INFLUENCE
OF
ACIDEMIA
ON
LEFT VENTRICULAR
FUNCTION
IN THE
NEWBORN
LAMB
Norman S. Talner, M.D., Thomas H. Gardner, M.D., and S.Evans Downing, M.D.
Departments of Pathology and Pediatrics, Yale University School of Medicine, New Haven, Connecticut
(Received January 14; accepted for publication February 15, 1966.)
Supported by research grants HE-9516, HE-8659, HE-6233, and Research Career Award Program Grants 5-K3-HE-18,409 (to S.E.D.) and 5-K3-IIE-18,438 (N.S.T.) from the National Heart Institute, the New Haven Heart Association, and the Life Insurance Medical Research Fund.
ADDRESS: (S.E.D.) Dept. of Pathology, Yale University School of Medicine, 333 Cedar Street, New
Haven, Connecticut.
PEDIATRICS, Vol. 38, No. 3, September 1966 457
D
URING birth infants are subjected to transient asphyxia. In some instances this is prolonged and severe, and associatedwith a progressive increase in hydrogen ion
concentration. This may further stress the left ventricle at a time when it must adjust to an increased systemic resistance follow-ing abolition of placental perfusion, and to an increased flow load following reversal of flow in the ductus arteriosus.14 Indeed, acidemia has been implicated as a factor in the genesis of congestive heart failure in severely asphyxiated
The objectives of the present communi-cation are to describe the effects of hydro-gen ion concentration on cardiac perfor-mance in the newborn lamb under con-trolled hemodynamic conditions,6 and to evaluate the influence of pH on the respon-siveness of the ventricle to catecholamines. A preliminary report on these experiments
has 7
METHODS
Twenty-six term lambs, varying in age from 12 hours to 4 days, were anesthetized
with pentobarbital, 15 mg/kg, and
pre-pared for measurement of left ventricular
performance (Fig. 1). Following
endotra-cheal intubation, the chest was opened in the midline and ventilation was maintained
with a Harvard respiratory pump. Heparin, 5 mg/kg, was given intravenously. The left ventricular output was measured with ei-ther a Shipley-Wilson rotameter or a gated sine wave electromagnetic flowmeter
(Med-icon) utilizing an 8 mm probe on the
as-cendmg aorta. The brachiocephalic artery
was ligated in order to minimize autonomic reflex activity by destroying the higher por-tions of the central nervous system. The ductus arteriosus was also ligated.
Cardiac output was controlled by means of a pump-operated arteriovenous bypass which permitted blood to be pumped from the flowmeter circuit to the superior vena cava at controlled flow rates. Arterial blood
pressure was controlled when desired by
means of an adjustable constant-pressure reservoir. Blood temperature was main-tamed with a heat exchanger at 37 ± 1#{176}C. Continuous measurements of arterial pH, Po2, and P02, as well as blood tempera-ture, were obtained from a flow-through electrode assembly (Fig. 1) incorporating a Beckman pH electrode, a modified Clark oxygen electrode, a Severinghaus CO2
elec-trode, and a temperature probe. These measurements were checked frequently with another electrode system which incor-porated a Radiometer pH electrode, a
modified Clark oxygen electrode, and a Severinghaus Pc02 electrode. Ventilation was adjusted to maintain an arterial Po2 between 60 and 100 mm Hg, with P-o
values less than 30 mm Hg.
Heart rate was maintained constant by electrical pacing of the right atrium. Aortic pressure was measured by passing a poly-ethylene catheter into the aortic arch via
458
measured with Sanborn transducers and re-corded with cardiac output and the output of the Beckman amplifiers on a Sanborn 358 direct-writing recorder. The extracor-poreal tubing, flowmeter, and reservoir were primed with freshly drawn heparin-ized (5 mg/100 ml) sheep blood. This prep-aration has been shown to be stable for as long as 8 hours, although measurements of left ventricular function were generally completed within 4 hours of the onset of the experiment.
Data derived from the foregoing mea-surements were used to plot ventricular function curves relating stroke volume and mean ejection rate to left ventricular end-diastolic pressure. These relationships were studied at constant mean aortic pressures and heart rate. The time from the onset of ventricular contraction to the development
of peak pressure in the left ventricle, the peak pressure time (PPT), which has been shown in a similar preparation to be a function of the velocity of muscle fiber shortening/i was also used as evidence for an inotropic change in the ventricle. Meta-bolic acidosis was produced in these experi-ments by infusing either 0.5 N HC1 or 0.5 to 1 N lactic acid intravenously with a Har-yard constant-infusion pump until the de-sired pH was attained. Responses to norep-inephrine were observed during tile con-tinuous infusion of this hormone at a con-stant rate (1-2i.g/kg/min).
Calculations were:
1. Stroke volume (ml) cardiac output (ml/min)/heart rate (beats/mm).
2. Mean ejection rate (mi/systolic see) stroke volume/duration of ventricular ejec-tion (see).
FIG. 1. Autosupported heart preparation. Pump-operated (Sarns roller pump) aorticocaval shunt for
control of cardiac output. Controlled pressure reservoir for maintaining constant mean aortic pressure. Bipolar electrodes for pacing of right atrium to maintain constant heart rate. Rot. = Shiplev-\Vilson rotameter. Tr. = Sanborn transducers. S.V.C. = superior vena cava. I.VC. = inferior vena cava.
w
9
LAMB N’ A14 -wt 51kg- Age 3days-Hct 42-Temp 375
AP75 HR220
‘7
0-0pH 7.50- I’c2 61
.-. pH 68- ‘#{176}263
f
I
m
z
30
15
KS
5,,
D 10 15 5 10 15
LVEDP-cm H20 LVEDP-cm HO
Fic. 2. Left ventricular function in a 3-day-old lamb at 1)11 7.38 (left panel) and (luring m’ta-bolic aciclosis at a p11 of 6.86 (right panel). Al =
aortic Iressttre. LVEDP = left ventricular
end-diastolic j)ressure. LVP = left ventricular pressure
(
full trace). P() in mm I 1g. Chart speed 100 mm/sec. At the same aortic flow, aortic pressure, and
heart rate metabolic acidosis failed to induce a
change in ltft ventricular end-diastolic pressure.
3. Stroke work (gram-meters) mean aortic pressure (cm H2O) X stroke volume /100.
4. Stroke power (gram-meters/systolic see) =: stroke work/duration of ventricular
ejection.
RESULTS
Data were obtained from 20 technically
successful experiments in a total of 26.
These experiments permitted construction of
84
ventricular function curves demon-strating tile relationship of left ventricular end-diastolic pressure to stroke volume, mean ejection rate, stroke work, and stroke power.Effect of Acidemia on Left Ventricular
Function
Original traces from tile representative
ex-periment obtained from a 2-day-old lamb
are shown ill Figure 2. In this animal the
heart rate was maintained at 180/mm and
the mean aortic pressure at 75 mm Hg. The
tracings ill tue control panel were obtained
at a pH of 7.38. The pH was then reduced
by the slow infusion of 0.5 N lactic acid at a rate of 1.96 cc/mm. The tracings in the
right panel were obtained at a pFI of 6.9 and selected to show essentially the same left ventricular output as in the control panel. \Vhile the mean aortic pressure and the heart rate were held constant, the same
left ventricular output, hence, the same
stroke volume, was associated with no
change in left ventricular end-diastolic
pressure in the presence of severe
meta-bolic acidosis.
In only four animals subjected to severe
metabolic acidemia was there significant
depression of left ventricular function
(
greater than 10% reduction of stroke vol-ume for a given LVEDP). Figure 3 showscomplete ventricular function curves ob-tamed from a 3-day-old lamb in which this occurred. In the left panel the open circles
indicate the relationship of the left
ventric-ular end-diastolic pressure to stroke volume at a pH of 7.50. Following the infusion of lactic acid over a 20-minute period which lowered the pH to 6.98 another ventricular function curve (closed circles) was
in-scribed. This was shifted slightly to the
Fie. 3. Ventricular function curve in a 3-day-old
lamb relating stroke volume (left panel) and mean
ejection rate (right panel) to left ventricular
end-diastolic pressure (LVEDP). Open circles = con-trol. Closed circles = values obtained during me-tabolie acidemia. Stroke volume and mean
ejec-tion rate curves are shifted slightly to the right during acidemia indicating a small depression of ventricular function. Arrow indicates stroke
20 LAMBS-AGE l2Hrs to 4 Days 64 VENTRICULAR FUNCTION CURVES 0
(‘4
1
ACIDEMIAACIDEMIA +
NOREPINEPHRINE
V10
NOREPINEPHRINE
E
w 7
I.
5
4
3
LAMB N’ A10 wt. 59kg. Ha 36 temp. 36.5’C
AP75 HR230
0-0 pH 749 - Po2 75-Pco2 23
.-. pH 6.99- P02 83-Pc02
f
.
50
50
so m 3o
U’
U’
0 10
5 10 15
LVEDP-cm H20
:,
lu
LVEDP-cm H20
460
ACIDEMIAright of the control suggesting a small de-pression of ventricular function. In the right panel, the mean ejection rate was plotted against left ventricular end-diastolic pressure and demonstrates a similar small decrease in the velocity of the ejection. However, severe depression of left ventric-ular function was never observed at pH values of 6.80 or greater.
In five other preparations a small im-provement of ventricular performance was
demonstrated as shown in Figure 4. The
control ventricular function curve was ob-tamed at a pH of 7.49. Following infusion of lactic acid, the pH was lowered to 6.99 and a repeat ventricular function curve in-scribed. The curves for both stroke volume and mean ejection rate (right panel) were shifted to the left indicating a small im-provement in ventricular function.
Whereas these small individual variations
were observed, most preparations (11 of 20) manifested no discernable change of yen-tricular function between pH 7.5 and 6.9. The average change following acidemia in stroke volume and mean ejection rate at a left ventricular end-diastolic pressure of 10 cm of water are summarized in Figure 5. It
Fic. 4. Ventricular function curve in a 3-day-old lamb relating stroke volume (left panel) and mean
ejection rate (right panel) to left ventricular
end-diastolic pressure (LVEDP). Open circles =
con-trol. Closed circles = acidemia. Stroke volume and
mean ejection rate curves are shifted to the left
during acidemia indicating a small improvement in left ventricular function. Arrow indicates stroke
volume at LVEDP 10 cm H,O.
Fic. 5. Average changes in stroke volume (SV10)
and mean ejection rate (MER10) for all
prepara-tions at a left ventricular end-diastolic pressure
(LVEDP) of 10 cm H2O. Ventricular bars =
stan-dard error of the mean. Acidemia = change in
response to metabolic acidosis. No significant change in SV10 or MER10 response to acidemia was found. Open bar shows average changes in SV10 consequent to norepinephrine infusion with
pH 7.36 to 7.50. Cross-hatched bar indicates
av-erage change in SV10 following norepinephrine in-fusion during acidemia (pH 6.80 to 6.90). The responses to norepinephrine are unimpaired
dur-ing acidemia.
is apparent that no significant mean change
in these parameters of ventricular function occurred in the 20 preparations consequent to metabolic acidosis (P >0.7)
In order to assess the possibility that the myocardial response to acidosis was a time-dependent phenomenon, two lambs were maintained in a continuous state of severe metabolic acidosis (pH between 6.8 and
7.0) for up to 2 hours. A typical experiment is shown in Figure 6. Over this time
I
9 w
LAMB NI A9 frGE 2nXS wt. 3.6kg. A75 R2OO
I
I
I
L.4CTIC HCO3 LSCflC
ACID ACID 4
I
2 76 74 72 70 I.e0 1 j
TIME- HOURS eO U 5O E40 z 30
L
02 10 15
LVEOP-cmH0 D ARTICLES 7 7 7 6.
Fic. 6. Influence of prolonged acidemia on left
ventricular function. No depression of stroke vol-ume at a left ventricular end-diastolic pressure
of 10 cm H2O (SV,0) occurred during 2 hours of
acidemia. Correction of acidemia with NaHCO, produced no change in SV10. Reinfusion of lactic acid and lowering the pH to 6.9 did not diminish
sv’o.
of left ventricular performance. Further-more, correction of the acidemia with NaHCO3 failed to alter this measure of
yen-tricular contractility. The pH was once
again rapidly reduced to 6.9 with lactic acid. No reduction of left ventricular con-tractility was observed, however.
Effect of Acidosis on Inotropic Response of
the Newborn Heart to Catecholamines
The continuous infusion of
norepine-phrine, 1-2 .tg/kg/min, in these prepara-tions was in every instance accompanied by an increase in stroke volume and an in-crease in mean ejection rate at any given left ventricular end-diastolic pressure. A representative study is illustrated in Figure
7. In the left panel are shown the results obtained at a pH of 7.38. The preparation was then made acidotic by the infusion of lactic acid and maintained at a pH of 6.97. The responsiveness of the lamb to norepi-nephrine was again examined (Figure 7,
right panel). It is apparent that no impair-ment in the myocardial response to norepi-nephrine occurred (closed circles)
conse-quent to an increase in hydrogen ion
con-centration. The average change in stroke
volume occurring with catechol stimulation over a normal pH range and following in-duction of acidemia is summarized in Fig-ure 5. Myocardial responsiveness to ca-techolamines was unaltered over the wide pH range utilized in these experiments (P
>0.5).
DISCUSSION
Burnard and James5 have suggested that the increase in hydrogen ion concentration,
which occurs in neonatal asphyxial states,
may cause depression of myocardial
func-tion. This concept evolved from experimen-tal evidence set forth by numerous investi-gators indicating that depression of the contractile strength of the adult heart can occur when pH is lowered.914 The findings in the present investigations are at variance
with this conclusion. They are, however, consistent with evidence previously report-ed from this laboratory that in adult cats hydrochloric or lactic acidemia of the dura-tion and degree produced in these studies does not alter myocardial contractility.15
The responsiveness of the adult
myocar-LAMB M7 Wt 5kg. 3E 3DAYS TEMP 31C.
I0-0 cONTROL
I -. NE 2TIkimN
L__!
HR 2400-0 pH 73e-Pofl
.-. pH737- Po 70
I .i. .1.
0-0 pH692-Poee
.-. pH697- Poe0
, 5 20
LVEDP-cmHO
FIG. 7. Effect of metabolic acidosis on the mo-tropic response of the newborn heart to catechola-mines. Ventricular function curves obtained
be-fore (open circles) and during the administration of norepinephrine (closed circles) 2 jsg/kg/min. Left panel = relationship between mean ejection rate (MER) and left ventricular end-diastolic
pres-sure (LVEDP) at pH 7.37 to 7.38. Right panel =
relationship between MER and LVEDP at pH 6.92 to 6.97. Myocardial responsiveness to
nor-epinephrine is not diminished in the presence of
dium to catecholamines has also been
re-ported to be diminished in the presence of
metabolic acidosis.lO,16 The present study
also fails to support this conclusion and agrees with the experimental data reported previously in the adult cat.15
These differing conclusions may be re-lated to certain features of methodology used by previous investigators in their mea-surement of ventricular contractility. In studies where induction of acidosis was as-sociated with a decrease in heart rate, the shift in the ventricular function curves could be solely a consequence of the change in rate. At a slower heart rate, the left atrial pressure would be greater because of the greater stroke volume required to maintain a given cardiac output. In other investigations designed to assess myocar-dial contractility by measurement of isomet-ric systolic tension, ventricular contractile
force measurements can be shown to be a
function of a number of hemodynamic
vari-ables. These include changes in heart rate, stroke volume, and ejection resistance.17’18
Hence, conclusions drawn from
measure-ments with the Walton-Brodie strain-gauge arch may reflect hemodynamic alterations independent of a change in the inotropic state of the myocardium. Although the strain-gauge arch closely reflects stroke work measurements, it should be stressed that stroke work is a measure of the inotro-pie state of the heart only under precisely controlled conditions.19
This apparent resistance of cardiac mus-cle to a wide range of pH may be ex-plained by the buffering capacity of cardiac muscle. Benson et al.,20 have shown that the
buffer capacity of canine cardiac muscle with respect to P.o appears to be approxi-mately equal to that of skeletal muscle. Utilizing [a] rat diaphragm and the labeled
DM0
(5,5-Dimethyl-2-4-oxazolidinedione-2-C14) method for determination of
intracel-lular pH, Adler, Roy, and Relman2l have
shown that no significant change in
intracel-lular pH occurs when extracellular pH is
varied between 7.4 and 6.9. Opie,ZZ using an
isolated rat heart preparation, studied the myocardial effects of varying the pH of the
perfusing fluid. Over the pH range 7.1 to
8.0, no detectable effects on the amplitude of left ventricular contraction was noted. At a pH of 6.9 the amplitude of left ventricu-lar contraction increased by up to 100% fol-lowed by a diminution in the amplitude of contraction. By correcting for the fall in coronary perfusion pressure, left ventricular performance could be restored for a short period of time. Delcher, et al.23 also ob-tamed a normally functioning rat heart pre-paration at a pH of 6.8.
Although cardiac muscle manifests no functional change consequent to an in-crease in hydrogen ion concentration, the role of hydrogen ion in the presence of an hypoxic myocardium may be quite significant. Preliminary data reported from this laboratory indicate that left ventricular performance in the newborn lamb may be slightly depressed by hypoxemia in the presence of a pH in the normal range.
When hydrogen ion concentration is in-creased, production of hypoxemia results in a marked impairment of ventricular
per-rm
Acidosis may produce striking alterations in the functional state of systemic arterial and pulmonary vascular smooth muscle. Enson, et 24 and Rudolph and Yuan25
have shown that lowering the pH will in-crease pulmonary vascular resistance. Studies reported from this laboratory com-paring the response of systemic and
pulmo-nary vascular smooth muscle during meta-bolic acidosis have shown a shift to the right of the pressure-flow curve for the sys-temic circulation, indicating a diminution in systemic resistance, and a shift to the left in the pulmonary pressure-flow curve, mdi-eating an increase in pulmonary vascular
resistance) These observations would
sup-port the conclusion that while cardiac
mus-dc manifests minimal functional change
during metabolic acidosis, systemic
SUMMARY
The performance of tile left ventricle in 20 newborn lambs was examined in a prep-aration which allowed precise control of aortic I)ressure, cardiac output, heart rate, and temperature.
Reduction of arterial pH from a normal range (7.35 to 7.5) to severe acidemia (6.8 to 7.0) by hydrochloric or lactic acid infu-5i011 resulted in no significant impairment
of left ventricular function.
Prolonged acidemia (over 2 hours) failed to produce a reduction in left ventricular stroke volume or mean ejection rate for a given left ventricular end-diastolic pres-sure.
Responsiveness of the left ventricle of the lamb to catechoiamine stimulation was not diminished over the pH range 7.5 to 6.8.
Under conditions of these investigations the apparent resistance of the myocardium of the newborn lamb, as well as the adult cat, to wide variations in pH may reflect a buffering capacity of cardiac muscle which
would allow minimal change in
intracellu-lar p1-I, even though extracellular pH may indicate the presence of severe metabolic acidosis.
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Acknowledgment
The expert technical assistance of Mr. Thomas
M. Powers, Miss Karen Betman, and Mrs. Alyce
