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Cerebral physiological and metabolic effects of hyperventilation in the neonatal dog.

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Cerebral Physiological and Metabolic Effects
of Hypervendation in the Neonatal Dog
Richard S. K. Young, MD, and Susan K. Yagel, BS
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To clarify the changes that occur during marked hypocarbia in the neonate, we measured brain blood flow and
metabolite levels after 90 minutes of hyperventilation in neonatal dogs. Brain blood flow decreased significantly in
diencephalon, brainstem, and spinal cord but not in cerebral cortex or white matter. There was no substantial change in
the electroencephalogram. Lactate concentrations, both in telencephalon and in superior sagittal sinus blood, increased
significantly, dthough there was no alteration in levels of ATP or phosphocreatine. Marked hypocarbia in the neonatal
dog produces an elevated brain lactate level that may be related to changes in glycolytic rate rather than to tissue
ischemia or hypoxia.
Young RSK, Yagel SK. Cerebral physiological and metabolic effects of hyperventilation in the neonatal dog.
Ann Neurol 16 337-342, 1984
Hyperventilation has a profound effect on cerebral hemodynamics in the adult brain. T h e hypocarbia that
results from hyperventilation may reduce cerebral
blood flow (CBF) by as much as 50% in the adult
human and animal [ 5 , 11, 221. The effect of marked
hypocarbia on brain blood flow and metabolites in the
neonatal animal has not been fully defined, however {2,
10, 241. Some assert that the cerebrovascular responsiveness of the newborn human is at least as sensitive to
changes in arterial carbon dioxide tensions as is that in
the adult human [25]. Others have found little o r no
decline in neonatal cerebral blood flow with marked
hypocarbia [2].
The cerebral metabolic consequences of prolonged
hyperventilation in the neonate are also uncertain. The
elevations in lactate levels in both cerebrospinal fluid
and brain [13, 14, 191 that accompany prolonged hyperventilation in the adult human and laboratory
animal have been ascribed to tissue ischemia resulting
from marked vasoconstriction and to decreased oxygen
availability during alkalosis (the Bohr effect). To determine whether prolonged hyperventilation may also
lead to brain ischemia and elevation of brain lactate
levels in the neonate, we measured CBF and levels of
brain glucose, lactate, ATP, and phosphocreatine (PCr)
after 90 minutes of hyperventilation in neonatal dogs.
nance) in oxygen by mask. They were then tracheostomized,
paralyzed with pancuronium bromide ( 1 mgjkg, subcutaneously), and mechanically ventilated (Harvard small animal
ventilator) with a gas mixture consisting of 30% oxygen and
70% nitrous oxide (for analgesia). After infiltration of the
groin with local anesthetic (xylocaine, lp, 1.0 ml), the
femoral arteries and vein were exposed and catheterized with
30 gauge TeAon catheters. One femoral artery catheter was
used to monitor heart rate and mean arterial blood pressure
continuously with a Statham transducer and to withdraw arterial blood samples (200 PI) anaerobically for determination of
pH, arterial carbon dioxide tension (PaCOZ),and arterial oxygen tension (PaOz) (Radiometer, Model BMS 3-Mk 2) and
glucose, lactate, and catecholamine concentrations. Plasma
glucose levels were measured in duplicate using a Beckman
Glucose Analyzer 11; lactate levels were measured spectrophotometrically (Beckman, DU 6) using highest quality
reagents (Sigma) and standard enzymatic analyses [3]. Plasma
catecholamine concentrations were determined by radioenzymatic assay [18]. Body temperature was monitored with a
rectal thermocouple (Yellow Springs Telethermometer) and
maintained at 37°C by a servocontrolled heating lamp.
In the control animals (normocarbic group), ventilatory
rate and tidal volume were adjusted to maintain arterial normoxia (90 to 125 Torr) and normocarbia (35 to 40 Torr). In
the experimental animals (hypocarbicgroup),ventilatory rate
and tidal volume were adjusted to maintain PaCOz between
15 and 20 Torr. Hypocarbia was maintained for 90 minutes
in the experimental animals, and normocarbia in the control
animals for an equivalent amount of time.
Methods
Systemic Factors
Cerebral Physiology
Mongrel dogs (1 to 10 days old) of both sexes were rapidly
anesthetized with halothane (3.0%, induction; O.SC/c, mainte-
The electroencephalogram (EEG) was continuously recorded
with a Beckman polygraphic recorder utilizing scalp elec-
From the Division of Neurology, Department of Pediatrics, The
Milton S. Hershey Medical Center, Pennsylvania State University,
Hershey, PA.
Address reprint requests to Dr Young, Division of Neurology, Department of Pediatrics, The Milton S. Hershey Medical Cmrcr,
Pennsylvania State University, P O Box 850, Hershey, PA 17033.
Received Oct 17, 1983, and in revised form Jan 4 , 1984. Accepted
for publication Feb 12, 1984.
337
trodes (Model R13). CBF was measured as previously described 1261. Briefly, 50 pCi of [ ''C]iodoantipyrine (Amersham) was infused intravenously at a constant rate over a
60-second period. During the infusion, drops of arterial
blood were serially collected at a rate of three drops per
second and later analyzed (20 p1sample) for radioactive content in a liquid scintillation counter (Beckman, LS 3155P).
The blood circulation of the animal was stopped by injecting
a solution of pentobarbital sodium (50 mg/kg) and potassium
chloride into a catheter situated in the inferior vena cava. The
brain was removed within 5 minutes, quick frozen in Freon
12 ( - 29"C), and sectioned at 40 I*. intervals in a cryostat. The
sections were mounted on glass slides, which were then applied to single-emulsion mammography film with a set of "C
reference standards (Amersham). Calibration curves were
obtained for each area of film by relating the optical density
of each area of brain to ['4Cliodoantipyrine concentrations.
Four control and five experimental animals were studied.
Cerebral Metab0lite.r
A separate group of animals was used for cerebral metabolic
determinations (four control and seven experimental animals). Animals were first tracheostomized and catheterized as
described previously. The scalp was infiltrated with xylocaine
(l%), incised, and reflected back. A plastic funnel was then
directly affixed to the exposed skull and sutured in place. The
animal's head was secured to a stereotaxic frame (Harvard
Apparatus), and a 22 gauge metal cannula was lowered into
the superior sagittal sinus. The cannula was fabricated with a
Silastic sleeve [12) for the anaerobic measurement of cerebral pH, venous oxygen tension (Pv02), venous carbon dioxide tension (PvCOz), and glucose and lactate concentrations.
Following 90 minutes of either normocarbia or hypocarbia,
the brain was prepared for determination of cerebral metabolite levels by the funnel freezing method [21). Liquid nitrogen was poured into the funnel for 5 minutes, after which the
animal was decapitated and the head immersed in liquid nitrogen. Brains were stored in a freezer at -80°C (Revco).
The brains were later dissected from the calvaria in a cold
room. A 50 mg sample of cerebral cortex and underlying
white matter was chiseled free under liquid nitrogen irrigation, extracted into perchloric acid, and spectrophotometrically assayed for tissue concentrations of ATP, PCr, lactate,
and glucose using highest quality reagents and standard enzymatic analyses [ 3 ] .
Statistical Analysis
Statistical analyses were made by comparing the systemic and
cerebral physiological and metabolic changes in the normocarbic and hypocarbic animals using a Tektronix 405 1
computer. The Student t test was used to compare two sets of
data. All values cited are means ? SEs.
Results
Systemic Alterations
After 90 minutes the experimental animals were
significantly hypocarbic ( p < 0.05, Student t test) compared with the control animals (Table 1). Arterial p H
was significantly higher in the hypocarbic animals.
338 Annals of Neurology Vol 16 No 3
Table I . Physiological and Metabolic Variables in Neonatal
Dogs After 90 Minutes of Normocarbia or Hypocarbia"
Condition
Variable
Systemic physiological
variables
Pulse (beatshin)
Blood pressure
(mm Hg)
Systemic metabolic
variables
Pa02 (mm Hg)
PaCOz (mm Hg)
pH (arterial blood)
Base deficit (mmoVL,
arterial blood)
Epinephrine (nmoVL,
arterial blood)
Norepinephrine
(nmoVL, arterial
blood)
Lactate, arterial
(mmoVL)
Lactate, plasma
venous (mmoVL)
Glucose, arterial
(mmoVL)
Normocarbic
209 ? 13
61 t 3
97
39
?
6
-+
1
0.01
*
Hypocarbic
230
?
6
59
k
2
114
?
7
17
L
lh
-3 t 1
7.49 t 0.01b
-7 t 1'
218 t 53
744 t 192'
213
5
64
356 +- 30'
2.35
2
0.33
7.35
2.68 t 0.44
9.81 t 0.96
4.93 t 0.42"
6.03
?
1.49'
10.62 t 0.71
"All values are expressed as means 2 SEs; data represent pooled
measurements of five to twelve animals.
Statistical significance (difference from normocarbic group by Student r test): ' p < 0.001; ' p < 0.05; ' p < 0.01.
PaOz = arterial oxygen tension; PaCOL = arterial carbon dioxide
tension.
There was no significant difference between the two
groups in PaOz, arterial glucose level, arterial blood
pressure, or heart rate. The hypocarbic animals had
significantly higher plasma arterial levels of epinephrine and norepinephrine. Lactate concentrations in
both arterial and plasma venous blood were elevated in
the hyperventilated animals after 90 minutes (see Table
1). The accumulation of lactate in the hypocarbic animals was sufficiently great to produce a significant base
deficit in arterial blood (see Table 1).
Cerebral Physiological Changes
Blood flow was measured in fifteen regions of brain
(Table 2). In the control animals CBF was highest in
diencephalon, brainstem, and spinal cord and lowest in
telencephalic white matter. After hyperventilation for
90 minutes, there were significant decreases in CBF
only in diencephalon, caudal brainstem, and spinal cord
(see Table 2).
The EEG of the normocarbic animals consisted of
low-voltage, fast activity (Figure). The EEG of the animals subjected to 90 minutes of hyperventilation
showed little difference from that of the normocarbic
animals.
September 1984
Table 2. Cerebral Blood Flow in Normocarbic
and Hypocarbic Neonatal Dogs"
Condition
Normocarbic Hypocarbic
Region
(n = 4 )
(n = 5 )
5% Change
Frontal cortex
Parietal cortex
Temporal
cortex
Occipital cortex
Caudate
Hippocampus
Thalamus
Hypothalamus
Cerebellum
Corpora
quadrigemina
Pons
Medulla
Spinal cord
corpus callosum
Centrum
semiovale
33 2 1
32 2 3
24 2 2
30 2 4
38 2 4
22 r 2
- 10
33
2
+ 18
22
27
32
22
30
27
3
2 3
2 Zb
27
25
25
43
34
31
34
f2
2 3
f4
48
45
31
14
8
t 3
f 1
f2
4
t2
f2
2 4
2
f2
2 2
4
2
2'
2
+- 3
f
2
32 f 4b
27 ? 2'
25 ? 3b
14 2 2
7 2 1
+ 16
-9
- 14
+7
- 34
-55
-3
- 26
- 50
- 67
- 48
0
- 14
"All values are expressed as means ? SEs in milliliters per 100 gm
per minute. Statistical significance (difference from normocarbic
group by Student t test): ' p < 0.05; ' p < 0.01.
Electroencephalogram in normocarbic and hypocarbic dogs. There
is no substantial difference between the two conditions.
Cerebral Metabolic Changes
Lactate levels in blood from the superior sagittal sinus
were significantly elevated after 45 minutes (normocarbic, 1.91 ? 0.18 mmoYL; hypocarbic, 3.20 f
0.29 mmoYL, p < 0.01) and 90 minutes (normocarbic,
2.25 ? 0.26 mmovL; hypocarbic, 4.97 & 0.42 mmoY
L p < 0.001) of hyperventilation. Similarly, brain lactate concentration was elevated in the animals subjected to hyperventilation for 90 minutes (normocarbic, 1.85 5 0.13 mmollkg; hypocarbic, 3.03 2 0.28
mmollkg; p < 0.001). Despite the elevation of lactate,
however, there was no significant difference between
the normocarbic and hypocarbic animals in brain glucose levels (normocarbic, 3.41 ? 0.55 mmoYkg; hypocarbic, 4.53 & 0.59 mmoI/kg); ATP (normocarbic, 2.11 & 0.08 mmollkg; hypocarbic, 2.35 f 0.19
mmol/kg); or PCr (normocarbic, 2.45 ? 0.18 mmol/
kg; hypocarbic, 2.52 f 0.16 mmollkg).
The arteriovenous oxygen tension difference (Pcav)Oz) was not significantly different in control and hypocarbic animals (Table 3). The arteriovenous lactate
content difference (Cla-vllactate) was positive in the
normocarbic animals but negative in the hypocarbic
animals, and the values for the normocarbic and hypocarbic groups were almost significantly different Cp <
0.08). In the hypocarbic animals there was a nearly
significant increase in the arteriovenous glucose content difference (Cca-v)glucose) before and after hyperventilation (0 minutes, 0.10 & 0.49 mmoVL; 90 minutes, 1.15 ? 0.28 mmoa, p = 0.05).
F p l - P3
Fp2 - P,
Fpl
- Fp2
p3
-
Pb
NORMOCARBIC
Fpl -PI
Fp2 - P,
Fpl
- Fp2
p3
-
p4
HYPOCARBIC
Young and Yagel: Brain Blood Flow and Metabolism during Hyperventilation
339
Table 3, Cerebral Arteriovenous Differences"
Condition
Difference
Normocarbic Hypocarbic
C(a-v)Ol (mm Hg)
C(a-v)glucose (mmoVL)
C(a-v)lactate (mmoVL)
49
0.68
0.10
~
~~
~
5
5
5
0.20
* 0.07
81 ? 19
1.15 t 0.26b
-0.25 ? -0.17
~
"All values are expressed as means 5 SEs, data represent pooled
measurements of five co twelve animals
bSignificanrly different from 0 minutes (p < 0.05).
Discussion
In the adult human, hypocarbia that results from hyperventilation produces a significant reduction in CBF and
may lead to mental confusion and seizures (11. Previous work has also shown that hyperventilation can
cause alterations in the EEG that resemble those seen
during hypoxia, and that hyperbaric oxygenation during hypocarbia reverses those alterations {19]. The cerebral physiological and metabolic effects of prolonged
hyperventilation in the neonate are less well understood.
The effect of hypocarbia on CBF has been examined
previously in the neonatal dog ( 2 , 241 and in other
animals ( 2 0 , 231. Batton and colleagues (21 measured
CBF in twelve regions of neonatal canine brain during
hypocarbia employing the {"CCfiodoantipyrine technique. There was a trend toward a reduction in CBF in
posterior fossa structures, with a statistically significant
decline occurring in diencephalon. Our CBF data agree
with those of Batton and colleagues and show that
those areas of brain having the highest blood flowdiencephalon and brainstem-are
the only areas to
undergo significant reductions in flow during hypocarbia.
The only other study delineating regional changes in
CBF during hypocarbia in the neonatal dog is that of
Shapiro and associates [24]. The findings of that study
cannot be compared directly to the present results or
those of Batton and colleagues, however, for two reasons. First, Shapiro and associates employed the indicator ['*CC)antipyrine. Experiments by Eckman and coworkers (61 show that antipyrine is diffusion limited
and that its use may cause underestimation of blood
flow by as much as 50% compared with determinations
with ['4C}iodoantipyrine {6,171. The second reason
precluding easy comparison of the present study with
that of Shapiro and colleagues is the difference in
PaC02 in the control population. The animals in the
present study had a mean PaC02 22 mm H g lower
than that of the control group (control, 39 mm Hg;
hypocarbic, 17 mm Hg). In contrast, the mean PaC02
in the hypocarbic group in the study by Shapiro and
colleagues was only 12 mm Hg lower than that of the
group with which they were compared (control, 34 mm
Hg; hypocarbic, 22 m Hg). The difference in mean
340
PaC02 between control and hypocarbic animals in the
study by Batton and co-workers occupies the middle
ground (control, 37 mm Hg; hypocarbic, 22 mm Hg;
difference, 15 mm Hg). Ir is therefore plausible that
significant reductions in CBF occurred in diencephaIon, brainstem, and spinal cord in the present study,
only in diencephalon in the study of Batton and colleagues, and in neither brainstem nor diencephalon in
the study by Shapiro and associates because of the differences in the degree of hypocarbia experienced by
the experimental animals versus the degree of normocarbia in the control animals with which the hypocarbic animals were compared.
CBF in periventricular white matter and corpus callosum did not change significantly. Structures with the
greatest responsivity to hypocarbia-diencephalon,
brainstem, and spinal cord-have the highest rates of
blood flow, are the most myelinated in the neonatal
period, are the oldest phylogenetically, and exhibit the
greatest responsivity to hypercarbia (41. Cavazzuti and
Duffy {41 maintain that carbon dioxide reactivity is
most pronounced in structures that exhibit high control
blood flows and functional maturity (e.g., brainstem
and spinal cord) because of neurogenic influences that
appear only after new synaptic connections are well
established. Telencephalic white matter, as opposed to
diencephalon, spinal cord, or brainstem, myelinates relatively late {7}. Cavazzuti and Duffy conclude that
white matter blood flow in the neonatal dog is only
marginally responsive to changes in PaC02, whereas
the sensitivity of specific brainstem nuclei to carbon
dioxide is considerable. Thus, with the exception of the
mentioned somewhat lower diffusibility of antipyrine,
we are unable to provide an explanation for the observation of Shapiro and colleagues {24] that during hypocarbia only subcortical white matter experiences
significant decreases in CBF.
Control values for CBF in the present study are
somewhat higher than those previously reported from
this laboratory (261. This result may be attributable to
the heterogeneity of the mongrel animals used in these
experiments. Our normative CBF data in this study are
consistent with those of other investigators using the
('*C}iodoantipyrine method, however ( 2 , 4, 17).
Less has been written about the cerebral metabolic
than the cerebral physiological consequences of hypocarbia in the neonatal dog. Perhaps the most striking
finding in these experiments has been the increase in
lactate concentrations in telencephalon and in superior
sagittal sinus blood in the hypocarbic animals. Studies
of a variety of adult animals including rat (8, 13, 141,
cat (91, dog 1191, and humans {I] document that hypocarbia produces an increase in lactate, both in cerebrospinal fluid and in brain. MacMillan and Siesjo [ 1 4 ]
recorded brain lactate concentrations of 3.42 and 5.25
mmoVkg at carbon dioxide tensions of 21 and 14 mm
Hg, respectively, in the rat. Ishitsuka [13] suggests that
Annals of Neurology Vol 16 No 3 September 1984
in the hyperventilated rat, lactate accumulation results
from both decreased brain perfusion and a decrease in
transfer of oxygen from blood to tissue (Bohr effect).
Is the neonatal dog brain partially responsible for the
increased lactate levels measured in sagittal sinus
blood? Because lactate readily passes between blood
and brain in the neonatal dog 1121, unlike its adult
counterpart [191, it might be argued that lactate from
the systemic circulation was entering the brain and then
exiting through the sagittal sinus. The C(a-v)lactate was
positive in the control animals but negative in the hypocarbic animals, however. In addition, the difference
in C(a-v)lactate in normocarbic and hypocarbic animals
approached significance (p < 0.08). Gregoire and colleagues [lo] also observed a negative (though smaller)
C(a-v)lactate in hypocarbic puppies and suggested that
some of the lactic acid was being produced by the
brain. Actual levels of arterial lactate were not elevated
in the hypocarbic animals in the study of Gregoire and
co-workers, although the degree of hypocarbia in their
animals was considerably less than that present in our
hypocarbic animals (PaC02, 3 1 mm Hg; present study,
17 mm Hg).
Does tissue ischemia play a major role in the genesis
of elevated cerebral venous and brain lactate levels in
the neonatal dog? We do not believe so. The only areas
developing significant reductions in CBF were deep
cerebral gray matter and brainstem. In contrast, the
mean values for CBF in four areas of cerebral cortex
are similar in the control and hypocarbic animals (normocarbic, 27 t 2 mV100 g d m i n ; hypocarbic, 31 -C
3). Blood from the superior sagittal sinus is derived to a
large extent from the cerebral cortex. Thus, after only
45 minutes of hyperventilation, significant elevations of
lactate level occur in blood from the cortical surface of
brain, which is undergoing little or no reduction of
blood flow.
Could brain hypoxia be the cause of the elevated
brain lactate levels? Although the present results do
not provide a clear-cut answer to this question, several
lines of evidence suggest that tissue hypoxia does not
occur. First, oxygen tensions in arterial blood were
never in the “hypoxic” range. Second, arteriovenous
oxygen content differences were not significantly different in the hypocarbic and normocarbic animals, as
has been previously noted in mildly hypocarbic puppies [lo] and markedly hypocarbic humans {l}.Third,
no changes in EEG were seen during hypocarbia in
these neonatal animals. Most important, the hypothesis
that brain hypoxia results in increased brain lactate is
considerably weakened by the fact that there was no
perturbation of ATP or PCr levels in our hypocarbic
animals.
Is there an alternate explanation regarding the mechanisms of lactate production during hypocarbia? Plum
and Posner [19] and MacMillan and Siesjo [ 1 4 ] have
argued that alkalosis may trigger increases in lactate.
Incubation of brain in alkalotic solutions leads to increased amounts of lactate even in the presence of hyperbaric oxygen fl9]. The mechanism may be the
stimulation of phosphofructokinase, leading to acceleration of glycolysis and increased lactate production.
The activity of this allosteric enzyme may be enhanced
by two modifiers that were present in our hypocarbic
animals: tissue alkalosis and epinephrine release { 151.
The effect of pH is critical in determining the kinetics
of phosphofructokinase. A change of as little as 0.2
unit in the p H of a reaction mixture about the neutral
point can cause a considerable change in activity. Epinephrine (which increased significantly in our hypocarbic animals) also strongly stimulates phosphofructokinase activity by increasing the amount of cyclic
adenosine monophosphate [ 151.
The present data suggest that increased glycolysis
occurred in the hypocarbic animals. After 90 minutes
of hyperventilation, the C(a-v)glucose was nearly significantly different from that prior to the onset of hyperventilation (p = 0.05). Although Gregoire and colleagues [lo] did not find any change in C(a-vjglucose in
their hypocarbic animals, it is important to recognize
the considerable difference in the degree of hypocarbia
in their hypocarbic group and that in the present study.
It is likely that some of the production of lactate is
attributable to tissues other than brain. After 90 minutes the increase in lactate levels in femoral venous
blood (reflecting metabolism of leg muscle) in the hypocarbic animals is significantly greater than that in the
normocarbic animals. Alkalosis secondary to bicarbonate infusion triggers an increase in lactate in muscle
El5, 191, presumably resulting from stimulation of
phosphofructokinase f l 5 , 161.
Thus, marked hypocarbia in the neonatal dog produces significant decreases in CBF only in the deeper,
phylogenetically older areas of brain that have high
control blood flows: spinal cord, diencephalon, and
brainstem. Lactate levels rise in cerebral venous blood,
in brain, and in systemic blood. Although the present
report does not precisely indicate what triggers the elevation in lactate levels during hypocarbia in the
neonatal dog, tissue alkalosis and subsequent changes
in glycolytic rate may play a larger role than tissue
ischemia or hypoxia.
Presented in part at the Twelfth Annual Meeting of the Child Neurology Society, Williamsbug, VA, Oct 13, 1983.
Supported by Grant NS-17039 from the National Institute of
Neurological and Communicative Disorders and Stroke to Dr
Young. Dr Young is a recipient of a Clinician-Scientist Award from
the American Heart Association.
The authors are grateful for the advice of Drs R. Hawkins, H. Morgan, and E. Rannels; for the secretarial assistance of Tina M Gingrich
and Mae Wallace; and for the encouragement of Dr Nicholas Nelson. Catecholamine assays were kindly done by John Seton (laboratory of Dr Timothy Harrison).
Young and Yagel: Brain Blood Flow and Metabolism during Hyperventilation
34 1
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Neurol 12:445-448, 1982
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physiological, effect, metabolico, hyperventilation, neonatal, dog, cerebral
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