Download Electrolytes and pH Changes in Relation to Hypothermic Ventricular

Electrolytes and pH Changes in Relation to
Hypothermic Ventricular Fibrillation
By
BENJAMIN G. COVINO AND A. H.
HEGNAUER
Coronary aiteriovenous electrolyte differences were studied in normo- and hypercnpneic dogs at
normal temperature and at 24 C. The ions measured were sodium, potassium, calcium, magnesium,
ohlorideand hydrogen. Coronary arteriovenouselectrolytedifferencesdid not changeduringcooling in
16 dogs which did not suffer ventricular fibrillation. Ten hypercapneic hypothermic dogs exhibited
characteristic Ca, K, and H ion changes at 24 C. before succumbing to ventricular fibrillation. The
data suggest that ventricular fibrillation at low body temperatures is related to a gain of Ca and a
loss of K and H ions by the hypothermic hypercapneic myocardium.
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I
Thus, pH probably does alter the cellular
equilibrium state for calcium also. That such
changes in the membrane equilibria for potassium and calcium may augment myocardial
excitability and so provoke ventricular arrhythmias has been demonstrated experimentally12 and clinically.18
Electrolyte studies made on hypothermia
animals thus far 1 ' 2 ' 8 do not afford much information about the ionic balance of the myocardium itself. Hence the present study, in
which the concentrations of a number of electrolytes in arterial and coronary venous blood
were measured in groups of normocapneic
and hypercapneic dogs at normal and low
temperatures. The data, presented herein, are
concerned with sodium, potassium, calcium,
magnesium, chloride and hydrogen ions as
affected by temperature and pH.
T has become common observation that
50 to 70 per cent of pentobarbitalized hypothermic dogs succumb to ventricular fibrillation between the temperatures of 25 and 19 C ,
unless pulmonary ventilation is maintained at
a rate sufficient to keep the systemic blood pH
near normal.1"6 The progressive hypercapnea
which otherwise accompanies the fall in body
temperature apparently acts in most instances
as a cardiac excitant. In a systematic study of
the ventricular excitability cycle in hypothermic dogs6"8 it was revealed that a significant rise in excitability occurs at all points in
the cycle except at its very beginning (i.e.,
during the inscription of the electrocardiographic QRS) when hypercapnea develops,
us in spontaneous respiration.
It remained to be determined whether the
augmented ventricular excitability and consequent high incidence of ventricular fibrillation were due to the low pH per se or to some
process which was triggered by the low pH.
In this regard it is known that the potassium
balance of the cell may be altered by the pH
of the surrounding medium.9 Although no
similar studies have been carried out with calcium, Van Slyke10 and McLean and Hastings"
have reported that a fall in pH will slightly
increase the plasma level of ionized calcium.
METHODS
Twenty-six apparently healthy mongrel dogs,
ranging in weight from 7.3 to 17.4 Kg., were anesthetized with intraperitoneal pentobarbital sodium (30
mg./Kg.). The following procedures were carried out
in all dogs prior to immersion in an iced bath: insertion of an endotracheal tube; placement of standard
limb leads for electrocardiographic recording; exposure of both external jugular veins and the right
common carotid artery; insertion of a catheter, bearing a thermocouple at its tip, into the right atrium
via the jugular vein to yield an approximation of
heart temperature. Temperature was continuously
recorded on a Leeds and Northnip Speedomax.
By Cambridge pH recorder, pH measurements
were made on heparinized systemic whole blood at
normal temperature, 35 and 30 C. and every two degrees thereafter to terminus. Coronary venous pH
was measured only at normal temperature nnd at
From the Department of Physiology, Boston
University School of Medicine, Boston, Mass.
This work was supported by Contract AF1S(6OO)66 with the Wright Air Development Center, WrightPatterson Air Force Base, O. and was carried out
during Dr. Covino's tenure of a Life Insurance Medical lloseiirch Fellowship.
Received for publication June 16, 1955.
575
Circulation Hetfnrck, Voiumr III, jVorrmVr /flW
576
MYOCARDIAL ELECTROLYTES AND EXCITABILITY
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24 C. Arterial samples were from the exposed carotid
artery. Coronary venous sampling was performed as
follows: Left thoracotomy was performed at the
fifth intercostal space, the ribs retracted, and the
pericardium incised longitudinally. The great circumflex vein was punctured with a 20 gage needle
bent into a right angle, and the blood was withdrawn
into a heparinized syringe. This simple but direct
method obviated the need for coronary sinus catheterization with its attendant arrhythmia-producing
hazards. Following arterial and coronary venous
sampling, the pericardium was sutured, the ribs
approximated, and the incision closed after reduction
of the pneumothorax. The above procedure was then
repeated after induction of hypothermia, at 24 C.
Artificial respiration with room air was instituted
during open chest procedures, and throughout the
cooling process in those dogs whose blood pH was to
be maintained near normal. The remaining dogs
were allowed to respire spontaneously during cooling
to 25 C , at which time artificial respiration with a
5 per cent COJ-OJ mixture was started in order to
insure adequate oxygenation without a concomitant
rise in pH.
Arterial and coronary venous blood samples were
centrifuged immediately at 3000 r.p.m. for 15 to 20
minutes and the plasma taken for electrolyte and
protein measurements. Sodium and potassium were
determined by means of a Baird flame photometer;
chlorides by the method of Volhard"; total calcium
by the Tisdall method"; and magnesium by the
method of Simonson and associates." Plasma protein
concentration was obtained by the copper sulfate
technic,17 and the ionized calcium concentration was
calculated from the total calcium level and the
plasma protein concentration by means of the nomograms of McLean and Hastings,18 which according to
them is valid at all temperatures in the range of the
present study.
RESULTS
The data reported are from two series of experiments. Series A consisted of 8 dogs in
which arterial pH was maintained between
7.35 and 7.55 via controlled respiration
throughout the period of cold water immersion.
All animals in this series survived to heart
temperatures of 16 to 18 C , at which time the
heart passed into asystole. Series B was composed of 18 dogs in which a state of acidosis
was allowed to develop through spontaneous
respiration during induction of hypothermia.
As had been noted previously, 6 ' 8 two subgroups could be distinguished here on the basis
of the terminal cardiac event. Ventricular
fibrillation occurred in 10 dogs between the
temperatures 18 and 23 C. The remaining
eight dogs suffered asystolic deaths at 16 to
18 C. One may, therefore, discuss the ionic
balance of the heart in three distinct groups of
animals: group 1, comprised of normocapneic
hypothermic dogs; group 2, hypercapneic hypothermia fibrillators; group 3, hypercapneic
hypothermic non-fibrillators.
Sodium, Chloride, Magnesium. Coronary
arterial and venous electrolyte determinations
were made in all dogs at normal temperature
and at heart temperatures of 24 C. The mean
coronary A-V differences and their standard
deviations are given in tobies 1 and 2. Since,
apart from K, the mean arterial levels of the
several ions were unaffected by the experimental procedures, omission of those figures
was deemed warrented and advisable.
A comparison of the data for Na, Cl and
Mg at 24 C. (table 2) with those at normal
temperature (table 1) indicates that these
ions, whether considered in terms of levels
or coronary A-V differences, are unaffected
by acute hypothermia, regardless of systemic
pH. The mean arterial pH for all groups at
normal temperature was 7.42. This was also
the mean for the hypothermic normocapneic
dogs. For the hypothermic acidotic, fibrillators
and nonfibrillators the mean pH values at
24 C. were 7.16 and 7.14 respectively. Since
neither levels nor A-V differences of these
ions are affected by this pH range at low temperature one may reasonably conclude that the
balance between blood and myocardium is also
stable. One observation regarding the coronary
A-V difference in Na is worthy of mention.
Of 20 dogs, 25 showed a higher level of Xti in
the venous blood than in the arterial, suggesting a negative cardiac Xa balance at both
normal and low temperatures. This cannot actually represent a negative Xa balance, for a
steady loss at this rate could last at most for a
few moments. Another explanation must obtain, but does not readily suggest itself. The
A-V Na-difference is real in all groups at both
temperatures studied (p = <0.01).
Potassium, Calcium a7ul Hydrogen Ions. Determination of the K, Ca and H ion concentrations in arterial and coronary venous blood
did reveal certain basic differences at 24 C.
between those animals which succumbed to
577
B. G. COVINO AND A. H. HEGNAUER
TABLE 1.—Coronary A-V Electrolyte Differences in inEq. per Liter in £6 Dogs Prior to Subjection
to Immersion Hypothermia
Group 1. 8 normoeapiicio nonfibrillafcora
Group 2. 10 hypcrcapneio fibrillators
Group 3. 8 hypercapneio non-fibrillaInrs
pH
Total Ca
K
+0.01
(±0.02)
+0.02
(±0.01)
+0.03
(±0.01)
-0.2
(±0.24)
-0.1
(±0.18)
-0.2
(±0.22)
+0.10
(±0.10)
0.0
(±0.13)
+0.12
(±0.18)
Na
Cl
MR
-2.0
-3.0
(±1.6)
-0.5
(±1.2)
-0.2C
(±0.08)
-0.20
(±0.12)
-0.20
(±0.04)
(±2.0)
-5.0
(±3.2)
-6.0
(±2.4)
0.0
(±2.0)
TABLE 2.—Coronary A-V Electrolyte Differences in mEq. per Liter, Measured in Three Groups of
Hypothermic Dogs at £4 C.
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(Jroup 1. S normocapneic non-fibrilltitors
Group 2. 10 hypercapnoic fibrillators
Group 3. S hypercapneic non-fibrillators
pH
Total Ca
K
Na
Cl
MR
+0.03
(±0.01)
+0.08
(±0.04)
+0.03
(±0.01)
-0.2
(±0.15)
+0.4
(±0.34)
-0.1
(±0.16)
-0.1
(±0.16)
-0.2
(±0.59)
-3.0
(±2.8)
-3.0
(±2.6)
-3.0
(±3.2)
+2 0
(±1.5)
-0.2
(±0.04)
ventricular fibrillation, and those which died in
asystole at lower temperatures.
These are revealed in table 2. In regard to
plasma K concentrations the most conspicuous
features are (1) The concentrations are lower
in both arterial and coronary venous blood at
24 C. in all tliree groups (p = <0.01 in every
instance). The mean values at 24 C. are 0.6
mEq. per L. less than at normal temperature.
Since the difference is of the same magnitude
in all groups it would appear to be totally unrelated to pH; (2) nine of the 10 hypothermic
dogs exhibited a negative coronary A-V difference at 24 C. Elimination from the series,
(for analytic purposes) of the only dog in this
group that failed to demonstrate such a difference but rather deviated widely in the other
direction, yields the mean difference for the
remaining 9 dogs of —0.30, a value which is
significant at the 5 per cent level. Among the
1G clogs of groups 1 and 3 (all asystolic deaths)
only 4 had negative coronary A-V differences
at 24 C , the mean value for the 4 being —0.13.
The distinction between "fibrillators" and
"nonfibrillators" becomes more conspicuous
when one considers the Ca balances. Groups
1 and 3 showed a slight but insignificant negative coronary A-V difference at both normal
temperature and 24 C. Group 2, the fibrilla-
0.0
(±0.18)
0.0
0.0
(±0.97)
+ 1.5
(±1.8)
(±0.11)
-0.3
(±0.07)
tors, did not differ in this regard at normal
temperature, but showed a significant positive
balance at 24 C , i.e., the coronary venous Ca
level was less than the arterial. Despite the
fact that in 2 of the 10 dogs no difference in
total Ca was observed the mean difference was
significant (p = <0.02). Moreover, if one considers only the ionized Ca, which increases at
the expense of the nonionized fraction at low
pH and temperature, 16 then all of the fibrillators showed a positive coronary A-V difference; whereas the nonfibrillators regardless of
pH and temperature showed either no difference or a slight negative balance. The fact
that in 10 of 10 fibrillators a positive Ca balance
occurred concomitantly with a negative Iv
balance in 9 of the 10, whereas under the same
conditions of pH and temperature a normal Ca
and K pattern obtained in the 8 nonfibrillators of group 3, suggests strongly that one is
dealing with a basic, perhaps causative, mechanism in regard to hypothermic ventricular
arrhythmias. The explanation for the resistance
to Ca penetration into the myocardium of the
non fibrillators at low systemic pH is a problem unto itself, solution of which has not been
attempted.
Coincident with the above measurements
were those of pH on both the systemic arterial
578
MYOCARDIAL ELECTROLYTES AND EXCITABILITY
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and coronary venous blood. The mean coronary
A-V pH differences are given for all groups at
both normal and low temperatures. It very
soon became obvious that one could predict
with absolute accuracy at 24 C. which dogs
would succumb to ventricular fibrillation as
opposed to death in asystole at lower temperatures. In every instance the coronary venous
pH of the group 2 dogs at 2-4 C. was more than
0.05 pH units lower than the arterial, the mean
being 0.08 units. In no instance was there a
difference as great as 0.05 units among the
non-fibrillators of either group 1 or group 3.
Considering these three ions together it
appears that the myocardium of some dogs at
low temperature and pH loses its resistance to
Ca penetration and such penetration occurs in
exchange for K and H ions, with a consequent
rise in excitability, the initiation of arrhythmias, and ventricular fibrillation. The character of the failure which thus permits the
entrance of excess Ca into the myocardium is at
present unknown.
DrscussioN
The etiology of hypothennic ventricular
fibrillation has been vigorously pursued for the
past five years. Swan and associates1 first reported that prevention of acidosis during cooling was capable of controlling these cardiac
irregularities. This observation has been confirmed repeatedly since the time of that initial
report.2'6 The suggestion has also been made
that acidosis exerts its deleterious effect via a
change in the electrolyte balance of the
heart.1' " The data presented herein reveal
that sodium, chloride, and magnesium play no
observable role in the production of ventricular
arrhythmias at low temperature.
The ions which apparently do determine the
various types of hypothermic deaths are potassium, calcium, and hydrogen. The data suggest
that the augmented ventricular excitability
and the extrasystolic activity observed in
acidotic hypothermic dogs is the result of a
myocardial exchange between intracellular
potassium and hydrogen ions and extracellular
calcium ions.
Little attention has been paid to the role of
calcium in the genesis of hypothermic ventricular fibrillation, although the arrhythmiaproducing effects of calcium in normothermia
are well known. Hoff and co-workers20 and
Grumbach and associates12 have demonstrated
experimentally that a gradual increase in the
calcium concentration of the blood lowers the
threshold of the intact normothermic mammalian ventricle as indicated by the onset of
ventricular arrhythmias. However, studies
performed on the isolated papillary muscle of
the cat by Grenicr and associates21 and Green
and co-workers22 reveal that a rise in the
calcium concentration of the perfusing medium
produces a decreased excitability. This apparent contradiction between results obtained
with in vivo and in vitro preparations may possibly be resolved if one considers the rate at
which the intracellular level of calcium is increased and the possible dual effect of calcium
on cellular excitability, i.e., a primary excitability increase followed by a secondary depressant effect. There can be little doubt that
calcium would penetrate the isolated muscle
much more rapidly than the intact heart.
Thus, only the depressant effect due to a rapid
marked increase in the intracellular level of
calcium might be observed in an in vitro preparation whereas the intact heart would exhibit
the initial excitatory action of a small calcium
rise. Evidence for such a theory is forthcoming
from the report of Hoff and associates20 who
observed in the intact dog a primary excitatory stage as the plasma level of calcium was
increased. Most dogs suffered ventricular
fibrillation during this period. However, those
animals which survived this initial phase of
increased excitability then entered a secondary
stage of depression during which cardiac arrest occurred. Our data tend to support the
thesis that a small increase in the intracellular
calcium level augments cellular excitability.
The perfect correlation, between the small but
significant influx of calcium into the hypothermic acidotic myocardium and the
elevated ventricular excitability, which is the
predisposing condition for the observed ventricular fibrillation,''7 definitely suggests a causal
relationship between the two phenomena.
B. G. COVINO AND A. H. HEGNAUER
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The negative coronary A-V potassium difference observed in 90 per cent of our dogs at
low temperatures suggests that the hypothermic myocardium loses potassium. This
finding is confirmed by the work of Olsen and
co-workers23 who, by the use of radio-active
potassium, were able to demonstrate a reduction in the intracellular myocardial potassium concentration of hypothermic dogs. The
outflow of potassium from the ventricular
musculature may act synergistically with calcium penetration to augment the excitability
of the ventricle prior to the onset of fibrillation
at low temperatures. In this regard, Harris
and associates24 also observed a potassium
exodus from the myocardium just prior to
ventricular fibrillation in normothermic dogs,
subjected to coronary ligation.
The results obtained in this study differ
from those reported by Montgomery and
associates." This is probably not surprising in
view of the difference in the experimental procedures. In order to obtain coronary venous
samples Montgomery and associates26 utilized the technic of coronary sinus catheterization which necessitated pretreatment of these
clogs with acetylcholine, prostigmine or vagal
stimulation to prevent ventricular fibrillation,
due to the presence of a catheter in the coronary
sinus. That vagal stimulation and probably
acetylcholine itself may alter the potassium
balance of the heart has been demonstrated .28 • w
SUMMARY AND CONCLUSIONS
Arterial and coronary venous concentrations
of sodium, chloride, magnesium, potassium,
calcium and hydrogen ions were measured in
normo- and hypercapneic dogs subjected to
immersion hypothermia.
Neither temperature nor pH had any effect
on the arterial or coronary venous levels of
sodium, chloride or magnesium.
Myocardial exchange between intracellular
potassium and hydrogen ions and extracellular calcium ions was observed only in those
hypothermic acidotic dogs which succumbed
to ventricular fibrillation. All dogs suffering
fibrillary deaths exhibited a positive calcium
coronary A-V difference and a negative hydro-
579
gen ion difference. Ninety per cent showed a
negative potassium coronary A-V difference.
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Electrolytes and pH Changes in Relation to Hypothermic Ventricular Fibrillation
BENJAMIN G. COVINO and A. H. HEGNAUER
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Circ Res. 1955;3:575-580
doi: 10.1161/01.RES.3.6.575
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