ANESTH ANALG

1981;M):517-20

Halothane-Induced Cardiac Arrhythmias following

Administration of Aminophylline in Experimental
Animals
Joseph A. Stirt, MD,* Jack M. Berger, MD, PhD,t Steven D. Roe, BS,t
Sandra M. Ricker, BS,$ and Stuart F. Sullivan, MD§

STIRT, J. A., BERGER, J. M., ROE, S.D., RICKER,S. M., AND SULLIVAN, S. F.: Halothane-induced cardiac arrhythmias
following administration of aminophylline in experimental animals. Anesth Analg 1981;60:517-20.

Cardiac arrhythmias often occur when patients receiving aminophylline are anesthetized with halothane. This animal
study was designed to define what constitute arrhythmogenic doses of aminophylline when administered before
halothane anesthesia. One group of six dogs was given aminophylline, 10 mg/kg IV, followed in 3 minutes by
inhalation of 1% halothane. In two additional groups of dogs the same experimental protocols were used except that
aminophylline doses were 25 mg/kg and 50 mg/kg. In the first group, two of six dogs developed ventricular
arrhythmias during induction of halothane anesthesia. One of six dogs given 25 mg/kg of aminophylline developed a
ventricular arrhythmia. Three of six dogs given 50 mg/kg of aminophylline developed ventricular arrhythmias.
Sustained ventricular arrhythmias occurred in 33Y0 of the animals with “therapeutic” serum theophylline levels and in
33% of the animals with “toxic” levels. Induction of halothane anesthesia within 15 minutes of aminophylline
administration may be dangerous and is likely to result in severe and persistent ventricular arrhythmias.

Key Words: PHARMACOLOGY: aminophylline; ANESTHETICS, Volatile: halothane; HEART: arrhythmia.

I S THE COMBINED use of aminophylline and hal-

othane dangerous? If so, what are the dangers, and
under what conditions do they exist? Recent reports
(1, 2 ) indicate that severe cardiac arrhythmias often
occur when patients receiving aminophylline are sub-
sequently anesthetized with halothane. In animals,
aminophylline causes ventricular arrhythmias when
given in large doses during halothane anesthesia (3-
5 ) . Previous studies from our laboratory (6, 7) have
shown that aminophylline given in therapeutic
amounts after prolonged halothane anesthesia does
not produce arrhythmias but that toxic aminophylline
doses are arrhythmogenic when given immediately
after both short (15 minutes) and long (6 hours)
periods of halothane anesthesia.
Although aminophylline is used during anesthesia
* Assistant Professor.
t Research Associate.
$ Technical Services Supervisor.
5 Professor.
Supported by a grant from the UCLA Department of Anesthe-
siology.
Received from the Department of Anesthesiology, UCLA School
of Medicine, Los Angeles, California 90024. Accepted for publica-
tion March 3, 1981.
Reprint requests to Dr. Stirt.
in the management of bronchospasm, a more frequent
situation is that represented by a patient who needs
general anesthesia but who has recently received
aminophylline. This study was designed to ascertain
what doses of aminophylline administered before
anesthesia are arrhythmogenic during halothane an-
esthesia induction, and how soon after aminophylline
administration such arrhythmias are likely to occur.
Methods and Materials
The experiment consisted of three parts. Six differ-
ent dogs were used in each of the three parts.
Part 1
Six mongrel dogs (average weight 21.0 kg) were
given sodium thiopental, 20 mg/kg IV, followed by
succinylcholine, 1 mg/kg IV. Endotracheal intubation
was performed immediately with a cuffed orotracheal
tube, an airtight seal was produced, and the animals
were ventilated with a Harvard animal respirator de-
livering air at 12 breaths/min. Tidal volume was
adjusted to produce an end-tidal COz of 4.5% as
measured by an on-line gas mass spectrometer (Per-
kin-Elmer MGA-1000). No further changes in res-
ANESTHESIA AND ANALGESIA
Vol 60, No 7, July 1981 51 7
 AMINOPHYLLINE, HALOTHANE, AND ARRHYTHMIAS

pirator settings were made during the study. A lead
I1 electrocardiogram was attached and recorded
throughout the study.
A femoral artery catheter was inserted and attached
to a pressure transducer (Bentley Trantec), and sys-
tolic, diastolic, and mean arterial pressure (MAP) were
recorded throughout the study. Heart rate (HR) was
measured from the blood pressure tracing. A periph-
eral intravenous route was secured and 0.9% NaCl
infused at 100 ml/hr.
When these preparations had been completed, an
arterial blood sample was drawn from the femoral
artery catheter for analysis of oxygen(P0,) and carbon
dioxide (Pco,) tension and serum pH, ionized calcium,
and potassium levels. Between 10 and 15 minutes
after thiopental administration, aminophylline (the-
ophylline ethylenediamine, Invenex), 10 mg/kg, was
infused intravenously over 1 minute. One minute
after completion of aminophylline administration, a
second arterial blood sample was obtained and ana-
lyzed for blood gas tensions and pH, and, in addition,
serum levels of theophylline were determined in du-
plicate by a homogenous enzyme immunoassay
(EMIT, Syva Company, Palo Alto, CA) in which
competitive protein binding was determined spectro-
photometrically using a labeled enzyme and specific
binding antibody (8).
Immediately following the second blood sample,
1% halothane was added to the inspired air mixture.
Inspired and mixed-expired halothane concentrations
were measured each minute for the duration of the
experiment (30 minutes of halothane anesthesia) with
a gas mass spectrometer. Arterial blood samples were
obtained 2, 5, 10, 15, and 30 minutes after halothane
was begun, and analyzed for 0 2 and CO2 tension
levels, pH, and serum theophylline concentration.
Serum potassium and ionized calcium levels were also
measured in the 15-minute sample. Student’s t-test
was used to compare the significance of differences
between groups.
Part 2
The same experimental protocol was followed as in
part 1, except that the aminophylline dose was in-
creased to 25 mg/kg.
Part 3
The same experimental protocol was followed as in
part 1, except that the aminophylline dose was in-
creased to 50 mg/kg.
Results
In part 1 of the experiment, two of the six dogs
developed ventricular arrhythmias (Table 1).In part
2, one of the six dogs developed a ventricular arrhyth-
mia after aminophylline and halothane (Table 2). In
part 3, three of the six dogs developed ventricular
arrhythmias (Table 3).
In animals that developed arrhythmias, there was
no significant change ( p < 0.05) in ionized serum
calcium levels from control values in any of the three
parts.
In all 18 animals in the study blood pressure began
decreasing and heart rate began increasing 20 to 30
seconds after beginning the aminophylline infusion.
Both blood pressure and heart rate stabilized within

TABLE 1
Arrhythmias, Time of Onset of Arrhythmias after Beginning Administration of Halothane, Serum Theophylline Levels, Expired
Halothane Concentrations, Arterial Blood Gas Tensions, Heart Rate (HR), and Mean Arterial Blood Pressure (MAP) at Time
Arrhythmias Occurred after Aminophylline, 10 mg/kg*
Arterial
Theophylline levels Mixed-expired blood gas
Study Arrhythmia Time of onset halothane tensions pH Ca2+ K+ HR MAP
no. of arrhythmia at time of
Peak Time of arrhythmia
Po2 pc4
value arrhythmia
min mg/L Yo torr rneq/L beats/ torr
min
1 - - 25 11 0.72 91 29 7.53 2.09 3.3 216 100
2 PVCs, bigeminy 5 17 11 0.60 76 33 7.45 2.21 4.4 220 160
3 1 PVC 15 23 15 0.72 86 34 7.53 2.19 3.7 216 130
4 - - 21 14 0.70 93 31 7.40 2.21 4.2 168 110
5 PVCs, bigeminy 11 18 11 0.69 97 29 7.44 2.09 4.2 228 135
6 - - 26 13 0.63 82 33 7.45 2.36 4.4 168 110

In animals without arrhythmias, values are those 10 minutes after beginning administration of halothane. In all cases, potassium
and ionized calcium levels were measured 15 minutes after beginning administration of halothane.

ANESTHESIA AND ANALGESIA

518 Vol 60, No 7, July 1981
 STIRT ET AL

TABLE 2
Arrhythmias, Time of Onset of Arrhythmias after Beginning Administration of Halothane, Serum Theophylline Levels, Expired
Halothane Concentrations, Arterial Blood Gas Tensions, HR, and MAP at Time Arrhythmias Occurred after Aminophylline, 25
mg/kg*
Arterial blood
Theophylline levels Mixed- gas tensions
Time of expired
Study
no. Arrhythmia onset of halothane pH Ca2' K' HR MAP
Time of
arrhythmia
vpae(zt arrhyth-
mia
at time
of arrhythmia PO? PCOI

min mg/L % torr meq/L beats/min torr

- - 48 38 0.82 98 25 7.47 1.95 3.7 252 90
- - 54 48 0.79 94 27 7.44 1.59 3.7 228 85
- - 45 27 0.68 84 29 7.41 2.27 4.1 240 95
Bigeminy 8 60 34 0.74 97 27 7.51 2.14 4.7 264 100
Bigeminyt - 66 66 . 0.69 93 31 7.45 2.27 4.8 180 60
- - 57 44 0.59 94 31 7.53 2.18 3.8 240 90

* In animals without arrhythmias, values are those 5 minutes after beginning administration of halothane. In all cases, potassium
and ionized calcium levels were measured 15 minutes after beginning administration of halothane.
t Arrhythmia before halothane.

TABLE 3
Arrhythmias, Time of Onset of Arrhythmias after Beginning Administration of Halothane, Serum Theophylline Levels, Expired
Halothane Concentrations, Arterial Blood Gas, Tensions, HR, and MAP at Time Arrhythmias Occurred after Aminophylline, 50
mg/kg*
Theophylline levels b$mz; gas tensions
Arterial blood

Study Arrhythmia Time of onset

pH Ca++ K+ HR MAP
no. of arrhythmia Peak
value ar:r-
Time of
at time of
arrhythmia pcOz

min mg/L % torr meq/L beats/rnin torr

1 Bigeminy 10 60 44 0.69 86 30 7.38 2.14 4.5 262 120
2 Bigeminy 8.5 102 63 0.68 90 27 7.41 2.31 4.0 240 95
3 - - 115.5 48 0.71 84 32 7.39 2.19 4.0 144 70
3 PVCs, bigeminy 18 75 54 0.69 94 26 7.42 2.20 4.1 240 90
5 - - 108 66 0.79 105 22 7.49 2.12 4.2 204 75
6 - - 96 48 0.73 84 35 7.30 2.12 3.7 192 70

In animals without arrhythmias, values are those 15 minutes after beginning administration of halothane. In all cases, potassium
and ionized calcium levels were measured 15 minutes after beginning administration of halothane.

2 minutes after completion of the aminophylline in-
fusion, before beginning administration of halothane.
There was no significant difference in control heart
rates between animals that developed arrhythmias
and those that did not. However, animals developing
arrhythmias had an average heart rate of 244 & 6
beats per minute (mean & SE) at the time ectopy
began. Animals without arrhythmias had an average
heart rate of 204 f 10 beats per minute at comparable
times. This difference was statistically significant ( p
C 0.05).
Discussion
Therapeutic serum theophylline levels in conscious
humans are 10 to 20 mg/L (9). In our study, in animals
that had arrhythmias following aminophylline, 10
mg/kg, serum theophylline levels were 11 mg/L at
the time arrhythmias occurred.
The occurrence of arrhythmias at "therapeutic"
serum theophylline levels in 33% of the animals after
short (5 to 11 minutes) periods of halothane exposure
when aminophylline had been given before halothane
contrasts sharply with the results of our previous
studies (6, 7),in which aminophylline was adminis-
tered during halothane anesthesia. In the latter studies
aminophylline, 10 mg/kg, produced similar therapeu-
tic serum theophylline levels but resulted in no ar-
rhythmias, although toxic serum theophylline levels
(more than 20 mg/L) were arrhythmogenic.
The time of onset of arrhythmias and their duration

ANESTHESIA AND ANALGESIA

Vol 60. No 7, July 1981 519
 AMINOPHYLLINE, HALOTHANE, AND ARRHYTHMIAS
in this study varies considerably from that seen in a
previous study (7). In all cases but one in the present
study, ventricular arrhythmias began 5 to 18 minutes
following induction of halothane anesthesia (8 to 21
minutes following aminophylline administration),
and always persisted for the duration of the experi-
ment. When aminophylline was administered during
halothane anesthesia (7), arrhythmias in eight of nine
animals began within 3 minutes of aminophylline
administration, and each time spontaneously resolved
within 2 minutes.
The pharmacokinetics of theophylline in dogs, de-
scribed earlier (6),may be important in the genesis of
arrhythmias. The decay curve of intravenous theoph-
ylline consists of two components, a rapid phase
representing drug redistribution and a slow phase
reflecting drug elimination and metabolism. The rapid
phase lasts approximately 15 minutes (6).
In both our previous (7) and present studies, ven-
tricular arrhythmias always occurred during or min-
utes after the rapid phase of, theophylline decay,
within 21 minutes of aminophylline administration.
Ventricular vulnerability seems greatest when serum
and, presumably, myocardial theophylline levels are
changing most rapidly.
As both blood pressure and heart rate stabilized in
all animals following the aminophylline infusion be-
fore halothane administration, cardiovascular re-
sponses to the relatively rapid rate of infusion prob-
ably did not contribute to the occurrence of arrhyth-
mias. However, the significantly higher heart rates in
animals that developed arrhythmias would seem to
indicate that a marked tachycardiac response to ami-
nophylline is more likely to be associated with sub-
sequent arrhythmic activity.
In summary, halothane anesthesia was induced fol-
lowing intravenous administration of lo-, 25-, and 50-
ANESTHESIA AND ANALGESIA
520 Vol60, No 7 , July 1981
mg/kg doses of aminophylline which produced serum
theophylline levels in both the therapeutic and toxic
ranges. Ventricular arrhythmias occurred in 33% of
the animals with therapeutic serum theophylline lev-
els (10 to 20 mg/L) and 33% of the dogs with toxic
(more than 20 mg/L) levels. Halothane anesthesia
induction within 15 minutes of aminophylline admin-
istration may be dangerous and is likely to result in
severe and persistent ventricular arrhythmias.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the expert technical assist-
ance of Aleece €. Townsend and Brad L. Whizin, and the secretarial
skill of Patricia A. Herberg.
REFERENCES
1. Barton MD. Anesthetic problems with aspirin-intolerant pa-
tients. Anesth Analg 1975;54:376-80.
2. Roizen MF, Stevens WC. Multiform ventricular tachycardia
due to the interaction of aminophylline and halothane. Anesth
Analg 1978;57:738-41.
3. Takaori M, Loehning RW. Ventricular arrhythmias during
halothane anaesthesia: effect of isoproterenol, aminophylline,
and ephedrine. Can Anaesth SOCJ 1965;12:275-80.
4. Takaori M, Loehning RW. Arrhythmias induced by amino-
phylline during halothane anaesthesia in dogs. Can Anaesth
SOCJ 1967;14:79-86.
5. Sharma PL. Effect of some adrenergic receptor antagonists on
aminophylline-induced ventricular arrhythmias in dogs an-
aesthetized with halothane in oxygen. Indian J Med Res
1969;57883-92.
6. Stirt JA, Berger JM, Ricker SM, Sullivan SF. Aminophylline
pharmacokinetics and cardiorespiratory effects during halo-
thane anesthesia in experimental animals. Anesth Analg 1980;
59:186-91.
7. Stirt JA, Berger JM,Ricker SM, Sullivan SF. Arrhythmogenic
effects of aminophylline during halothane anesthesia in exper-
imental animals. Anesth Analg 1980;59:410-16.
8. Gushaw JB, Hu MW, Singh P, Miller JG, Schneider RS. Ho-
mogenous enzyme immunoassay for theophylline in serum.
Clin Chem 1977;23:1144.
9. Piafsky KM, Ogilvie RI. Dosage of theophylline in bronchial
asthma. N Engl J Med 1975;292:1218-22,