LABORATORY INVESTIGATION
CARDIOPULMONARY RESUSCITATION
Improved hemodynamic function during hypoxia
with carbicarb,* a new agent for the management
of acidosis
ROBERT M. BERSIN, M.D.,
AND
ALLEN
I.
ARIEFF, M.D.
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ABSTRACT Carbicarb is a mixture of Na2CO3/NaHCO3 that buffers similarly to NaHCO3, but
without net generation of CO2. We studied the effects of carbicarb in an animal preparation of hypoxic
lactic acidosis (HLA). HLA was induced by ventilating dogs with an hypoxic gas mixture (8% 02/92%
N2). Dogs with HLA (n = 28) were then treated with 2.5 meq/kg of either NaHCO3 or carbicarb over
1 hr. Measurements were made, after 1 hr of hypoxia and 1 hr of therapy, of: cardiac hemodynamics,
blood gases, liver intracellular pH (pHi), oxygen consumption, and regional lactate production. After
therapy, the arterial pH rose with carbicarb (7.22 to 7.27, p<.01), and fell with NaHCO3 (7.18 to 7.13,
p<.01). Mixed venous Pco2 did not change with carbicarb but increased with NaHCO3 (p<.05).
Arterial lactates stabilized with carbicarb but rose with NaHCO3 (by 3.1 mmol/liter, p<.005). Lactate
use by muscle, gut, and liver all improved with carbicarb and decreased with NaHCO3. The liver pHi
(normal = 6.99, hypoxia = 6.80) improved with carbicarb (to 6.92), but decreased further with NaHCO3
(to 6.40). Muscle 02 consumption rose with carbicarb, whereas it decreased with NaHCO3. Arterial
pressure fell less with carbicarb ( - 12 vs -46 mm Hg, p<.006) and the cardiac output was stable
with carbicarb but decreased with NaHCO3 (from 143 to 98 ml/kg/min, p<.004). Stroke volume also
improved with carbicarb but there was no change in pulmonary capillary wedge pressure, suggesting
that carbicarb had a beneficial effect on myocardial contractility. These data demonstrate that administration of carbicarb to dogs with HLA results in improvements in the arterial blood gases, tissue pHi,
lactate production, and cardiac hemodynamics. These findings are in contrast to the effects of NaHCO3
and may be related to less systemic CO2 generation by carbicarb. Carbicarb thus appears to be superior
to NaHCO3 for the treatment of hypoxic states in the presence of lactic acidosis.
Circulation 77, No. 1, 227-233, 1988.
THE MOST COMMON causes of metabolic acidosis are
cardiopulmonary arrest and other states characterized by
impaired cardiac performance and reduced tissue
perfusion.1 In these states, hypoxia and circulatory insufficiency combine to reduce tissue oxygen availability,
causing anaerobic metabolism and lactic acidosis.
The lactic acidosis in turn appears to have direct
negative effects on myocardial function.38 Indeed,
From the Cardiology and Geriatrics Division, Department of Medicine, Veterans Administration Medical Center and the University of
California School of Medicine, San Francisco.
Supported by grants from the National Heart, Lung, and Blood
Institute, No. HL01791, the Research Service of the Veterans Administration and International Medication Systems, Limited.
Address for correspondence: Robert M. Bersin, M.D., Cardiology
Division (Box 0124), UCSF Moffitt Hospital, 505 Parnassus Ave, San
Francisco, CA 94143.
Received Aug. 19, 1987; accepted Sept. 24, 1987.
Dr. Bersin is a recipient of the Physician-Scientist Award, National
Institutes of Health.
Presented in part at the 59th Scientific Session, American Heart
Association, November, 1986, Dallas, and the Annual Meeting, American Society for Clinical Investigation, May 1987, San Diego.
Carbicarb is a registered trademark.
Vol. 77, No. 1, January 1988
this effect appears to be most pronounced when the
acidosis is due to hypoxia, since myocardial contractile
function is depressed more by the combination of hypoxia and lactic acidosis than by either process alone.9' 1O
Since tissue oxygen delivery is critically dependent on
cardiac output in hypoxic states and cardiopulmonary
arrest, the negative inotropic effect of lactic acidosis
assumes a critically important role in determining clinical outcome in these situations. Because of this, the
goal of cardiopulmonary resuscitation has been to correct both the hypoxia and the lactic acidosis simultaneously in order to restore myocardial function as rapidly as possible.11
The correction of lactic acidosis in hypoxic states has
traditionally been accomplished with the administration of sodium bicarbonate (NaHCO3). However,
investigations from our laboratory and others12-16 suggest that the administration of NaHCO3 in this setting
may be counterproductive. Using an animal preparation of hypoxic lactic acidosis (HLA) in dogs, we
227
BERSIN and ARIEFF
demonstrated that the administration of NaHCO3 was
associated with depression of cardiac function, acceleration of lactate production, and a paradoxic lowering
of the blood pH and bicarbonate concentrations.15 16
The potential mechanisms by which bicarbonate may
have these deleterious consequences include: (1) the
production of C02 as a result of bicarbonate administration, which may then aggravate intracellular
acidosis,3 4 17, 18 (2) enhanced glycolysis, which may
stimulate or accelerate lactic acid production as the pH
increases,19 (3) increased oxygen-hemoglobin binding, which may then impair tissue oxygen availability. 20 This latter phenomenon assumes particular
importance in hypoxic states and cardiopulmonary
arrest.
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However, both an increase in glycolysis and a shift
of the oxygen-hemoglobin binding curve are predicated on an increase of the blood pH as a result of
NaHCO3 administration. If the blood pH is not
increased, then these two mechanisms cannot explain
the effects of NaHCO3 on hemodynamic function and
lactate production. Rather, a likely mechanism for
these effects is the generation of C02 resulting from an
adminstration of NaHCO3.
To test this hypothesis, we compared NaHCO3
to a new agent, carbicarb, in an animal preparation of HLA.'5' 16 Carbicarb is an equimolar solution of sodium carbonate and sodium bicarbonate. It
buffers excess hydrogen ions in the blood in a manner
similar to that of NaHCO3, but it does so without
changing Pco2 levels.21 22 Thus, a comparison of
these two agents allows one to determine the importance of CO2 production to the observed effects of
NaHCO3 on cardiovascular function, tissue oxygen
delivery, and lactate metabolism.
Methods
Studies were carried out in two groups of mongrel dogs, mean
weight of 20 kg, as follows. HLA was induced both groups of
dogs by delivery of low oxygen gas mixtures under general
anesthesia. Dogs were anesthetized with sodium pentobarbital
(18 to 20 mg/kg iv), intubated, and mechanically ventilated with
an anesthesia machine (Harvard). The anesthesia machine was
adjusted to deliver a mixture of nitrogen and oxygen gas to each
animal. In preliminary experiments, it was found that there was
marked individual variation among dogs such that the percent
flow of oxygen required to establish hypoxia in each dog was
critical and required individual adjustment. If the oxygen content of the gas mixture and the resultant arterial Po2 were too
high, lactic acidosis did not occur, even with an arterial Po2 as
low as 30 mm Hg. If the Po2 was too low (below 20 mm Hg),
the animals suffered fibrillatory arrest and died. The optimum
gas mixture was found to be a mean of 8% oxygen and 92%
nitrogen, which served to maintain arterial Po2 between 25 and
30 mm Hg. With an arterial Po2 of 25 to 30 mm Hg, metabolic
acidosis was established rapidly (less than 30 min), with the
228
arterial pH achieving a steady state of 7.20 + 0.05 and the
arterial lactate rising to a plateau above 5 mmol/liter. Thereafter,
the blood pH changed little and the arterial lactate rose more
slowly, generally at a rate of 1 to 2 mmol/liter/hr as continuous
hypoxia was maintained. 16 Minute ventilation was also individually adjusted to normalize the arterial Pco2 at 37 + 2 mm
Hg and once adjusted was kept constant throughout the experimental protocol.
After 1 hr of continuous hypoxia, measurements were
made of: (1) circulatory hemodynamics, including cardiac
output, mean right atrial pressure, pulmonary arterial systolic,
diastolic, and mean pressures, pulmonary capillary wedge
(PCW) pressure, hind limb blood flow. and hepatic portal
vein blood flow, (2) blood gases. regional oxygen consumption, 2,3-diphosphoglyceric acid (2.3-DPG), and the p50
of blood, (3) regional net lactate metabolism, and (4) liver
intracellular pH (pHi). Blood gases. oxygen saturations, and
lactate were measured in samples from the aorta, pulmonary
artery, inferior vena cava, femoral vein, hepatic portal vein
(HPV), and hepatic vein.
Cardiac output was measured in triplicate with the thermodilution technique23 by insertion of a balloon-tipped, flowdirected catheter into the pulmonary artery and by use of a
cardiac output computer (Instrumentation Laboratories, Lexington, MA). Hind limb muscle flow was estimated by measurement of femoral artery blood flow with the use of Statham
flowmeters (Gould Statham Model SP202, Oxnard, CA). Gut
blood flow was estimated similarly by measurement of HPV
flow. Right atrial mean pressure and pulmonary arterial pressures were recorded from the pulmonary artery catheter. Central
aortic mean pressure was recorded with a catheter placed in the
abdominal aorta via a femoral artery. All pressures were measured in millimeters of mercury with Gould pressure transducers
and a physiologic monitor (Electronics for Medicine Model
IM-4, Honeywell Systems). Total peripheral resistance (TPR)
was calculated with the formula: TPR = (MAP X 80)/CO,
where MAP is mean arterial pressure and CO is cardiac output.
Similarly, pulmonary vascular resistance (PVR) was calculated
with the formula: (PVR) = [PAM - PCW)80]/CO, where PAM
is mean pulmonary arterial pressure. The electrocardiogram and
heart rate were monitored continuously with the use of a threelead system and the physiologic monitor.
Blood gases were measured at 37° C with an automated blood
gas analyzer (Model ABL-30, Radiometer. Copenhagen.
Denmark). Oxygen saturations and hemoglobin contents were
measured simultaneously on the same blood samples with an
automated oximeter (Model OSM-3, Radiometer, Copenhagen,
Denmark). Oxygen contents (vol%) were calculated with the
formula: 02 content = 1.34 x hemoglobin content X % 02
saturation. Systemic oxygen consumption was then calculated
with the formula: systemic 02 consumption = (aortic-pulmonary artery) 02 content difference x CO. Similarly, hind
limb oxygen consumption was estimated with the formula: hind
limb oxygen consumption = (femoral artery -femoral vein)
02 content difference x femoral artery flow. Liver oxygen
consumption was estimated with the formula: liver oxygen
consumption = [HPV + 0.41 aortic- 1.41 hepatic vein] 02
content x HPV flow, based on direct measurement of HPV flow
and the observation that hepatic artery flow is normally 41 % of
total hepatic blood flow, as previously published. 15 The p50 of
blood was calculated on arterial samples corrected for temperature with the use of directly measured oxygen saturations,
oxygen tensions, blood pH, and published tables.24 25
Measurements of 2,3-DPG (mmol/ml) were made on 0.5 ml
samples of arterial blood deproteinized immediately with 1.0 ml
0.55M perchloric acid and frozen at -5° C. The 2,3-DPG
content was then measured spectrophotometrically on these samCIRCULATION
LABORATORY INVESTIGATION-CARDIOPULMONARY RESUSCITATION
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ples by the NADH oxidation method (Sigma Chemicals, St.
Louis).26 Blood lactates were also measured spectrophotometrically on deproteinized samples from all sites sampled (Sigma
Chemicals, St. Louis).27 Net lactate production by the gut and
hind limb was estimated by determining the difference in blood
lactate levels in the appropriate arteries and veins and by multiplying the differences by the organ blood flow. For net hepatic
lactate extraction, addition of (0.71)(HPV lactate) +
(0.29)(aortic lactate) yields the afferent hepatic lactate. The
efferent (venous) lactate is the hepatic vein lactate. Subtraction
of the efferent (venous) from afferent lactate multiplied by the
liver blood flow yields the liver lactate uptake. Systemic lactate
production was determined by the formula: (pulmonary artery
- arterial) lactate difference x CO.
Liver pHi was estimated by the 14C-dimethadione (DMO)
technique.28 A dose of 50 to 75 mCi of 14C-DMO was injected
intravenously 1 hr before determination of liver pHi. At the time
of determination of pHi, blood samples were taken from the
hepatic vein and HPV to establish the extracellular reference pH,
lactate concentration, and whole blood 14C-DMO activity. A
tissue sample was then obtained and processed for 14C-DMO
activity and lactate. Corrections for the liver extracellular space
were made by measurement of the endogenous chloride space,
as previously described.28
After measurement of the above variables during continuous
hypoxia, each dog was randomly assigned to one of two treatment groups. In group I, the dogs were administered 2.5 meq/kg
body weight of IM NaHCO3 by continuous infusion over 1 hr.
Group II animals received 2.5 meq/kg body weight of IM
carbicarb by continuous infusion over 1 hr. At the end of each
1 hr infusion, the above-mentioned measurements were all
repeated to determine end-therapy values.
Statistical analyses were made by comparing end-therapy
values to individual hypoxic values with use of paired t tests to
determine significant effects of therapy within treatment groups.
Comparisons between treatment groups were made by unpaired
t tests of net changes from individual hypoxic values. Differences between treatment groups were considered significant
when p<.05. Statistical analysis were accomplished with
MacIntosh Plus computer and a Statview 512 + Statistical
Software package (Calabassas, CA).
Results
A total of 28 dogs were studied, 13 in the NaHCO3
treatment group (group I) and 15 in the carbicarb group
(group II). The pretreatment room-air (normoxic) values for each measured variable were not significantly
different between groups.
Blood gas analysis. The arterial pH improved significantly with carbicarb (from 7.22 to 7.27, p<.01),
whereas it declined with NaHCO3 (from 7.18 to 7.13,
p< .01) (figure 1) Likewise, the arterial bicarbonate
concentration increased with carbicarb an average of
1 mmol/liter for each millimole per kilogram body
weight administered (from 14.4 to 16.6), whereas it
fell paradoxically with NaHIC03. The arterial Pco2 did
not change with either carbicarb (from 35.0 to 35.2,
p = NS) or NaHCO3 (from 34.4 to 33.6, p = NS). However, the mixed-venous Pco2 showed a differential
response. With carbicarb, the mixed-venous Pco2 did
not vary (from 39.2 to 39. 1, p = NS). With NaHCO3,
Vol. 77, No. 1, January 1988
7.30
CAR BICAR B
7.25
7.20
I-o
7.15
7.10
7.00
CAR BICAR B
6.80
CL
6.60
cc
6.40
6.20
HYPOXIA
END THERAPY
FIGURE 1. Effects of carbicarb and sodium bicarbonate on arterial pH
and liver intracellular pH during hypoxia. The mean values + SEM are
shown.
the other hand, the mixed-venous Pco2 rose significantly (from 38.5 to 40.8, p<.05).
The arterial Po2 was reduced from 96 to 25 mm Hg
with the establishment of hypoxia. Corresponding arterial oxygen contents fell from 18.9 to 6.6 vol%. Despite
the low arterial Po2 in both groups, systemic oxygen
extraction remained normal (4.1 vol% at room air vs
4.1 vol% with hypoxia, p = NS) and systemic oxygen
consumption did not fall (from 4.5 to 5.2 ml 02/min/kg
body weight, p= NS). Therapy did not change the
arterial Po2 (mean net change + 1 mm Hg in group I
vs + 4 mm Hg in group II, p = NS) or arterial oxygen
content ( + 0.7 vs + 0.2 vol%, p= NS). Arterial 2,3DPG levels did not change (+ 0.43 vs 0.22 mmol/g
hemoglobin, p = NS) and the p50 of blood remained
normal throughout the experiment in both treatment
groups (from 28.9 with hypoxia to 28.3 with therapy,
p = NS; normal = 29.0). Thus, neither blood oxygen
carrying capacity nor blood oxygen-hemoglobin binding was affected by either therapy.
Hemodynamics. With the establishment of hypoxia,
the cardiac output increased by 24% from 115 to 143
ml/min/kg body weight. With the administration of
NaHCO3, the cardiac output fell substantially to 98
ml/min/kg body weight (p<.004), whereas with carbicarb the cardiac output did not change (150
ml/min/kg body weight, p = NS) (figure 2). There were
no significant ditferences in the pulmonary arterial
on
-
229
BERSIN and ARIEFF
160CL
CARBICARB
4
I
2-
-
NS
p=
p<.02
1:2
140-E
120-
p<.03
100-
NaHCO3
1
I-
Y
n
v i
CARBICARB
i NaHCO3
-2
z
120
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100
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CARBICARB
-6-
W
cr.
cc
80
60
NaHCO3
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CL
PCW
(mm Hg)
STROKE VOLUME
(cc/beat)
p<.006
FIGURE 3. Net change in stroke volume and PCW pressure with
carbicarb and sodium bicarbonate during hypoxia. The mean values
SEM are shown.
4000
3000
CAR BICARB
NaHCO3
cc
p
2000
C)
=
NS
pH and cardiac output after NaHCO3 so that as arterial
pH fell, so did the cardiac output (figure 4). However,
even in the few animals in which NaHCO3 raised the
arterial pH, the cardiac output still tended to fall unless
the arterial pH was restored to normal. Significant
correlations between mixed venous Pco2, arterial pH,
and cardiac output were not present after carbicarb.
1 000
HYPOXIA
r = .70
END THERAPY
o z~~~~~~~~~~1r
..
0
FIGURE 2. Eifects of carbicarb and sodium bicarbonate on cardiac
output, arterial blood pressure, and systemic vascular resistance during
hypoxia. The mean values + SEM are shown.
2
(5
1-
-
PVR, PCW pressure, or heart rates in group
II dogs. Thus, the fall in cardiac output with
NaHCO3 was due to a primary reduction in stroke
volume, whereas the improvement in cardiac output
with carbicarb was attributable to a modest improvement in stroke volume (figure 3).
The TPR fell modestly with both infusions (-475
vs -480 dynes-seccm -, p NS). As a result.
changes in arterial pressure reflected primary changes
in cardiac output. Since administration of NaHCO3
resulted in a significant reduction in cardiac output,
arterial pressure fell precipitously (from 105 to 59 mm
Hg, p<.001). With carbicarb, on the other hand, cardiac output improved as peripheral resistance fell, and
thus arterial pressure did not change (figure 4).
With administration of NaHCO3, changes in the
cardiac output with therapy correlated with changes in
the mixed venous Pco2. As mixed venous Pco2 rose,
the cardiac output fell, and vice versa (figure 4). A
positive correlation was also found between the arterial
pressures,
I vs group
230
cc
E
0n
m
-.5
-1
-1.5
-2
-2.5
0
-3
I
z
-3.5
-.3
3
-.25 -.2
-.15 -. 1
-.05 0 .a1
.05
.15
ARTERIAL pH (net A with NaHCO3 administration)
-
r =
.4
.91
.E
0
.2
o~-,1~
\
0
-
-.2
-.4
0
tl:
0
-.6
CL
0
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\o~~~~~~
-1
-1.2
-1.4
-1.6
-8
-6
-4
-2
0
2
4
6
8
10
12
MIXED-VENOUS pC02 (net A with NaHCO3 administration)
FIGURE 4. Relationship between the net change in arterial pH and
mixed venous Pco, and the net change in cardiac output with administration of sodium bicarbonate during hypoxia. These relationships
were not present with administration of carbicarb.
CIRCULATION
LABORATORY INVESTIGATION-CARDIOPULMONARY RESUSCITATION
3a._
IC
H.E
cc
pc.05
XC
{ CARBICARB
4.
0
_.
W0
-1
-2
I
i NaHCO3
SYSTEMIC 02 SYSTEMIC 02
CONSUMPTION
DELIVERY
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
since the mixed venous Pco2 did not vary and the mean
arterial pH and cardiac output improved.
Both therapeutic agents reduced hepatic portal
blood flow to the same degree (-92 vs - 82 ml/min,
p = NS). However, hind limb blood flow was reduced
substantially more by NaHCO3 than by carbicarb
(-53 vs - 19 ml/min).
Oxygen delivery and consumption. Whole body oxygen
delivery was reduced by 1.7 ml 02/min/kg body weight
(23% decrease) as a result of administration of
NaHCO3. Whole body oxygen consumption also
decreased, although to a lesser extent (- 0.5 ml
02/min/kg body weight, 8% decrease) than oxygen
delivery (figure 5). Systemic oxygen extraction increased ( + 1.3 vol%) to partially offset the decrease of
cardiac output. In contrast, carbicarb increased whole
body oxygen delivery by 1.3 ml 02/min/kg body
weight (p<.05) and oxygen consumption by 1.1 ml
02/min/kg body weight (figure 5). Systemic oxygen
extraction did not change (- 0.2 vol%, p = NS). Oxygen delivery, extraction, and consumption by the liver
NaHCO3
11 -
10 i
G-LJ5
p<.O3
9-
8-
CARBICARB
F-
Ic_
6
HYPOXIA
END THERAPY
FIGURE 6. Effect of carbicarb and sodium bicarbonate on arterial
blood lactate concentrations during hypoxia. The mean values ± SEM
are shown.
Vol. 77, No. 1, January 1988
CARBICARB
NaHC03
1.0 -
I
g-W
c
0.0-
ARTERIAL
FIGURE 5. Net change in systemic oxygen delivery and consumption
with administration of carbicarb and sodium bicarbonate during hypoxia. The mean net changes ± SEM are shown.
W
*
*
2.0 -
.
c-
-3.
z
ITT
,0
O4S
cm
p<.03
3.0 -
ZW
w
5
4.0 -
T
21
_
00.
p =.06
HPV
LIVER
FIGURE 7. Net changes in the arterial, HPV, and hepatic intracellular
lactate concentrations with carbicarb and sodium bicarbonate during
hypoxia. The mean net changes + SEM are shown.
and gut did not differ with the two infusions. However, hind limb oxygen delivery and consumption
decreased significantly with NaHCO3 and increased
with carbicarb.
Lactate metabolism. With the establishment of hypoxia, the arterial lactate concentration rose from 1.97 to
7.18 mmol/liten After NaHCO3, the arterial lactate
continued to rise at an accelerated rate, whereas with
carbicarb, the arterial lactate rose at a much slower rate
(+ 3.14 vs + 1.21 mmol/liter/hr, p<.03) (figure 6).
Lactate concentrations in the HPV and liver followed
the same pattern (figure 7), as did lactate concentrations in the hepatic vein, vena cava, and femoral vein.
Net hepatic lactate clearance did not change with
NaHCO3, whereas it improved significantly with carbicarb (+ 245 vs + 4087 gmol/kg body weight per
hour). Net gut lactate production was reduced more by
carbicarb than by NaHCO3. Net lactate production by
carcass was also improved with carbicarb, but worsened with NaHCO3 ( + 1544 versus - 2061 gmol/kg
body weight per hour).
Liver pHi. The liver pHi was 6.99 during normoxia
and 6.80 during hypoxia. With administration of
NaHCO3, the liver pHi declined to 6.40, whereas with
carbicarb it improved to 6.92 (p<.04) (figure 1). A
factor analysis demonstrated that the two best predictors of changes of liver pHi were the HPV pH and Pco2.
As HPV pH fell and the Pco2 rose with NaHCO3, the
liver pHi fell. Although liver intracellular lactate concentrations rose at the same rate as blood lactate levels,
they did not appear to predict changes in liver pHi.
Discussion
These studies demonstrate that in dogs with HLA,
a mixture of 50%
the administration of carbicarb
sodium carbonate and 50% sodium bicarbonate
improves arterial pH and elevates the blood HCO3concentration without changing the blood Pco2, stimulating lactate production, or affecting cardiovascular
231
BERSIN and ARIEFF
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performance. Systemic oxygen delivery and consumption also improve with administration of carbicarb. In
contrast, in dogs with similar degrees of HLA, the
administration of NaHCO3 results in a decline of arterial pH and HCO3 concentrations, increased venous
Pco2 concentrations, accelerated lactate production,
and reduced cardiac index and mean arterial pressure.
Both the delivery and consumption of oxygen decline.
The most striking finding of this study was the
depression of both cardiac output and blood pressure
with NaHCO3 administration, an observation that was
not made after carbicarb. The reduction of cardiac
output after NaHCO3 appears to be the result of a
primary reduction in left ventricular contractility. Left
ventricular preload (PCW) did not change. Left ventricular afterload (TPR) decreased modestly. The heart
rate did not change. Thus, stroke volume decreased
primarily at a time when the loading conditions of the
left ventricle were constant, suggesting that contractility was depressed. Although dP/dt was not measured, the peak systolic arterial pressure fell, on the
average, by more than 60 mm Hg. With no change in
heart rate, dP/dt most likely decreased.
The mechanisms by which myocardial contractility
is impaired after administration of NaHCO3 are not
known, but may involve the generation of CO2.29 The
inverse correlation found between the mixed venous
Pco2 and cardiac output would suggest that the generation of CO2 as a result of administration of NaHCO3
might be a factor in the observed depression of contractile function.3 4 7, 8, 30, 31 Such depression of
myocardial contractile function might be related to a
decrement of cardiac pHi brought about by a greater
increase of the Pco, in the myocardium than other
tissues. 32, 33
In the present study, arterial Pco2 did not change
with the administration of either NaHCO3 or carbicarb.
However, the mixed venous (pulmonary artery) Pco2
rose with NaHCO3 administration and did not change
with carbicarb. Other studies suggest that when hypoxic states are complicated by circulatory failure, such as
in cardiopulmonary arrest, there is indeed a significant
component of respiratory acidosis that is only reflected
by the venous blood gases. Weil et al.32 showed that
in patients in cardiopulmonary arrest, the mixed
venous Pco2 was on average 36 mm Hg higher than the
arterial Pco2, confirming that even at times when the
arterial blood gases are normal, respiratory acidosis
may be present at a cellular level. Furthermore, Caparelli et al .33 demonstrated that respiratory acidosis may
be more pronounced in the coronary vascular bed than
in other vascular beds. In dogs with experimental car232
diac arrest, the coronary sinus Pco2 was even higher
(107 mm Hg greater) and pH significantly lower (0.63
pH units less) than either mixed venous or arterial
values.33 As a consequence, myocardial pHi is probably decreased more than the pHi in other vascular beds
during hypoxic states and cardiopulmonary arrest.
Myocardial pHi was not measured in the present study
because the method employed28 would have required
open biopsy of myocardium. However, we did evaluate
the pHi of the liver (figure 1) and found that it fell
significantly with NaHCO3. In a previous study, the
HPV Pco2 rose by 12 mm Hg, and in the present study
the HPV Pco2 and pH predicted the liver pHi. Moreover, we previously evaluated the pHi of skeletal muscle
with NaHCO3 in dogs with HLA and observed similar
reductions in pHi.34 Thus, it is likely that myocardial
pHi also declined significantly in the present study, and
perhaps even more drastically than did liver pHi.
because of an even greater contribution of respiratory
acidosis in the coronary vascular bed with administration of NaHCO3. As such, this may have been a major
contributory factor to the observed decline in cardiac
output that occurred with NaHCO3 and not carbicarb.
The consequence of the reduced cardiac output after
administration of NaHCO3 was reduced tissue oxygen
delivery (figure 5). The blood flow to gut, skeletal
muscle, and liver all decreased, and since arterial oxygen contents, 2,3-DPG, and p50 did not change, oxygen delivery to these tissues declined. This in turn led
to increased lactate production in these vascular beds.
As a consequence, blood pH declined even more as
blood lactate continued to rise. As the blood pH continued to fall, myocardial contractility became further
impaired.3 4 7. 8.
Thus, administration of
NaHCO3 initiated a cycle of depressed left ventricular
contractile function, decreased cardiac output, and
increased acidosis that ultimately terminated in cardiogenic shock.
In contrast, cardiac output increased after carbicarb
and myocardial contractility most likely improved.
Therefore, tissue oxygen delivery did not decline, and
the production of lactate was not accelerated. The
change in lactate observed with administration of carbicarb was the same as that we have previously
observed with either no therapy or with NaCl
infusion. 16 The cycle observed after NaHCO3 administration did not occur with carbicarb because carbicarb
did not depress cardiac function. As a result, the arterial pH rose after infusion of carbicarb (figure 1), and
arterial pressure did not change (figure 2).
Thus, in experimental HLA carbicarb achieves the
goal of improving blood pH without detrimental effects
CIRCULATION
LABORATORY INVESTIGATION-CARDIOPULMONARY RESUSCITATION
on myocardial function or the circulation, whereas
bicarbonate does not. Carbicarb appears to be superior
to NaHCO3 in therapy of experimental HLA and trials
of the therapy of acidotic states in man, particularly
cardiopulmonary arrest, are warranted.
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233
Improved hemodynamic function during hypoxia with Carbicarb, a new agent for the
management of acidosis.
R M Bersin and A I Arieff
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Circulation. 1988;77:227-233
doi: 10.1161/01.CIR.77.1.227
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