553
pH Changes On the Surface of Brain and In Cisternal Fluid in
Dogs in Cardiac Arrest
S. JAVAHERI, M . D . , * A. CLENDENING, B . S . ,
N. PAPADAKIS, M . D . ,
AND J.S. B R O D Y ,
M.D.
SUMMARY We measured brain surface pH and cisternal cerebrosplnal fluid (CSF) acid-base variables in
Na-pentobarbital anesthetized dogs during KCI induced cardiac arrest. Electrocardiographically, an
agonal rhythm occurred within seconds, presumably resulting in rapid fall in cerebral blood flow. The mean
arterial blood pressure fell from 125 ± 22 (mean ± 1 SD) to 35 ± 28 mm Hg at 30 seconds and to 19 ± 3
mm Hg at 60 seconds after KCI injection. The mean brain surface pH (n = 8) dropped abruptly from 7.30
to 6.80 within 3 minutes after induction of cardiac arrest. Changes in cisternal CSF pH, however, occurred
slowly with the mean pH falling from 7.33 to 7.27 at 4 minutes and to 6.99 at 10 minutes after induction of
cardiac arrest. The fall in cisternal CSF pH was due to a rise in CSF concentration of organic acids as well as
a rise in CSF PCO2; the mean cisternal CSF | HCOj | fell 3.6 mEq/1 while the mean cisternal CSF lactate
concentration and the mean CSF PCO2 rose, respectively, 2.1 mEq/l and 37.8 mm Hg 10 minutes after
induction of cardiac arrest. We conclude that during acute ischemic anoxia gross pH disequilibria develop
between brain extracellular fluid and cisternal CSF; analyses of the latter fluid provide unreliable information about brain metabolic status and its acid-base balance even up to ten minutes after induction of cardiac
arrest.
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Stroke Vol 15, No 3, 1984
CHANGES IN IONIC COMPOSITION of cerebrospinal fluid (CSF) reflect derangements in brain metabolic function. In man lumbar CSF is most commonly
sampled. Wide differences, however, might exist between the composition of lumbar and cisternal CSF
during acute events;1-2 Kalim and associates2 have
shown that in cardiac arrest the normal compartmental
difference between cisternal and lumbar CSF is reversed, with the former being more acidic than the
latter. This is due to the closer proximity of the cisternal CSF to the brain which more rapidly reflects the
acute acidosis of brain extracellular fluid (ECF) under
such circumstances. It might be anticipated, however,
that changes in cisternal CSF ionic composition may
not immediately reflect ionic changes in brain ECF
during acute events, such as cardiac arrest; if true,
under such circumstances analyses of cisternal CSF
may provide unreliable information about the events
occurring within brain ECF.
The purpose of the present study was to quantitate
the magnitude of brain ECF acidosis as measured by
pH electrodes during cardiac arrest and to see how
faithfully cisternal CSF pH changes reflected brain
ECF acidity.
Methods
General
Mongrel dogs (n = 16) weighing from 15-20 kg
were anesthetized with intravenous injection of sodiFrom the Pulmonary Division, Boston City Hospital, Boston University School of Medicine, Boston, Massachusetts 02114 and Pulmonary
Division, VA Medical Center, Cincinnati, Ohio 45220.
This study was in part presented at the Meeting of the American
Thoracic Society, Washington, D.C., May 1980, U.S.A.
*This work was done when the author was the Director of Pulmonary
Function and Blood Gas Laboratories, Boston City Hospital, and Assistant Professor in Medicine, Boston, University School of Medicine,
Boston, Massachusetts 02114.
Address correspondence to: Shahrokh Javaheri, M.D., VA Medical
Center, Pulmonary Disease Section (11 IF), 3200 Vine Street, Cincinnati, Ohio 45220.
Received February 22, 1983; revision # 3 accepted November 7,
1983.
um pentobarbital (initially 30 mg/kg followed by 4.5
mg/kg 2 h later) and paralyzed by intramuscular injection of succinylcholine (40 mg initially and 20 mg
every 2 h). Ventilation was maintained on oxygen
through an endotracheal tube by a volume respirator
adjusted to keep the arterial P , ^ ( P a ^ ) normal. Endtidal PCO2 ( P E ^ ) was recorded continuously using an
infra-red CO2 analyzer. Two femoral arteries and one
femoral vein were cannulated for monitoring arterial
blood pressure, obtaining blood samples and intravenous injections. Through a midline incision atlantooccipital membrane was exposed for obtaining cisternal cerebrospinal fluid. Rectal temperature was
measured by a thermometer.
Fifteen minutes after stable P E ^ , simultaneous
femoral arterial blood (3 ml) and cisternal CSF (2 ml)
samples were collected for determination of gas tensions and pH and CSF potassium and lactate concentration. If CSF was bloody the animal was not used.
Measurement of Brain Surface pH
Details of our technique for measurement of the
brain surface pH have been described previously;3 a
modified technique of Rapoport,4 Loeschcke and coworkers5- 6 and Fencl and associates7-8 was used. Briefly, a small parietal craniotomy was performed and a
combination pH electrode (Ingold Inc., Lexington,
Mass.) was placed on the surface of the brain on the
pia-arachnoid membranes where large vessels were
absent.
The flat surface of the pH electrode was round with a
diameter of 4 mm. The reference electrode was either
placed on the pia-arachnoid or on the adjacent dura.
The weight of the electrode was balanced by a special lever. The pH electrode was connected to a pH
electrometer (Model 213, Instrumentation Laboratory,
Lexington, Mass.) and recorder. pH calibrations were
performed at 37°C with precision buffers (pH = 6.840
and 7.340) before and after each experiment; there was
essentially no shift.
Brain surface temperature was measured by a ther-
554
STROKE
mocouple (Model 127, Bailey Instrument, Saddlebrook, New Jersey) with its tip in the fluid adjacent to
pH electrodes. Brain surface was heated by a heating
lamp when surface temperature fell to 36.5°C.
Induction of Cardiac Arrest
After obtaining baseline samples and recording a
stable brain surface pH, cardiac arrest was induced by
bolus injection of 35—40 ml of saturated KC1. Electrocardiogram was recorded continuously. Brain surface
pH was measured in 8 animals; in these cisternal CSF
samples were obtained only at 0 time and after 3 minutes of induction of cardiac arrest in order not to disturb the position of the pH electrodes on the brain. In
the remaining 8 animals, however, CSF samples were
obtained periodically throughout the experiment (see
results). In this context, it is emphasized that KC1
induced cardiac arrest is an extremely reproducible
event.
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Measurements, Analysis and Calculation
A four-channel recorder (Hewlett Packard, San
Diego, California) was used for continuous recording
of blood pressure, P E ^ and brain surface pH. Gases
of known concentration were used to calibrate the infrared CO 2 analyzer (LB — 2 Bechman, Medical Gas
Analyzer). Arterial blood P ^ , P^ and pH and cisternal CSF PQJJ and pH were measured immediately in
appropriate electrodes (Model 213; Instrumentation
Laboratory) at 37°C. P ^ and P , ^ electrodes were calibrated with humidified gases of known P,^ and P C02 .
All pH electrodes were calibrated with precision buffers (6.840 and 7.384 at 37°C). These calibrations were
made repeatedly throughout the experiment before and
after each measurement.
VOL 15, No 3, MAY-JUNE
Through the three-way-stopcock a small amount of
cisternal CSF was initially drawn into a dry glass syringe for flushing and filling of its dead space. Cisternal CSF was then obtained anaerobically for immediate measurement of P , ^ and pH. Arterial blood
samples were obtained anaerobically by syringes
whose dead space was filled with heparin. All arterial
and cisternal gas tensions and pH measurements were
corrected for the animal's rectal temperature using
respective correction factors. 9 ' l0 Cisternal CSF
| HCOj | was calculated from the Henderson-Hasselbalch equation using appropriate pK'values and
CO, solubility factors.9 All pH values were converted
to I H + | for further calculations.
Lactate concentration in the cisternal cerebrospinal
fluid was determined spectrophotometrically (Sigma
Chemical Company, St. Louis, Missouri) and | K + |
by flame photometry.
For comparison of two means, two tailed paired or
unpaired t test (whichever appropriate) was used.
Analysis of variance was used when comparison was
made among more than two sample means. P values
<0.05 were considered significant.
Results
Electrocardiographic abnormalities characterized
by asystole ventricular fibrillation or an agonal rhythm
occurred within seconds after KC1 injection; the length
of such periods, however, was variable with an average of 41 seconds ( ± 30, 1 SD; n = 8). Hemodynamically, there was a relatively abrupt and pronounced
drop in the mean arterial blood pressure (table 1),
resulting in cerebral ischemia.
Figure 1 depicts typical changes in the brain surface
TABLE 1 Changes in the Mean Arterial Blood Pressure (MABP), Brain Surface [H+] and Cisternal Cerebrospinal
Fluid (CSF) Po2, Pco2, and H +, HCOj~, Lactate and K+ Concentrations During Cardiac Arrest (Mean ± so)
Time (min)
MABP (mm Hg)
0.0
125
±22
50.3
±3.0
7.30
46.3
±4.5
7.33
45.7
±3.7
22.9
±2.8
124.0
±22.0
3.1
0.5
35*
±28
55.2*
±6 0
7.26
47.5
±6.2
7.32
46.6
±2.0
22.2
±2.9
111.0
±14.0
1984
1.0
19*
±3
2.0
8*
±2
129.8*
±17.4
6.89
49.5
±5.9
7.31
46.6
4.0
8*
±2
10.0
8*
±2
Surface [H + ]
69.6*
—
—
(nmol/1)
±6.3
—
—
Surface pH
7.16
101.7*
54.1*
CSF[H + ]
48.5
±20.3
±6.5
(nmol/l)
±6.7
CSFpH
7.27
6.99
7.31
CSF Pcoj
83.5*
46.5
49.8*
±14.0
±5.8
±3.0
(mm Hg)
±2.3
22 4
21.3
19.3*
21.1
CSF [HCO3-]
±1.8
(mEq/1)
±1.6
±2.6
±2.6
96.0*
63.0*
34.0*
CSFPo,
100.0
(mm Hg)
±15.0
±7.0
±28.0
±12.0
CSF [K + ]
3.5
5.5*
—
—
—
±0.7
±0.2
±1.8
(mEq/1)
2.1
1.8
CSF lactate
3.9*
—
—
—
±0.4
±0.5
±0.2
(mEq/1)
•Indicates statistical significance withp < 0.05 compared to values at time 0.0 (KC1 injection). The brain surface pH
had fallen to 6.80, three minutes after KG injection in all animals studied (n = 8). For CSF values there are at least 5
measurements at each time. For comparison of surface and CSF [H + ] see page 8.
BRAIN PWJavaheri et al
125
btood
(rrtniHg)
0
7.384 i-
• u r f a c * pH
6.840 •60
r
iiain
0.0
15T
]4Jo
2.0
NaHCOidOm Eq IV)
6.0
KCI IV
time (mln)
FIGURE 1. Changes in the mean arterial blood pressure,
brain surface pH and end-tidal Pc02 (PECO2) vs time during
cardiac arrest.
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pH, mean arterial blood pressure and PEc02, photographed from the original record of one animal. The
initial segment of the pH recording demonstrates a
Rapoport test.4 Intravenously infused NaHC0 3 (10 ml,
1 M) resulted in a rise in P , ^ , and consequently brain
surface pH fell; this was followed by a gradual return
of the surface pH toward normal. These sequences of
events suggested that the blood-brain barrier had remained intact.4 Changes in the brain surface pH and
blood pressure were noted within few seconds after
KCI injection. The brain surface pH fell to 6.80 pH
units within less than 3 minutes, a pattern seen in all 8
animals studied. In some cases we noted that the slope
of the fall in brain surface pH was interrupted by a very
small and transitory rise in pH lasting for few seconds
(fig. 3). The reasons for this are not well understood; a
similar alkaline shift in cerebellar ECF pH during ischemia has been observed by Kraig et al in rat."
Figure 2 shows changes in brain surface and cisternal CSF pH during cardiac arrest. The slopes of
changes were profoundly different; the brain surface
pH fell by 0.50 and CSF pH by 0.34 pH units, respectively 3 and 10 minutes after induction of cardiac arrest. The increments in the mean surface | H + | were
4.9 ± 3.6 (SD), 19.3 ± 4.5 and 79.6 ± 18.0nmol/l,
respectively 30, 60 and 120 seconds after induction of
-Bratn Surface
• Clsternal CSF pH
7.47.313-
7.0&9-
3
4
S
8
Time (minutes)
10
FIGURE 2. Changes in brain surface and cisternal cerebro\pinal fluid (CSF) pH during KCI induced cardiac arrest. pH
mlues were obtained from the respective mean (H+) shown in
table 1.
555
cardiac arrest; respective values for changes in CSF
| H + | were 1.7 ± 4.5 (mean ± SD, paired values)
3.1 ± 4 . 8 and 3.4 ± 4.8 nmol/1 and these values were
lower than the respective values of surface | H + |
with/? values of 0.09, <0.0001 and 0.0001, respectively (two tailed, unpaired t test). With time, however, cisternal CSF pH fell gradually (fig. 2; see later).
We emphasize that we did not measure the temperature in the suboccipital cistern and therefore we chose
to correct all CSF pH values to the animal's rectal
temperature rather than brain surface temperature. Although the temperature correction factor is small9 the
differences between surface and CSF pH values during
cardiac arrest would have been more pronounced if we
had used the lower brain temperature as the correction
factor for CSF pH values.
Changes in cisternal CSF acid-base variables and
| K + | (table 1) were characterized by a slow and
gradual rise in Pco2 and H + , K + and lactate concentrations and a fall in CSF P ^ and | HCOj | within the
ten minutes after cardiac arrest. These trends were
uniformly observed in all animals.
The mean arterial P ^ fell from 320 ± 70 torr (SD)
to 63.3 ± 33 and the mean arterial blood | H + | rose
from 45.5 ± 4.2 to 53.5 ± 1 1 . 2 nmol/1 after 10
minutes of cardiac arrest. The mean arterial P ^ fell
from 35.5 ± 3.0 to 20.0 ± 3.0 torr and PEc02 gradually fell and approached zero due to the high ventilationperfusion ratio (unchanged mechanical ventilation
with reduced venous return and cardiac output).
Discussion
The results of the present study demonstrate that
extremely rapid and profound changes in the brain
surface pH occur during cardiac arrest; most importantly, however, such pH changes are reflected very
slowly in cisternal CSF. The latter grossly underestimated the severity of the metabolic events which occurred within the brain during acute anoxic ischemia.
The continuous recording of brain surface pH coupled with periodic measurements of cisternal CSF pH
in this study, clearly demonstrated the time dependent
pH disequilibria which might exist between brain and
cisternal CSF during acute events. This observation
makes measurement of the changes in the latter fluid a
poor candidate for assessment of brain tissue acid-base
balance under such circumstances.
Four minutes after induction of the cardiac arrest,
the mean CSF P ^ and HCOj , K + and lactate concentrations had changed very little (table 1); the mean
brain surface and CSF pH had fallen, respectively by
about 0.5 and 0.2 pH units 3 minutes after cardiac
arrest (fig. 2). We are not aware of any other studies in
the literature to compare our data with, but the notable
difference in pH changes between the two fluids should
reflect the time-dependent diffusion processes occurring between CSF and ECF during cerebral ischemia;
specifically this represents the delayed permeation of
CO2 and organic acids into CSF from ECF as they
diffuse into the latter compartment from within the
brain cells. The rise in CSF P c02 as measured in the
556
STROKE
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present study and tissue PCQ, as measued by Severinghaus and Feustel12 was mainly due to nonmetabolic
CO2 generation via titration of HCOj with organic
acids produced in excess during cerebral ischemia;13- M
in this context it is noted that in cisternal CSF the fall in
the mean | HCOj | was 3.6 and the rise in lactate
concentration was 2.1 mEq/1, 10 minutes after induction of cardiac arrest.
The development of rapid and profound brain surface acidosis measured by surface pH electrodes in the
present study is similar to the previously reported pH
changes during acute cerebral ischemia as measured by
pH electrodes8-13-16 (see later) or biochemically.14 We
have observed similar brain surface pH changes during
Na-pentobarbital induced cardiac arrest in dogs. 17
Such profound pH changes are due to excessive production of organic acids13 '4 (or their equivalents; see
reference 18) as a result of anaerobic consumption of
glucose during cerebral ischemia. Assuming that similar brain pH changes may occur in man, it is noteworthy that brain function can return to normal after 3 to 4
minutes of cardiac arrest.
It may be argued as to how accurately the changes in
brain surface pH as measured in the present study as
well as several other studies 8 -" represent actual
changes which occur within the brain tissue, particularly in view of the acute nature of the study19 and the
potential influence of a slow or an asymmetric DC
potential shift developing during cerebral ischemia and
affecting the surface pH values. The latter argument
i.e. the influence of asymmetric potential changes on
pH is also applicable to pH measurements by microelectrodes when the reference barrel is not side by side
to the actual pH barrel.
To this end, in one animal we simultaneously measured both brain surface fluid pH, by placing our surface electrode on one cerebral hemisphere, and brain
ECF pH by inserting a double-barrelled microelectrode20-21 5 mm below the cortex into the other hemisphere. Although the steady state pH values were different, the slopes of changes were remarkably similar
during induction of cardiac arrest (fig. 3).
The double-barrelled microelectrodes had a tip-diameter of 30 ^iM with the tip of the reference barrel (10
IMM) next to the tip of the pH barrel (20 juM). The
resemblance of the two pH tracings, therefore, suggests that the pH changes recorded by the surface electrodes were not affected by either artifactual cortical
Pcoj changes or asymmetric or slow DC potentials
developing during cardiac arrest. Further studies using
intracerebral pH microelectrodes have shown similar
pH changes during cardiac arrest (unpublished observations).
In conclusion, profound changes occurred in brain
ECF pH during cardiac arrest and analyses of cisternal
CSF provided unreliable information about the magnitude of the severity of brain metabolic derangements
under such circumstances. We have also shown that
time dependent pH disequilibria exist between cisternal CSF and brain surface fluid during respiratory arrest22 as well as during transients of acute metabolic
VOL 15, No
3, MAY-JUNE
1984
^
I
o
s
m
&
o o
o —
•
,
it
r
"
m
&
S
t
&
to
o
s
FIGURE 3. Changes in the mean arterial blood pressure and
brain extracellular fluid (ECF) and surface pH during KCl
induced cardiac arrest in one animal? the surface pH electrode
was placed on one cerebral hemisphere while a microelectrode
was inserted sterotaxically and under microscopic observation
into the other hemisphere (5 mm below the surface). The tip of
the double-barrelled microelectrode (the tip of the reference
and the pH sensitive electrodes combined) was about 30 fim.
Presumably a micropocket is formed around the tip of the microelectrode and is in equilibrium with brain ECF. The resemblance of pH changes on the surface and within the brain observed during cardiac arrest is remarkable. Since the brain
surface pH was recorded by a different recorder, it was drawn
manually at the same magnification as that of ECF pH; the
insert shows the original, however. Note the transient alkalinity
in ECF pH pointed out in the text. Extravasation of intravenously infused Evans blue showed part of the tract of the microelectrode with the most distal part being macroscopically invisible; knowing that microelectrode was inserted 5 mm below the
surface, we believe that the tip was located either at the depth or
in the very close proximity of the nadir of the invaginating
cortex.
For description of circuitry used with microelectrodes see
references 20 and 21.
This experiment was performed by the author while in the
Department of Normal Physiology and Pathological Physiology, Gent University, Gent, Belgium.
acid base perturbations.3-M In this context, other investigators have shown that during ischemia or hypoxia
rapid and pronounced changes occur in cerebral ECF
electrolyte composition;23 specifically ECF K + and
lactate concentrations have been shown to rise relatively abruptly24"27 while respective changes in CSF as
shown in the present study (table 1) as well as by
others24 28 occur relatively slowly. Therefore, taken
together, all these studies suggest that caution should
be taken in relying on changes in cisternal CSF for an
assessment of brain metabolic status during acute
events.
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S Javaheri, A Clendening, N Papadakis and J S Brody
Stroke. 1984;15:553-557
doi: 10.1161/01.STR.15.3.553
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