theophylline concentration of about 13 mg/1 in our infant. The use of clinical observation to anticipate and avoid theophylline toxicity has been suggested, 1 but definite clinical manifestations do not always precede serious toxicity in adults. 3 We suggest that this is also true in the newborn infant. Until dosage recommendations for theophylline are more soundly based, plasma theophylline concentrations should be measured in all premature infants receiving this
The Journal of Pediatrics June 1978
drug. We can highlight (Fig. 3) the extent to which drug accumulation may be anticipated when drugs with long half-lives are administered at frequent intervals in the newborn infant. Monitoring of plasma theophylline concentrations is indicated in the early days of therapy when drug accumulation is likely as the steady state is approached. The materials for the radioimmunoassay of theophylline were generously supplied by Dr. C.E. Cook, Research Triangle Institute, North Carolina. The secretarial help of Norma Downey was appreciated. REFERENCES
1. Shannon DC, Gotay F, Stein IM, Rogres MC, Todres ID, and Moylan F: Prevention of apnea and bradycardia in low birthweight infants, Pediatrics 55:589, 1975. 2. Kuzemko JA, and Paala J: Apnoeic attacks in the newborn treated with theophylline, Arch Dis Child 48:404, 1973. 3. ZwillichCW, Sutton FD, Neff TA, Cohn WM, Matthay RA, and Weinberger MM: Theophylline-induced seizures in adults. Correlation with serum concentrations, Ann Intern Med 82:784, 1975. 4. Jacobs M, Senior RM, and Kessler G: Clinical experience with theophylline, JAMA 235:1983, 1976. 5. Jenne JW, Nagasawa HT, and Thompson RD: Relationship or urinary metabolites of theophylline to serum theophylline levels, Clin Pharmacol Ther 19:375, 1976. 6. Loughnan PM, Greenwald A, Purton WW, Watters G, and Neims AH: Pharmacokinetic observations of phenytoin in the newborn and young infant, Arch Dis Child 52:302, 1977. 7. Aranda JV, Sitar DS; Parsons WD, Loughnan PM, and Neims AH: Pharmacokinetic aspects of the0phylline in premature newborns, N Engl J Med 295:413, 1976. 8. GiacoiaG, Jusko WJ, Menke J, and Coup JR: Theophylline pharmacokinetics in premature infants with apnea, J P~r)IA'rR89:829, 1976. 9. Lucey JF: Xanthine treatment of apnea of prematurity, Pediatrics 55:584, 1977. 10. CookCE, Twine ME, Myers M, Amerson E, Kepler JA, and Taylor GF: Theophylline radioimmunoassay, Res Commun Chem Pathol Pharmacol 13:497, 1976. 11. Gibaldi M, and Perrier O: Pharmacokinetics, in Swarbrick J, editor: Drugs and the pharmaceutical sciences, Vo! 1, New York, 1975, Marcel Dekker Inc, p 97. 12. Hendeles E, Bighley L, Richardson RH, Hepler CD, and Carmichael J: Frequent toxicity from IV aminophylline infusions in critically ill patients, Drug Intell Clin Pharm 2:12, 1977. 13. Ritchie JM: Central nervous system stimulants, the xanthines, in Goodman LS and Gilman A, editors: The pharmacologic basis of therapeutics, ed 5, New York, 1975, The Macmillan Co, p 367.