CLINICAL EXPERIENCE WITH NEUROGENIC CARDIAC ARRHYTHMIAS* A LTHOUGH ...

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CLINICAL EXPERIENCE WITH
NEUROGENIC CARDIAC ARRHYTHMIAS*
RONALD L. KATZ
Department of Anesthesiology
Columbia University College of Physicians and Surgeons
Anesthesiology Service
Presbyterian Hospital in the City of New York
New York, N. Y.
ANESTHETICS OTHER DRUGS
AND
A LTHOUGH occasional ventricular ectopic beats are frequently seen
during general anesthesia and surgical operation, persistent ven-
tricular arrhythmias are rare in the well-managed patient. This paper
will deal with some of the ventricular arrhythmias that may be seen
during anesthesia and operation. Although the major emphasis will be
on man, experiments in animals will be discussed where they help eluci-
date the mechanism of the arrhythmia.
Running through this discussion will be three basic themes. The
first is that although the arrhythmias appear similar in terms of their
electrocardiographic manifestations, the mechanisms responsible for the
various arrhythmias differ. The second is that most of these arrhythmias
can be explained in terms of an imbalance of the autonomic nervous
system. Sympathetic predominance may occur because of increase in
sympathetic activity or decrease in parasympathetic activity. Similarly,
parasympathetic predominance may be either absolute or relative. The
arrhythmias to be discussed are more commonly produced by sympa-
thetic predominance. The final theme is that although attention is natur-
ally focused on the heart as the site of ectopic activity, the arrhythmias
may be due to changes occurring not only in the heart but also in the
central nervous system as well as in the periphery. All three of these
areas must be considered in order to understand the arrhythmias.
Anesthetic agent itself. Under suitable conditions, cardiac arrhyth-
mias may be seen in the presence of most anesthetic agents. However,
there is a marked variation in the propensity to produce arrhythmias.
Mechanisms
*Presented at the Conference on and Management of Arrhythmias, held by the New
York Heart Association at the Hotel Waldorf-Astoria, New York, N. Y., January 24, 1967.
The studies reported in this paper were supported in part by Public Health Service Research
Grant GWO09069 from the National Institutes of Health.
Bull.N.Y.Acad.Med.
NEUROGENIC CARDIAC ARRHYTHMIAS I I 07
For example, the inhalation anesthetics-cyclopropane, trichlorethylene,
halopropane, and teflurane-are all capable of producing arrhythmia.
With cyclopropane or trichlorethylene, arrhythmias are usually seen
only when excessive concentrations are used. Therefore, when arrhyth-
mias are produced by these substances, it is usually possible to lower the
concentration of the anesthetic to a level at which the arrhythmia dis-
appears but the patient is still adequately anesthetized for the surgical
procedure. This is not the case with teflurane or halopropane. Arrhyth-
mias may be seen at concentrations that are not excessive in terms of
depth of anesthesia. Nitrous oxide and diethyl ether rarely produce
arrhythmia in and of themselves.
Halopropane has been studied in an attempt to determine the mech-
anism by which it produces arrhythmia. Ventricular arrhythmias are
seen in 40 to 50 per cent of patients receiving this drug.1 2 In the
cat, the incidence of arrhythmia produced by halopropane is approxi-
mately 6o per cent.3 The halopropane arrhythmia was shown to be a
blood pressure-sensitive phenomenon in some animals.3 Lowering the
arterial pressure, by a variety of methods, eliminated the arrhythmia
in 7 of 25 cats. In the remaining animals, the arrhythmia could not be
demonstrated to be sensitive to changes in blood pressure. The halo-
propane arrhythmia was not abolished by vagotomy, the intravenous
injection of atropine (2 mg./kg.), or the intravenous injection of o.i
to 0.2 mg./kg. of ethybenztropine, an anticholinergic drug with central
nervous system activity, nor was it abolished by acute bilateral adrenal-
ectomy. The arrhythmia was abolished by the intravenous injection of
small (IO to 20 ,ug./kg.) centrally acting adrenergic blocking doses of
Hydergine. This dose of Hydergine, although producing central adren-
ergic block, did not produce peripheral adrenergic block (i.e., epine-
phrine reversal was not seen after the intravenous injection of I
iig./kg. of epinephrine). The arrhythmia was also abolished by transect-
ing the spinal cord at C1 and destroying the brain or by intracollicular
decerebration, which leaves the pons and medulla intact but removes
the suprapontine structures. Thus, the importance of the central nervous
system and particularly of the superpontine mechanisms was demon-
strated.3 Beattie et al.4 also found that decerebration abolished cardiac
arrhythmias produced by chloroform. By transecting the brain stem at
various levels, they concluded that it was removal of the hypothalamus
that was responsible for the abolition of the chloroform arrhythmias.
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iI iI oo88 RR.. LL.. KKAATTZZ
They also were able to produce extrasystoles by stimulation of the
hypothalamus.
Anesthetic agent plus carbon dioxide. Perhaps the commonest cause
of cardiac arrhythmia in anesthetized patients is the combination of the
anesthetic agent and respiratory acidosis. Price and his coworkers5
showed clearly that the inhalation of carbon dioxide during cyclopro-
pane anesthesia produced cardiac arrhythmia. These workers showed
that the threshold arterial pC02 required to produce arrhythmia varied
from 44 to 72 mm. of mercury, with a mean of 58. They also demon-
strated that the concentration of cyclopropane affected the threshold
pC02 required to produce the arrhythmia; the higher the concentration
of cyclopropane the smaller the increase in pC02 required to produce
arrhythmias.6 The role of the sympathetic nervous system was studied
by these workers, who showed that stellate ganglion block could abolish
the arrhythmias.5
The inhalation of carbon dioxide during halothane anesthesia is
also capable of producing cardiac arrhythmia. With halothane, the
arterial pC02 required to produce cardiac arrhythmia was 6o to 140
mm. of mercury with a mean of 92.7
The anesthetic agent-carbon dioxide arrhythmias and their mech-
anisms have been studied in the cat.8 The inhalation of halopropane
plus io per cent carbon dioxide produced ventricular arrhythmias in
99 per cent of the animals studied. The halopropane-carbon dioxide
arrhythmia was not abolished by lowering the blood pressure. In ani-
mals in which the halopropane arrhythmia was abolished by lowering
the blood pressure (see above), the inhalation of i0 per cent carbon
dioxide restored the arrhythmia. The halopropane-carbon dioxide ar-
rhythmia, like the halopropane arrhythmia, was not blocked by vagot-
omy, atropine (2 mg./kg.) ethybenztropine (O.I to 0.2 mg./kg.) or
acute bilateral adrenalectomy. Neither decerebration nor Hydergine
(Io to 20 ,ug./kg.)-each of which did block the halopropane arrhythmia
-was capable of blocking the halopropane-carbon dioxide arrhythmia.
Reserpine pretreatment (o.i mg./kg. intraperitoneally) for one day,
which markedly reduces cerebral and myocardial catecholamines but
has little or no effect on adrenal catecholamine content, did not prevent
the halopropane-carbon dioxide arrhythmia. Neither did acute bilateral
adrenalectomy. However, a combination of these two procedures pre-
vented the halopropane-carbon dioxide arrhythmia. This arrhythmia was
Bull.N.Y.Acad.Med.
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NEUROGENIC CARDIAC ARRHYTHMIAS
also abolished by reserpine pretreatment (o. mg./kg. intraperitoneally)
for seven days, which depletes myocardial and adrenal catecholamines.
It is clear from these results that although the parasympathetic
nervous system does not appear to be involved, the sympathetic nervous
system is intimately involved in the production of the halopropane-
carbon dioxide arrhythmias. Since the arrhythmia was not abolished by
one day of pretreatment with reserpine or by bilateral adrenalectomy
but was abolished by a combination of these procedures, it appears
that a carbon dioxide-induced release of either myocardial or adrenal
catecholamines is capable of producing the arrhythmia. The mechanism
by which excess carbon dioxide causes the release of catecholamine was
also studied.3 Although acidosis may directly release catecholamines
from the adrenals,8 this could not account for the halopropane-carbon
dioxide arrhythmia, since the arrhythmia was abolished by removal
of the pons and medulla. The arrhythmia appeared to be due to an effect
of acidosis on the brain stem; this stimulated vasomotor areas and re-
sulted in an increased sympathetic outflow and release of catechola-
mines. Suprapontine structures were not essential for this arrhythmia
since it was not abolished by intercollicular decerebration. The essential
role of the brain stem was demonstrated by the abolition of the ar-
rhythmia when the pons and medulla were destroyed.
Anesthetic agent plus catecholarmines. Epinephrine is often injected
subcutaneously in order to produce local hemostasis. A dose of epine-
phrine that will not produce arrhythmias by itself may do so in the
presence of cyclopropane or of halogenated hydrocarbon anesthetics.
This phenomenon has been referred to as "sensitization" of the myo-
cardium to the action of catecholamines. The term "sensitization" is a
poor one, but is widely used for lack of a better. The anesthetics that
produce sensitization include trichlorethylene, ethyl chloride, cyclo-
propane, halothane, chloroform, and methoxyflurane (listed in order
of decreasing effect as determined in animal studies).9 In addition to
epinephrine, other catecholamines, such as norepinephrine, isopro-
terenol, epinine, and cobefrine, may produce cardiac arrhythmias in
patients or animals anesthetized with cyclopropane or halogenated
hydrocarbons.
The mechanism of the catecholamine-anesthetic agent arrhythmias
is not yet fully understood. Some of the factors that may have a role
include: i) increased blood pressure,10' 1 2) increased heart rate,11 12
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I I I 0 R. L. KATZ
1110 R.
3) release of potassium from the liver'3-all of which may be induced
by catecholamines. Although the rise in blood pressure is an important
factor in producing these arrhythmias, it is not absolutely essential, since
isoproterenol, a catecholamine that decreases blood pressure is capable
of producing the arrhythmia.'4 Similarly the increase in heart rate, and
the release of potassium from the liver, although important, are not
absolutely essential.
The roles of the alplha-adrenergic and beta-adrenergic stimulating
actions of the catecholamines have been studied.14 At one time the
arrhythmias were believed to be due to stimulation of alpha-adrenergic
receptors, since the catecholamine-anesthetic agent arrhythmias could
be blocked by alpha-adrenergic blocking agents. It is now clear that
this was an indirect (blood pressure) or nonspecific (myocardial de-
pressant) effect of the alpha-adrenergic blockers. Further, alpha-adren-
ergic blocking agents do not block the arrhythmias consistently. Beta-
adrenergic blocking agents do consistently prevent the catecholamine-
anesthetic agent arrhythmias. This action has been attributed to specific
beta-adrenergic receptor blockade. However, the picture is somewhat
clouded by the fact that some of the beta-adrenergic blocking agents
also have a local anesthetic action"'5 16 and quinidinelike action'7-'9 that
may account in part for the antiarrhythmic action.
There is some disagreement concerning the role of the central
nervous system and the autonomic nervous system in the genesis of
the catecholamine-anesthetic agent arrhythmias. It has been reported
that these arrhythmias could be blocked by intercollicular decerebra-
tion, pontine lesions, bilateral thoracic sympathectomy, or visceral
denervation plus bilateral splanchnicotomy.20'21 However, the structures
removed by these procedures are not essential for the production of
the arrhythmias, since ithas been shownthat the arrhythmias canbe pro-
ducedin decerebrate, spinal, or reserpinized animals3 as well asin animals
with denervated hearts22 23 and in the heart-lung preparation.24
Although there are many case reports of arrhythmias or cardiac
arrest following the use of epinephrine for local hemostasis, most of
these are attributed to the use of excessive amounts of catecholamines.
It has been clearly shown that catecholamines may be injected sub-
cutaneously in doses that are sufficient to produce satisfactory local
hemostasis but that will not produce cardiac arrhythmias in patients
anesthetized with halothane or trichlorethylene.5 26
Bull.N.Y.Acad.Med.
NEUROGENIC CARDIAC ARRHYTHMIAS I I I I
Anesthetic agent plus peripheral manipulation. Certain operative
maneuvers may produce cardiac arrhythmias in anesthetized patients.
A common cause is manipulation of the adrenal glands. The arrhythmia
is probably attributable to the release of catecholamines by the manipu-
lation. This arrhythmia may be seen in patients with normal adrenal
glands as well as in those who have pheochromocytoma. In the latter,
large amounts of catecholamines may be released and may produce
bizarre ventricular arrhythmias. Cardiac arrhythmia may also be seen
during manipulation or scraping of bone, traction on the abdominal
viscera or mesentery, and stimulation of the epiglottis and larynx during
intubation.
Anesthetic agent plus succinylcholine. Bradycardia, sinus arrest,
supraventricular and ventricular arrhythmia have been reported follow-
ing the injection of succinylcholine in infants, children, and adults
anesthetized with nitrous oxide, trichlorethylene, ether, halothane, or
cyclopropane. It has also been possible to produce similar arrhythmias
in the cat, dog, and monkey.2743 In monkeys anesthetized with halo-
thane, Galindo and Davis34 found that succinylcholine lowered the
threshold of cardiac excitability and produced severe ventricular ar-
rhythmias. They explained the cardiac effects of succinylcholine in
terms of changes in the permeability of the membrane for potassium,
with resultant loss of potassium from the cell, decrease in resting mem-
brane potential, and increase in serum potassium. They also felt that
succinylcholine produced its effects by sympathetic postganglionic
stimulation and by a direct effect on the myocardium.
Dowdy and Fabian30 found that succinylcholine produced ven-
tricular arrhythmia in the digitalized cat, dog, and man. They discussed
the similarity in the effects of digitalis, acetylcholine, and succinyl-
choline on the flux of potassium across membranes and they suggested
that the digitalis-succinylcholine arrhythmia might be related to myo-
cardial ionic movements of potassium.
Studies in our laboratory demonstrated that the injection of suc-
cinylcholine produced ventricular arrhythmias in decerebrate cats
anesthetized with halopropane. A rise in blood pressure was also seen.
The injection of succinylcholine after alpha-adrenergic blockade pro-
duced a fall rather than a rise in blood pressure. However, the halopro-
pane-succinylcholine arrhythmias were not prevented consistently. Sub-
sequent injection of a beta-adrenergic blocking agent prevented the
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I I I 2 R. L. KATZ
'liz R. L. KATZ
succinylcholine arrhythmia but did not abolish the fall in blood pressure;
the latter was eliminated by the injection of atropine. The halopropane-
succinylcholine arrhythmias were also prevented by beta-adrenergic
blockade alone. The effects of succinylcholine are therefore believed to
be due to the release ofacetylcholine and catecholamines by a ganglionic
stimulating action. Craythorne et al.29 explained the succinylcholine
arrhythmias in terms of stimulation of the sympathetic and parasympa-
thetic nervous systems. Similar conclusions were reached by Williams
et al.,/ who found that ganglionic blockade depressed the circulatory
responses to succinylcholine.
The mechanism of cardiac arrhythmia induced by repeated injec-
tions of succinylcholine, but not by the first injection, was studied by
Schoenstadt and Whitcher.32 These investigators showed that suc-
cinylcholine did not produce cardiac arrhythmia in patients who re-
ceived hexafluorenium, a substance that inhibits the hydrolysis of
succinylcholine to succinylmonocholine and choline by pseudocholines-
terase. Patients given acetylcholine did not develop arrhythmia after
a second dose of acetylcholine, but patients given succinylcholine
after acetylcholine developed arrhythmia. It was therefore suggested
that choline produced by the hydrolysis of succinylcholine sensitizes
the patient to subsequent doses of succinylcholine and that, after sensi-
tization by choline, the arrhythmia is produced by the entire succinyl-
choline molecule.
Atropline and gallamine. The intravenous injection of gallamine
during cyclopropane anesthesia will produce ventricular arrhythmia.85
This effect has been attributed to the vagal blocking action of galla-
mine. The mechanism of arrhythmia is believed to be similar to that
seen after the injection of atropine;3' 37 the vagal blockade results in a
relative sympathetic predominance.
Vasopressin. The injection of Pituitrin during anesthesia has pro-
duced cardiac arrhythmia. Since this substance contains a mixture of
vasopressin and oxytocin, there was some question as to which com-
ponent was responsible for the arrhythmia. It was demonstrated that
vasopressin was responsible for the arrhythmia, an effect that may be
due to its constrictive action on the coronary arteries.
Central nervous system. The role of stimulation of the central
nervous system in the production of cardiac arrythmia can be seen
in a variety of ways. During surgical operations, stimulation of the
Bull.N.Y.Acad.Med.
NEUROGENIC CARDIAC ARRHYTHMIAS I I I 3
brain stem or of the hypothalamus will often produce ventricular
arrhythmia. In addition, in patients receiving electroconvulsive therapy
treatment, cardiac arrhythmia was seen in 33 per cent of 400 treat-
ments.38 Cardiac arrhythmia is also seen after the injection of picrotoxin
given for the treatment of coma caused by barbiturates.
The roles of the sympathetic and parasympathetic nervous systems
in the production of centrally induced cardiac arrhythmia have been
carefully studied in animals by Bircher et al.39 These workers produced
cardiac arrhythmia by injecting pentylenetetrazol, picrotoxin, and de-
slanoside into the fourth ventricle or intravenously. Except for the
intravenous deslanoside the arrhythmias produced were central in
origin and were mediated by the parasympathetic and sympathetic
nervous systems; the former dominated. In order to block the arryth-
mias in all the animals, both parasympathetic and sympathetic blocking
agents or procedures were required.
Alkalosis, digitalis, andpotassium. The relation between digitalis and
potassium is well known. Patients who are well digitalized but who be-
come hypokalemic may develop digitalis toxicity. Arrhythmia may also
be seen in digitalized patients who are hyperventilated during anes-
thesia. The alkalosis produced by hyperventilation induces a decrease
in plasma potassium, which may result in digitalis toxicity and cardiac
arrhythmia. In addition, digitalized patients receiving carbohydrates
(glucose infusion) may sometimes develop arrhythmia. When carbo-
hydrates are metabolized, the carbohydrates and potassium enter the
cell, presumably under the influence of insulin. This produces a de-
crease in extracellular potassium that may be responsible for cardiac
arrhythmia.
TREATMENT OF CARDIAC ARRHYTHMIAS SEEN DURING ANESTHESIA
Drugless treatment. The most logical and physiological method of
treating the cardiac arrhythmias that appear during anesthesia is to
eliminate the cause of the arrhythmia. In the vast majority of cases this
simple and obvious maneuver can easily be accomplished. For example,
with anesthetics that produce arrhythmias when given in excessive
concentration, merely lowering the concentration will abolish the ar-
rhythmia. In some cases it may be preferable to change to another
agent. If the arrhythmia is due to release of catecholamine, induced
by an elevated level of carbon dioxide, elimination of the excess carbon
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1114 R. L. KATZ
1114 R. L. KATZ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
dioxide by hyperventilation and restoration of a normal arterial pC02
will abolish the arrhythmia. Where the arrhythmia is due to the injec-
tion of catecholamine, stopping the injection of catecholamines and
ventilating the patient with oxygen will usually result in a return to
normal sinus rhythm. If arrhythmias are due to adrenal manipulation
or abdominal exploration, cessation of these maneuvers will abolish the
arrhythmia. Thus, it is clear that in the vast majority of cases the ar-
rhythmia can be eliminated merely by removal of the cause.
Antiarrhythmic drugs may be required in situations in which it is
not possible to change the anesthetic management or to discontinue
surgical manipulation. Sometimes the deleterious cardiovascular effects
produced by the arrhythmia require a more rapid restoration of normal
sinus rhythm than can be achieved by modifying the anesthetic manage-
ment. In these situations antiarrhythmic drugs are useful.
Procaine and procaine amide. A number of drugs have been pro-
posed for the treatment of cardiac arrhythmias seen during anesthesia.
Local anesthetics and their derivatives have been especially valuable.
Procaine (Novocaine) was used by Burstein40 to treat cardiac ar-
rythmia in anesthetized patients. There are certain drawbacks to its use.
These include: rapid hydrolysis and therefore brief duration of action;
stimulation of the central nervous system, which may progress to con-
vulsions; hypertension; tachycardia. Study of the products of procaine
hydrolysis has demonstrated that diethylaminoethanol had antiarrhyth-
mic action.41 Study of its derivatives resulted in the development of
procaine amide,42 which is an effective and commonly used antiarrhyth-
mic drug in unanesthetized patients. However, its usefulness during
anesthesia if often limited by hypotension.
Lidocaine and QX-572. In our operating rooms the most commonly
used antiarrhythmic drug is lidocaine (Xylocaine). This substance is
especially suitable for the treatment of cardiac arrhythmias occurring
during anesthesia and operation. Its duration of action is brief (io to
20 minutes) and it does not usually decrease blood pressure. In a study
comparing the effects of procaine amide and lidocaine in man,43 pro-
caine amide was found to decrease myocardial contractile force and
blood pressure. However, lidocaine, in antiarrhythmic doses, had little
or no effect on myocardial contractile force, and it increased blood
pressure slightly. Because of its relative lack of toxicity and its great
effectiveness, lidocaine is probably the antiarrhythmic drug of choice in
Bull.N.Y.Acad.Med.
NEUROGENIC CARDIAC ARRHYTHMIAS I I I 5
anesthetized patients. Frequently this agent is given to abolish the ar-
rhythmia immediately. It is then possible to eliminate the cause of the
arrhythmia in the IO to 20 minutes during which a normal sinus rhythm
can be expected. Where it is not possible to eliminate the cause of the
arrhythmia, repeated doses of lidocaine can be given.
An effective, safe, long-acting antiarrhythmic agent, suitable for use
in anesthetized patients, would be of great value. Lidocaine analogs
have been studied in an attempt to produce an agent that was as safe
and effective as lidocaine but longer-acting. QX-572, which resulted
from these studies, was found to be an effective antiarrhythmic agent
in animals"4 and in man.2 When infused into the coronary artery of
the dog, QX-572 produced a positive inotropic effect and increased
cardiac output and coronary blood flow. After intravenous injection
peripheral vasodilation was seen. This drug appeared to possess many
of the qualities of an ideal antiarrhythmic agent. It was, however, aban-
doned because its gastric absorption was poor, thus limiting its use
mainly to intravenous injection. Other analogs of lidocaine are currently
under investigation.
Oxytocin. The polypeptide vasopressin is known to produce cardiac
arrhythmia when injected duringanesthesia. However, oxytocin (Synto-
cinon), which differs from vasopressin by only two amino acids, has
an antiarrhythmic effect. Oxytocin was capable of blocking halopro-
pane, halopropane-epinephrine, and halopropane-carbon dioxide ar-
rhythmias in the cat.45 It was also effective in the treatment of cardiac
arrhythmias seen during anesthesia and operation.45 However, its gen-
eral usefulness was limited because of a brief duration of action (ap-
proximately Io minutes) and the development of tachyphylaxis follow-
ing repeated doses.
Mephentermine and diphenyihydantoin. Two agents that have been
used to treat cardiac arrhythmias are mephentermine (Wyamine), a
vasopressor and sympathomimetic agent48 and diphenylhydantoin (Di-
lantin), an anticonvultant.47 There are not yet sufficient studies to
determine the value of these agents in anesthetized patients.
Beta-adrenergic blocking agents. There is a great deal of interest
and activity in the use of beta-adrenergic blocking agents for the treat-
ment ofcardiac arrhythmia. Itiswell established that the beta-adrenergic
blocking agents have an antiarrhythmic effect in situations in which the
arrthythmia is believed to be due to increased sympathetic activity. The
Vol.43,No.12,December 1967