(Stroke. 1995;26:1028-1034.)
© 1995 American Heart Association, Inc.
Articles |
Acidemia and Brain pH During Prolonged Cardiopulmonary Resuscitation in Dogs
From the Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Md.
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Abstract |
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Background and Purpose Cardiopulmonary resuscitation (CPR) generating low perfusion pressures and beginning immediately after cardiac arrest maintains cerebral ATP but not cerebral pH or arterial pH. We tested the hypothesis that preventing severe arterial acidemia prevents cerebral acidosis, whereas augmenting arterial acidemia augments cerebral acidosis.
Methods In dogs anesthetized with pentobarbital and fentanyl, cerebral pH and ATP were measured with 31P MR spectroscopy and blood flow was measured with radiolabeled microspheres. A pneumatically controlled vest was placed around the thorax, and chest compressions were begun immediately after electrically induced cardiac arrest. Cerebral perfusion pressure was maintained with epinephrine at 30 mm Hg for 90 minutes. The arterial acidemia observed during CPR was untreated in a control group, corrected to a pH of 7.3 with the use of sodium bicarbonate, or maintained below pH 6.5 with intravenous lactic acid after 14 minutes of CPR.
Results At 10 minutes of CPR, cerebral ATP (99±1.5%, control), blood flow (35±3 mL/min per 100 g), O2 consumption (4.0±0.2 mL/min per 100 g), and cerebral pH (7.05±.03) were unchanged from prearrest values (mean±SEM). After 10 minutes of CPR in the control group, cerebral pH progressively fell (6.43±0.10 at 90 minutes) in parallel with cerebral venous pH. In the bicarbonate group cerebral pH was maintained higher (6.91±0.08). Cerebral blood flow, O2 consumption, and ATP were sustained near prearrest values in both groups. In the lactate group, however, the rate of decrease of cerebral pH was augmented (6.47±0.06 by 30 minutes), and cerebral blood flow and metabolism were significantly reduced.
Conclusions Cerebral pH decreased in parallel with blood pH when resuscitation was started immediately upon arrest even when cerebral O2 consumption and blood flow were near normal. Although cerebral metabolism was near normal during the first hour of CPR, systemic bicarbonate administration ameliorated the cerebral acidosis. This finding indicates that the blood-brain pH gradient is important at the subnormal cerebral perfusion pressures seen in CPR.
Key Words: acidosis, lactic • cardiopulmonary resuscitation • cerebral blood flow • spectroscopy, nuclear magnetic resonance • dogs
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Intracellular acidosis is thought to contribute to cell death.1 2 Cardiopulmonary resuscitation (CPR) is associated with systemic arterial acidemia3 and acidosis of the heart4 and brain.5 However, correction of this acidemia, although controversial6 is not recommended during conventional CPR.7 8 Administration of sodium bicarbonate (in the absence of epinephrine) can reduce coronary perfusion pressure,9 10 and the correction of arterial acidemia does not appear to correct intramyocardial acidosis.11
Six minutes of cardiac arrest causes complete loss of cerebral ATP and a decrease in cerebral pHi to 6.3. However, CPR with a cerebral perfusion pressure (CPP) greater than 60 mm Hg restores ATP and pHi measured by MR spectroscopy (MRS).12 In a recent study5 a CPP of 30 mm Hg was variably successful in restoring cerebral ATP and never restored cerebral pHi after a cardiac arrest time of 6 minutes. In that same study generating a CPP of 30 mm Hg immediately upon arrest maintained cerebral ATP but was associated with a continuous fall in cerebral pHi. The progressive decrease in cerebral pHi paralleled the progressive decrease in arterial pH associated with prolonged CPR. This observation suggests that systemic metabolic acidemia influences cerebral pHi at low CPP associated with CPR.
An intravenous lactate infusion increases brain lactate levels.13 Ordinarily metabolic acidemia changes cerebrospinal fluid pH over a period of hours14 15 and does not have an immediate effect on cerebral tissue pH.16 However, at low perfusion pressure the brain may not be able to adequately regulate its pH when blood pH becomes markedly reduced. In the present study we investigated whether blood pH directly influences cerebral tissue pH under conditions of low perfusion pressure associated with CPR.17 We tested the hypothesis that correcting systemic acidemia with sodium bicarbonate administration prevents the time-dependent decrease in cerebral pH that occurs when CPR is initiated immediately upon ventricular fibrillation, whereas augmenting systemic acidemia with lactic acid infusion augments the decrease in cerebral pH.
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Materials and Methods |
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All studies received approval of our institution's Animal Care and Use Committee. We studied 16 male mongrel dogs weighing 15 to 20 kg. All dogs were fasted overnight except for free access to water. Anesthesia consisted of sodium pentobarbital (10 mg/kg IV) and fentanyl (50 µg/kg IV). The trachea was intubated, and the lungs were ventilated with 100% inspired O2. By means of femoral cannulation, catheters were inserted into the descending thoracic aorta, left ventricle, and right atrium. An axillary artery was cannulated for microsphere reference sampling. The temporalis muscle and skin were fully retracted from the skull to prevent contamination of the MRS spectrum. A midline burr hole was made in the skull, and a catheter was inserted into the sagittal sinus proximal to the confluence of the sinuses. A temperature sensor (Mallinckrodt Anesthesia Products) was placed in the epidural space over the parieto-occipital region. A vest with an inflatable bladder that covered two thirds of the thoracic circumference was secured snugly around the thorax with hook and loop fastener straps. A warm water–perfused blanket was wrapped around the abdomen. The animal was placed onto a copper-lined cradle with the head fixed in position by a stereotaxic frame. Dogs received an additional 6 mg/kg per hour of sodium pentobarbital during the surgery. Pancuronium bromide (0.2 mg/kg IV) was administered to prevent movement. Lactated Ringer's solution containing no glucose (30 mL/kg) was infused during the surgery to ensure adequate cardiac filling pressures during subsequent CPR.
Ventricular fibrillation was induced by passing a 60-Hz current through a pacing electrode catheter in the right heart. CPR commenced immediately after arrest. The thorax was compressed by cycling vest pressure as previously described.18 The level of pressure in the vest was adjusted by varying the pressure in the reservoir chamber. The rise time to achieve a stable level of vest pressure was 150 milliseconds. Compressions occurred at a rate of 60/min with a 40% duty cycle. The microprocessor controlling vest inflation also controlled a pressure-limited ventilator to deliver 98.5% O2 and 1.5% CO2 (to attenuate hypocapnia) at a variable airway pressure of 20 to 35 cm H2O interposed after every fifth chest compression. All dogs received a bolus of 40 µg/kg of epinephrine at the start of CPR, followed by 10 µg/kg per minute continuous intravenous infusion to maintain vascular tone without affecting cerebral metabolism.19 20 21 Saline was infused at a rate of 4 mL/min for 90 minutes of continuous CPR. Vest pressure was continuously adjusted to maintain a CPP of 30 mm Hg. With this amount of epinephrine and saline infusion, CPP was maintained with minimal alterations in vest pressure. Mean sagittal sinus pressure, which is within a few millimeters of mercury pressure of intracranial pressure during CPR in dogs,22 was used as the downstream pressure to calculate CPP.
After 12 minutes of CPR, the animal was randomized to one of three groups: (1) a control group (n=5) with no additional intervention; (2) a bicarbonate group (n=6), in which the arterial pH was corrected with an infusion of sodium bicarbonate (1 mol/L); and (3) a lactic acid group (n=5), in which the arterial pH was brought to 6.4 with an infusion of lactic acid (1 mol/L).
Spectra were obtained with the use of a CSI MRS spectrometer (General Electric) with a 4.7-T horizontal superconducting magnet (Oxford Instruments). The magnet has a 40-cm bore with a sensitive volume of approximately 25 cm3 over which the magnetic field homogeneity is 0.1 ppm. An inductively coupled, two-turn, 7-cm-diameter copper surface coil double-tuned to 81 MHz (31P) and 200 MHz (1H) was placed directly over the skull. The field was shimmed on the water proton signal to less than 0.3 ppm. 31P MRS signals were collected every 3 seconds with the use of a 110-microsecond, 80-W excitation pulse and a 2.9-second, 1-W saturation pulse 10 ppm upfield from phosphocreatine. MRS data were averaged and stored as 5-minute blocks.
The Fourier transformation of the sum of 100 free induction decays (data points, 1024; frequency range, 6.0 kHz) was performed after application of a 30-Hz exponential filter. Typical phosphocreatine line width was 40 Hz (0.5 ppm), with a signal-to-noise ratio of greater than 30:1. The phosphocreatine peak of the control spectrum was chosen as zero offset. The stability of the system was such that there was no frequency shift of phosphocreatine during CPR.
Each spectrum was analyzed by means of a least-squares best-fit routine
for ATP concentration. pHi was calculated from the shift of
Pi with the formula
pHi=6.73+log[(
-3.07)/(5.68-)] where equals
the frequency difference from phosphocreatine to Pi in
parts per million. Intracellular brain bicarbonate was calculated with
the use of the Henderson-Hasselbach equation, a pKa of
6.12, a CO2 solubility coefficient of 0.0314 mmol/L per
millimeter of mercury, pHi derived by MRS, and sagittal
sinus PCO2 as a close approximation to
intracellular PCO2.23
Arterial and sagittal sinus blood samples were analyzed for pH, PCO2, and PO2 with a Radiometer ABL3 electrode system. Oxygen content was measured by a Radiometer Hemoximeter OSM3. Blood glucose and lactate concentrations were analyzed with a Yellow Springs glucose analyzer (model 2300 STAT Plus).
Fifteen-micrometer-diameter spheres labeled with one of six isotopes (153Gd, 114mIn, 113Sn, 103Ru, 95Nb, 46Sc) (Du Pont–NEN Products) allowed cerebral blood flow (CBF) to be measured six times per animal. A dose of approximately 1.5 million spheres (prearrest) or 0.5 million spheres during CPR was injected into the left ventricle, while an arterial reference sample was withdrawn at a rate of 3.8 mL/min from the axillary artery for 2 minutes prearrest and at a rate of 1.9 mL/min for 5 minutes during CPR to ensure full washout of spheres during the low cardiac output state with CPR. Use of microspheres during CPR has been previously validated in this laboratory.24 The brain was dissected, and blood flow was measured from both cerebral hemispheres (CBF) and from the brain stem (pons, medulla, and midbrain). Blood flow and cerebral metabolic rate of O2 (CMRO2) were calculated as previously described.22 Cerebral O2 transport was calculated as the product of CBF and arterial O2 content.
All data were analyzed prearrest and at 10, 30, 50, 70, and 90 minutes of CPR. One-way ANOVA with repeated measures and the Fisher protected least significant difference test were used at a .05 significance level to analyze for intragroup changes in blood gases, blood flow, and MRS measurements from prearrest baseline and for changes during prolonged CPR from the 10-minute CPR value. At individual time points, comparisons were made to the control group by one-way ANOVA and Scheffé's test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Arterial pH was the modified variable in this study, whereas arterial PCO2 was actively maintained near prearrest levels in all groups. There were no intergroup differences in arterial pH or bicarbonate (Table 1
) just before cardiac
arrest or at 10 minutes of CPR (before pharmacological manipulation).
The control group experienced a steady decrease in arterial pH and
bicarbonate throughout CPR presumably due to release of lactic acid
from poorly perfused peripheral tissues. In the bicarbonate group
arterial pH and bicarbonate were maintained near prearrest values after
the start of the sodium bicarbonate infusion at 14 minutes of CPR. The
amount of bicarbonate (1 mmol/mL) infused was 28±7, 12±2, 16±2, and
14±3 mL during minutes 14 to 30, 31 to 50, 51 to 70, and 71 to 90,
respectively. In the lactate group arterial pH was maintained at
approximately pH 6.4 after the start of lactic acid infusion at 14
minutes. The amount of lactic acid (1 mmol/mL) infused was 18±4, 6±3,
8±4, and 2±1 mL during minutes 14 to 30, 31 to 50, 51 to 70, and 71
to 90, respectively. By 30 minutes of CPR, there were intergroup
differences in arterial pH and bicarbonate.
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There were no intergroup differences in confounding variables such as arterial hemoglobin or glucose. Arterial oxygen saturation, which is dependent on pH (Bohr shift), was higher in the bicarbonate group than the control or lactate group at the first interventional time point and thereafter.
In all groups CPP was maintained near 30 mm Hg throughout 90 minutes
of CPR (Table 2). CBF was well maintained near prearrest
values in control and bicarbonate groups throughout CPR. However,
because of decreases in arterial hemoglobin concentration (Table 1
) and
O2 content, cerebral O2 transport was less than
prearrest levels throughout CPR (Table 2). In the lactate group CBF
decreased after infusion of lactic acid and was different from control
and bicarbonate groups throughout the remainder of CPR.
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Brain epidural temperature continuously decreased during CPR. However,
temperature was not different between groups at the various time points
except between the lactate and control groups at 90 minutes (Table 2).
There were no differences in CMRO2 between the bicarbonate
and control groups. However, there was a decrease from prearrest values
after 90 minutes of CPR in the bicarbonate group. The lactate group
decreased CMRO2 after infusion of lactic acid (Table 2).
Cerebral ATP was well maintained in the control group until 50 minutes
of CPR but was reduced to 86% of baseline by 70 minutes. Cerebral ATP
was reduced in the lactic acid group after infusion of lactic acid and
was below measurable limits by 70 minutes. In contrast, ATP in the
bicarbonate group was not different from prearrest throughout 90
minutes of CPR.
During the first 10 minutes of CPR (before any drug interventions),
cerebral pHi was unchanged from prearrest levels
(7.07±0.02 to 7.05±0.03). Thereafter, pHi progressively
decreased to 6.43±0.10 by 90 minutes of CPR in the control group (Fig 1). In contrast, the bicarbonate group maintained
pHi at prearrest levels through 70 minutes of CPR; a small
decrease to 6.91±0.08 was evident only at 90 minutes. After infusion
of lactic acid, pHi was reduced in the lactate group. By 50
minutes of CPR, pHi was different between all three groups.
However, by 70 minutes there was no difference between the control and
lactate groups. The changes in cerebral pHi over prolonged
CPR mirrored those measured in sagittal sinus blood (Fig 1).
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P<.05 vs values at 10 minutes of CPR;
P<.05 vs control group at the same time point.
Cerebral pHi depends on metabolic acid titration of
intracellular bicarbonate
([HCO3-]i) and on tissue
PCO2, which in turn depends on CBF. To
help separate these effects, we estimated
[HCO3-]i by using sagittal sinus
PCO2 as an approximation of tissue
PCO2. In the control and lactate groups the
decrease in pHi was associated with both an increase in
sagittal sinus PCO2 and a decrease in
[HCO3-]i. However, the increase
in sagittal sinus PCO2 was greater in the
lactate group, and [HCO3-]i in
the control group was not different than that in the lactate group (Fig 2). Thus, differences in pHi between control
and lactate groups at 30 and 50 minutes were largely attributable to
tissue carbonic acidosis in the lactate group. In contrast, brain
bicarbonate levels were different between the control and bicarbonate
groups, whereas sagittal sinus PCO2 was
similar between groups.
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Blood flow was also analyzed in other regions (Table 3).
In the brain stem and spinal cord, blood flow was maintained at or
above prearrest levels in control and bicarbonate groups. Blood flow in
these regions decreased in the lactic acid group after infusion of
lactic acid. In control and bicarbonate groups, left ventricular blood
flow was maintained at greater than 20 mL/min per 100 g, a value
associated with the ability to successfully defibrillate canine
hearts.19
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The major findings of this study are as follows: (1) during prolonged CPR without intervening complete cerebral ischemia, cerebral pHi is strongly influenced by arterial pH despite normal levels of CBF and ATP; (2) correcting the arterial acidemia with intravenous sodium bicarbonate prevents the fall in cerebral pHi; (3) correction of arterial and cerebral pHi is not associated with differences in ATP or CMRO2 in the first hour of CPR; and (4) a bolus injection of lactic acid sufficient to drop the arterial pH to 6.5 is associated with a reduction of CBF and ATP, whereas a gradual lactic acidemia to an arterial pH of 6.7 as seen in the control group does not affect brain ATP and blood flow.
In the present study a control group with a slowly evolving systemic metabolic acidosis presumably from peripheral lactic acid generation during CPR was studied. As in the study by Shapiro et al,16 no change in cerebral pHi was seen when arterial pH was over 7.2. However, cerebral pHi was found to decrease when arterial pH fell below the prearrest brain pH of 7.08. The brain's ability to maintain normal energy and oxygen utilization as reflected by ATP and CMRO2 was not different from prearrest for the first 50 minutes of CPR. This is consistent with in vitro observations showing that lactic acidosis with a pH of less than 6.0 was required to directly cause cell death1 25 and with in vivo observations showing that severe hypercapnia with a pHi of 6.6 does not decrease ATP26 or cause histological injury.27
Two explanations can be offered for the progressive decrease in
cerebral pHi during prolonged CPR. First, the progressive
decrease in blood pH may act to limit extrusion of acid equivalents
across the blood-brain barrier. The parallel relationship of cerebral
pHi with sagittal sinus pH over time is consistent with
this explanation. Second, a cerebral perfusion pressure of 30 mm Hg is
close to the threshold for anaerobic metabolism below which
ATP decreases and tissue lactate greatly increases.28 At
this threshold, lactic acid production may be moderately increased
despite near normal levels of ATP and CMRO2. Arterial
oxygen transport was reduced from prearrest values with the onset of
CPR (Table 2). Oxygen transport may be further reduced if capillary red
cell flux becomes heterogeneous at low perfusion pressures.
The lack of a hyperemic response in cerebrum, as was seen in brain stem
and spinal cord, supports the possibility of inadequate oxygen delivery
to cerebrum and enhanced tissue lactic acidosis. In this case, blood
acidemia may act in concert with enhanced acid production to augment
tissue acidosis by reducing proton clearance. In either case,
correcting blood pH with sodium bicarbonate administration appears to
maintain a favorable gradient for proton extrusion.
Manipulating the metabolic component of arterial pH with exogenous
lactic acid had significant effects on cerebral pH. The intravenous
injection of lactic acid sufficient to decrease arterial pH below 6.5
also was associated with severe derangements of blood flow to cerebrum,
brain stem, and cervical spinal cord and with reduced cerebral
metabolism. We observed that the augmented rate of decrease of cerebral
pHi after lactic acid infusion was accompanied by an
augmented increase in cerebral venous PCO2
without a change in arterial PCO2. Assuming
tissue PCO2 approximates venous
PCO2, there was no augmentation in the
reduction of estimated intracellular bicarbonate concentration (Fig 2).
Thus, much of the augmented tissue acidosis with lactic acidemia was
attributable to additional tissue carbonic acidosis.
Tissue carbonic acidosis is likely to be the result of reduced CBF and possibly reduced buffering capacity of blood. One explanation of reduced CBF is that rapidly induced, extreme acidemia markedly decreases CMRO2, resulting in a markedly increased cerebrovascular resistance. Alternatively, the large decrease in blood pH may have rendered extrusion of acid equivalents across the blood-brain barrier unfavorable. The consequent decrease in cerebral pHi may have caused cell swelling. Swelling of perivascular astrocytes may limit CBF at critically low perfusion pressures and thereby create a vicious cycle of ischemia, ATP hydrolysis, enhanced acidosis, and further swelling. However, the slow drop in brain pH in the control group reached similar values at 70 and 90 minutes and was not associated with a decrease in CBF, suggesting that the rate of change of arterial pH may be important. Therefore, the current results do not strictly differentiate whether the rapid drop in pHi after lactic acid infusion was the cause or result of decreased CBF.
One concern with the use of sodium bicarbonate is creating a paradoxical tissue acidosis secondary to the inability to adequately clear CO2. Paradoxical cerebral acidosis has been observed after bicarbonate administration in rats with metabolic acidemia. However, in that study ventilation was not increased to maintain arterial PCO2.16 Contrary to the prediction of the CO2 generation hypothesis of paradoxical acidosis, we found no increase in sagittal sinus PCO2 with bicarbonate administration. This was partly due to manipulation of inspired CO2 to keep arterial Pco2 near prearrest levels as well as to the near normal levels of CBF maintaining tissue clearance of CO2. Bicarbonate therapy also maintained calculated sagittal sinus bicarbonate concentration and prevented the venous metabolic acidemia seen in the control and lactate groups. More importantly, prevention of the acidemia successfully prevented brain acidosis. Maintenance of blood pH preserves a favorable gradient for tissue extrusion of acid equivalents, which may be critical when perfusion pressure is low and the brain is near the threshold of anaerobic glycolysis. These results agree with the findings of others. Rosenberg et al29 did not observe paradoxical acidosis when bicarbonate was administered during the institution of cardiopulmonary bypass with normal perfusion pressures after 12 minutes of cardiac arrest. Sessler et al30 also found no evidence for paradoxical intracellular acidosis in the brain in hypoxic rabbits.
Differences in cerebral pHi between control and bicarbonate groups were significant at 50 minutes of CPR (36 minutes after the start of bicarbonate administration), but there were no differences in CBF, CMRO2, or ATP at 50 minutes that would account for differences in pHi. Brain ATP was maintained at prearrest levels through 50 minutes of CPR in both the control and bicarbonate groups. Thus, this study does not address whether bicarbonate administration improves energy metabolism. It is possible that at lower perfusion pressure measured in humans who could not be rapidly resuscitated,17 bicarbonate administration would have little effect on restoring cerebral metabolism and pHi. With higher vest inflation pressure, higher levels of CPP and CBF can be generated in dogs12 and high vascular pressures can be generated in humans.31 These higher levels of pressure and flow were associated with improvements in cerebral ATP and pHi without the use of bicarbonate.12 Recovery of ATP may remain the most critical variable for restoring cerebral pHi after cardiac arrest.
The routine use of sodium bicarbonate to convert the acidemia associated with CPR32 is no longer recommended.8 The strong arguments against the correction of arterial acidemia are based on the effect on the heart. Hyperosmolar sodium bicarbonate reduces coronary perfusion pressure by a vasodilating mechanism. The vasodilatory effect profoundly reduces arterial diastolic pressure, which directly reduces coronary blood flow and resultant success of cardiac resuscitation.9 10 Even when these adverse vasodilatory properties are reversed with a vasopressor drug such as epinephrine, there is still no apparent improvement in cardiac resuscitation.33 In this study, as in others, we found no improvement in coronary blood flow after correcting arterial acidemia with sodium bicarbonate despite the concurrent use of epinephrine. However, we also did not find a paradoxical worsening of coronary blood flow.
In summary, correction of the arterial acidemia associated with CPR with sodium bicarbonate corrects the brain acidosis when CPR is started immediately upon cardiac arrest at levels of CPP that ordinarily maintain cerebral ATP and CMRO2. Whether bicarbonate administration is beneficial at lower levels of CPP or when CPR is delayed was not addressed in this study. This is especially relevant because CPR-generated CBF is decreased after a period of no flow.5 Bicarbonate administration may not be as beneficial during low or trickle brain blood flow. However, on the assumption that tissue acidosis is detrimental, our data support the use of bicarbonate during prolonged hypotensive states when arterial pH decreases below 7.1 and ventilation is adequate.
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Acknowledgments |
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This study was supported by an American Heart Association Grant-in-Aid and a grant from the National Institutes of Health (PO1 NS 20020). This work was done during the tenure of an Established Investigatorship from the American Heart Association (Dr Eleff). The American Heart Association grants include contributions from the Maryland Affiliate, Inc. The excellent technical assistance of John Skelly is gratefully acknowledged.
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Footnotes |
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Reprint requests to Scott M. Eleff, MD, Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Hospital, 600 N Wolfe St, Meyer 8-134, Baltimore, MD 21287. E-mail seleff@neuron.accm.jhu.edu.
Received October 25, 1994; revision received December 22, 1994; accepted March 3, 1995.
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