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Cerebral metabolism in newborn dogs during reversible asphyxia.

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Cerebral Metabolism in Newborn
Dogs During Reversible Asphyxia
Robert C . Vannucci, MD, and Thomas E. Duffy, P h D
Acute, systemic asphyxia was induced in paralyzed, lightly anesthetized 1- to 2-day-old dogs by respiratory arrest.
Measurements of arterial blood pressure, acid-base balance, and concentrations o f pyruvate, lactate, and glucose in
blood were correlated with electroencephalographic activity and with concentrations of high-energy phosphates and
glycolytic substrates in the cerebral cortex. Most animals tolerated 1 5 minutes, but not 20 minutes, of asphyxia with
apparmtly normal behavioral recovery. Asphyxia was always accompanied by bradycardia, systemic hypotension,
and aprogressive decline in arterial pH; the concentration of blood lactate and the lactate/pyruvate ratio rose. Blood
glucose levels were unaffected, at least during the first 10 minutes. Concentrations of glucose and phosphocreatine in
cerebral cortex declined rapidly during asphyxia to low levels, but levels of adenosine triphosphate remained within
normal limits for up to 5 minutes despite the fact that electrical activity in brain ceased within 2 minutes. The
intravenous injection of carbon black into animals asphyxiated for 21/2, 5, 10, or 15 minutes revealed substantial
reductions in blood flow to brain during asphyxia; however, relative to the cerebral cortex, brainstem structures
received a preferential blood supply.
Vannucci RC, Duffy TE: Cerebral metabolism in newborn dogs during reversible asphyxia.
Ann Neurol 1:528-534, 1977
Perinatal asphyxia is a major complication of birth and
of early postnatal life that may lead to brain damage
and the chronic sequelae of cerebral palsy, epilepsy,
and mental retardation [ l , 21. Whereas asphyxia in
adult animals, including man, rapidly causes death or
permanent brain injury [3], it has long been recognized that newborns are more resistant to such insults
14-61. The greater tolerance of developing animals to
anoxidasphyxia reflects in part the lower cerebral
energy demands [7-91 and more resistant cardiovascular system [lo, 111 of the immature animal, but
other factors may also play a role.
Most experimental studies of neonatal asphyxia
have been performed on large animals, notably sheep
and monkeys, and have focused on physiological and
neuropathological changes [ 12- 141. Measurements
of carbohydrate and energy metabolism in brain during asphyxia have generally been restricted to rodents
[15, 161, owing to difficulties involved in freezing a
larger brain rapidly enough to preserve labile metabolites; in those experiments, physiological variables
were neither monitored nor controlled.
We decided, therefore, to extend these studies to
newborn dogs and to combine measurements of cardiovascular and cerebral function during asphyxia
with meawrements of the concentrations of highenergy phosphates and glycolytic substrates in the
528
cerebral cortex. The findings indicate that acute asphyxia rapidly leads to systemic hypotension and a fall
in cerebrocortical blood flow but that brainstem structures are preferentially perfused, at least temporarily.
When cortical ischemia ultimately occurs, tissue
adenosine triphosphate (ATP) levels slowly decline
but are never exhausted, even at the point of imminent death. This work was presented in part at the
Twenty-seventh Annual Meeting of the American
Academy of Neurology, Bal Harbour, FL, May 1975
[171.
Experimental Procedures
Purebred Beagle dogs of both sexes, 1 to 2 days old, were
obtained from White Eagle Farms, Doylestown, PA. The
pups were fed a simulated bitch's milk while housed in
Lucite animal boxes that were maintained at 33" to 35°C.
All experimental studies were performed o n paralyzed,
artificially ventilated animals that were lightly anesthetized
with nitrous oxide. The pups were initialiy anesthetized with
255 halothane, tracheostomized, and ventilated with a mixture of 17; halothane, 29% oxygen, and 70% nitrous oxide
by a Harvard respirator. Paralysis was achieved with either
d-tubocurarine chloride (2mg per kilogram of body weight)
or, in survival studies, succinylcholine (2 mglkg) administered subcutaneously.Tidal volume was set at 3.7 to 4.5 ml
at a rate of GO breaths per minute. These variables were
periodically adjusted to maintain arterial blood acid-base
homeostasis (Pao, > 80 mm Hg; Paco, = 33 to 37 mm H g ;
arterial pH = 7.37 to 7.40).Rectal temperature was brought
to and maintained at 37.0" ? 0.5"C with a thermistorcontrolled heating lamp. A catheter was inserted into the
right femoral artery for continuous recording of blood
pressure and for sampling of blood. The scalp was incised
along the midline, and a small plastic funnel was positioned
over the skull for subsequent freezing of the brain in situ
[ 181. T h e scalp wound edges were snugly approximated with
sutures to thc perimeter of the funnel, and the area was
infiltrated with 1% xylocaine. Bipolar needle electrodes
were inserted subcutaneously into the lateral chest wall and
under the scalp for monitoring the electrocardiogram and
the electroencephalogram. Pao,, Paco,, and arterial pH
were measured at 37°C on anaerobically obtained blood
samples (0.1 ml), using calibrated microelectrodes (L. Eschweiler and Co, Kiel, West Germany).
When all surgical procedures were complcted, halothane
was withdrawn and ventilation was continued with
oxygen-nitrous oxide (30 to 70tZ) for an additional 30
minutes. Brains of control animals that exhibited no E K G or
EEG abnormalities during the equilibration period were
frozen in situ by pouring liquid nitrogen into the scalp
funnel for at least 5 minutes. Experimental dogs were
subjected to systemic asphyxia by discontinuing mechanical
ventilation and simultaneously cross-clamping the respiratory lines. Brains of experirriencal animals were frozen in
situ at intervals following complete respiratory arrest. Some
asphyxiated pups were resuscitated afcer 10, 15, or 20
minutes of asphyxia in order to assess survival capabilities.
Other control and asphyxiated animals received an intravenous injection of fineiy divided carbon black' (25 mlikg at
the rate of 2 mIimin); after 3 minutes of circulation, the
animals were decapitated and the brains were removed and
immersed in formaldehyde-glacial acetic acid-absolute
methanol (1 : 1: 8).
Frozen brains with intact crania were stored at -80°C
until the time of dissection and extraction. Specimens were
bisected in the sagittal plane at -20"C, and sections of
precuneal cortical gray matter were dissected to a depth of 3
"Prepared for biological use by Pelikan Werke, Guenther Wagner,
Hanover, West Germany. Prior to use the suspension (particle size
20 to 30 nm) was filtered through Whatman No. 2 paper, and
osmolality was adjusted to 275 to 300 mOsm per liter with NaCl
[191.
mm. Cortical samples were powdered under liquid nitrogen
and weighed at -20"C, and perchloric acid extracts of the
tissues were prepared as described previously [201. Substrates in brain and whole blood were measured fluorometrically with pyridine nucleotides and appropriate enzymes.
The methods for ATP, adenosine diphosphate (ADP),
adenosine monophosphate (AMP), phosphocreatine, lactate, pyruvate, and glucose were essentially those described
by Lowry and Passonneau 1211, with minor modifications
[20, 223.
Results
Threshold of Asphyxia for Surviz)al
Trials were conducted to determine the maximum
asphyxia1 insult that newborn dogs could tolerate and
still recover clinically. Asphyxiated animals were resuscitated at a rate and depth of respiration identical to
that delivered prior to respiratory arrest. If pulse and
blood pressure recordings revealed improving cardiovascular function, the animals were gradually
weaned from the respirator and allowed to breathe
spontaneously through the tracheostomy tube. Clinical recovery was assessed in terms of (1)ability to suck
and feed, (2) coordinated movements, (3) righting
reflexes, and ( 4 ) avoiding responses to noxious
stimuli. Based upon these criteria, 3 out of 3 pups
tolerated 10 minutes of asphyxia, 4 out of 6 tolerated
15 minutes of asphyxia, but only 1 out of 4 tolerated
20 minutes of asphyxia. Therefore, respiratory arrest
for 15 minutes was taken as the threshold for subsequent physiological and biochemical studies.
Physiological Chunges during Asphyxia
Systemic asphyxia was associated with major alterations in arterial blood acid-base balance and in cardiovascular function. Within 295 minutes after respiratory arrest Pao, had fallen to 4 mm Hg. Carbon
dioxide tension increased progressively during asphyxia and arterial p H declined, such that after 10
minutes Pace, had nearly tripled and arterial p H was
below 6.8 (Table 1). Blood was unobtainable beyond
10 minutes owing to severe hypotension (to be dis-
Table 1 . Effect of Asphyxia on Acid-Base Balance and on Concentrations of
Glzlcose, Lartate, and Pyrmate i n Arterial Blood of Newborn Dogs"
Treatment
Paco,
(mm Hd
C o n t r o l ( N = 19)
35.0 t 1.0
Asphyxia
2% min (N = 12) 50.7 % 2.Q
5 m i n ( N = 9)
82.1 t 7.1"
1 0 m i n (N = 6 )
39.7 + 8.6b
PH
Glucose
(mmol/L)
7.38 2 0.01
5.91
7.18 t 0.06'
7.03 2 0.02h
6.79 t O . O j b
6.05 ? 0.78
5.88 I 1.03
6.57 i. 1.89
=k
0.74
Lactate
(mmoliL)
2.65
k
0.25
2.78 2 0.25
6.75 2 0.77b
10.15 2 0.59b
aValues represent means 5 1 SEM for the numbers of animals shown in parentheses.
bDifferent from control with p < 0.001.
c p < 0.01.
Pyruvate
(mmoI/L)
0.102
2
0.007
Lactate /
Pvruvate
26
*1
30 k 2
0.090 ? 0.004
0.075 2 0.006'
96 +- 15h
0.061 k 0.002h 167 2 1 l b
Vannucci and Duffy: Cerebral Metabolism in Experimental Asphyxia
529
Table 2. Concentrations of Glyrolytic Substrates and of
High-Energy Phosphates i n Dog Cerebral Cortexa
Concentration (mmol/kg)
80
40
0
0
2
4
6
8 1 0
Minutes of asphyxia
1
2
'IJ
14
0
F i g 1. Heart rate (HR)andbloodpressure (BP)i n newborn
dogs during asphyxia. Valuesfor heart rate are expressed as
beats per minute. Points represent means of 19 puppies (0
min). 12 puppies ( 1 to 2 min), 9 puppies 14 min), 6
pf~ppies
(6 to 10 mzn), a n d 3 puppies (12 to 14 min).
Vertical lines denote
1 SEM.A representative E E G showing
the effect of 14 minutes of asphyxia is superzmposedat the top.
The arrow indicates the beginning of respiratory arrest.
*
cussed). Blood lactate and pyruvate concentrations
were unchanged after 2% minutes of asphyxia, but by
10 minutes lactate had increased nearly fourfold and
pyruvate had decreased by 40%; the lactate/pyruvate
ratio was therefore increased to more than five times
normal. Blood glucose levels remained within normal
limits during the entire 10-minute period.
Mean arterial blood pressure increased slightly ( p <
0.05) during the first minute of respiratory arrest,
then declined to a low of approximately 10 mm H g
after 14 minutes (Fig 1). Heart rate was unchanged
during the first minute of asphyxia but decreased
abruptly between 1 and 2 minutes, and profound
bradycardia was recorded thereafter. Electroencephalograms, monitored in 7 animals during asphyxia,
showed no discernible abnormalities prior to 1 minute. Between 1 and 2 minutes there was a characteristic reduction in amplitude and frequency of the electrical activity, and by 29'2 minutes the EEG became
isoelectric (see Fig I).
High-Energy Phosphates and Glycolytic Substrates in
Cerebral Cortex
Concentrations of high-energy phosphates and
glycolytic substrates in cerebral cortex of normal puppies are compared in Table 2 with data for adult dogs
obtained by Drewes and Gilboe [23]. Glucose concentrations were similar in newborn and adult animals; the bradblood glucose ratio for puppies was
0.43, a value in agreement with the brainlblood glu-
530 Annals of Neurology Vol 1 No 6 June 1977
Substrate
Newborn
Adultb
Glucose
Pyruvate
Lactate
Lactate/pyruvate
Phosphocreatine
Creatine
ATP
ADP
AMP
ATP + ADP + AMP
2.55 ? 0.54
0.124 2 0.017
2.13 I+_ 0.27
17.4 2 1.0
2.38 2 0.09
2.98 2 0.09
2.14 2 0.05
0.20 0.01
0.017 2 0.003
2.36 I+_ 0.05
2.19
0.065
0.94
14.5
2.70'
*
...
2.12
0.32
0.044
2.48
aValues for newborn dogs represent means ? 1 SEM for 7 animals.
"Data of Drewes and Gilboe [231.
'Data of Minsker, Gilboe, and Stone [241.
ATP = adenosine triphosphate; ADP = adenosine diphosphate;
AMP = adenosine monophosphate.
cose ratio previously observed in 1-day-old rats (0.40)
[20]. Lactate and pyruvate concentrations were relatively high in puppies, twice that found in adult dogs.
However, the lactadpyruvate ratios were similar in
the two age groups, implying a comparable cytoplasmic redox state. Although phosphocreatine was
somewhat lower in newborns, the phosphocreatinel
creatine ratio-possibly a more meaningful relationship because it takes into account total available
creatine-had a value of 0.80. A similar value (0.83)
has been reported for the phosphocreatine/creatine
ratio of 1-day-old rat brain [25]. Concentrations of
ATP were the same in newborn and adult dogs, but
the levels of ADP and AMP were lower in puppies;
the ratio of ATP/ADP, as an index of the cortical
phosphorylation potential, was actually higher in
puppies.
Changes in Metabolite Levels during Aspbyxia
During asphyxia, glucose in brain tended to decline
steadily (Fig 2), although the differences from control
were significant only after 5 minutes. Lactate and
pyruvate concentrations were similar to control values
after 255 minutes of asphyxia, but beyond this point
lactate increased in almost linear fashion. Pyruvate
also rose, but only transiently; therefore, the lactate/
pyruvate ratio steadily increased.
Asphyxia also caused a partial depletion of energyrich phosphates in brain (Fig 3). Phosphocreatine fell
immediately and was at very low levels (10% of control) after 10 minutes. In contrast, ATP remained
unchanged for as long as 5 minutes of asphyxia, but
then declined to 3594 of control. Although changes in
ATP were partly realized as increased ADP and AMP,
the total adenine nucleotide pool (ATP + ADP +
AMP) was reduced (-12%). It is noteworthy that at
2% minutes of asphyxia, when the EEG was already
isoelectric (see Fig l), there was still substantial
energy available to the cerebral cortex, as reflected by
a normal ATP concentration.
3
Cerebral Pe$usion during Aspbyxiu
Minutes of asphyxia
F i g 2. Effect of asphyxia on g[ycolytic substrates in the
cerebral cortex of newborn dogs. Paralyzed animals were
subjected to respiratory arrest at 37°C. and their
brains were frozen after the specifled period of
asphyxia. Values, expressedas mmollkg wet weight of
brain, represent means of 3 t o 7animals. Verticallines
denote -1- 1 S E M .
3
14.
“ 0
3
6
9
12
15
Minutes of asphyxia
F i g 3. Effect of asphyxia on high-energy phosphates i n the
cerebral cortex of newborn dogs. The animals and
experimental conditions were the same as those described i n
Figure2. Values, expressedas mmolikg wet uvight of brain,
represent means of 3 t o 7 animals. Vertical lanes denote 1
S E M . Values- for adenosine monophosphate (not .rhoujn)
were 0.01 7 ? 0.003 mmollkg (0 mini, 0.026 ? 0.004
(2% mini, 0.07 2 0.02 (5 mini, 0.73
0.21 (10
mini, and0.66 2 0.12 (15 min). (ATP =adenosine
triphosphate; ADP = adenosine diphosphate; P-Cr =
p h oph
~ ocreatine .)
*
*
Because prolonged asphyxia adversely altered cardiovascular function in puppies (see Fig l), it seemed
likely that decreased cerebral perfusion (ischemia)
was compounding the asphyxia1 insult to brain. Accordingly, animals were injected intravenously with
carbon black during asphyxia, and cerebral perfusion
was assessed postmortem by the distribution of carbon particles in the brains of experimental animals
relative to the uniformly gray-black appearance of
well-perfused control brains (Fig 4). After 29’2 minutes of asphyxia the brains appeared uniformly dark,
though not as intense as control tissue. After 5 minutes of asphyxia there were areas of pallor throughout
the cerebral cortex, implying reduced cerebral blood
flow; after 15 minutes of asphyxia the brains were
completely pale. Coronal sections of brain from 2
puppies that received carbon black after 10 minutes of
asphyxia revealed a preferential distribution of carbon
(ie, preserved perfusion), notably in the diencephalon, lower brainstem, and cerebellum (Fig 5 ) .
Discussion
The present findings in a model of acute, systemic
asphyxia emphasize the complexity of the insult to
immature brain. Asphyxiated puppies rapidly become
anoxic and hypotensive; blood and, presumably, brain
p H falls owing to the accumulation of lactic acid and to
the animals’ inability to expel carbon dioxide; when
asphyxia is prolonged, cortical energy reserves decline. Swann et al [26] observed that 3- to 4-day-old
dogs developed arterial blood pressures of 8 to 10 mm
H g during extreme but reversible anoxia and concluded that even such low blood pressures must continue to provide an “efficient” circulation in the anoxic
animal. In the present experiments a mean arterial
blood pressure of 10 mm H g in asphyxiated puppies
was found to be compatible with apparently normal
recovery, but even higher blood pressures (> 20 mm
Hg) were inadequate to perfuse the brain. Thus,
blood flow to the cerebral cortex was significantly
compromised within 5 minutes of asphyxia, and there
was virtually no blood flow to the forebrain beyond 10
minutes (mean blood pressure, 23 mm Hg; see Fig 1).
After 5 to 10 minutes of asphyxia, therefore, functional activity in the ischemic areas of brain must have
been dependent solely upon endogenous (preformed
Vannucci and Duffy: Cerebral Metabolism in Experimental Asphyxia
531
0
2.5
5
15
Minutes of asphyxia
F i g 4. Brains of newborn dogs injected intravenouslj u i t h
carboiz blark during asphy.lcia. Specimens are repre.rentatif:e
of2 controlpuppie.rand of 3 puppitis at each ofthe i n d i c a d
periods o/ asphyxia. Note the relative pallor i n the
brain of the animal perfused after 5 minutes of
asphyxia and the zmirtualabsenieof carbon blctck from
the brain of the animal injected after 15 minutes of
asphyxia. ( ~ 1 . before
3
30% redt~rtion.)
F i g 5 . Coronalsection at the levelof the superior colliculus
from a newborn dog injected with carbon black after 10
mivirtes of ajphyxia. Note pallor of the cortical und
szibrortical areas relatizJet o the brainstem. ( XJ before 3 0 '%;
reduction.)
532 Annals of Neurology Vol 1 No 6 June 1977
and potential) energy stores. The low energy demands
of the newborn brain [8, 91, reflected in the present
study by the slow rate of decline of cortical ATP
during asphyxia (see Fig 3), probably account in part
for the animals’ ability to tolerate this period of total
cerebral ischemia.
The loss of electrical activity in brain after 2%
minutes of asphyxia correlated in time with the abrupt
decreases in blood pressure and heart rate (see Fig I),
implying a critical reduction in cerebral perfusion;
decreased cerebral blood flow was confirmed by the
lighter appearance of the brains of animals injected
with carbon black after 2$5 minutes of asphyxia (see
Fig 4 ) compared to controls. It is noteworthy that the
isoelectric EEG was obtained at a time when ATP
concentrations in the cerebral cortex were still within
normal limits (see Fig 3). This finding indicates that, as
in adult animals [27,28], maintenance of EEG activity
in the newborn more likely reflects adequate cerebral
perfusion rather than the availability of tissue energy
precursors, ie, the concentration of ATP. Moreover,
the role of the circulation in supplying the brain with
fuel does not appear to be a critical factor with regard
t o maintenance of the EEG during asphyxia, since
ample glucose (ca 1.5 mmol/kg) remained in the cerebral cortex when electrical silence occurred.
Studies with carbon black indicated that, whereas
cerebral blood flow was generally decreased during
asphyxia, the reduction in flow was not uniform in all
regions, brainstem structures being relatively spared
(see Fig 5 ) . Carbon particles injected into animals
asphyxiated for 10 minutes were distributed in the
cerebellum, medulla oblongata, pons, and diencephalon, regions of the dog’s brain that receive their primary blood supply via the vertebrobasilar system [291.
The demonstration of preferential blood flow to the
brainstem in asphyxiated newborn dogs is consistent
with data of Fisher et a1 [30] obtained in newborn
monkeys. Based upon the organ distribution of injected radioactive microspheres, Fisher e t a1 [30]calculated that, although blood flow to the infant brain
was reduced during asphyxia, there was a preferential
redistribution of blood to the paleoencephalon. Selective perfusion of the brainstem would be expected to
provide at least temporary protection for the vegetative centers of,respiratory and vasomotor control and
thus prolong survival in asphyxia. Paradoxically, however, the neuropathological picture of the acutely asphyxiated newborn is characteristically one of subcortical, not cortical damage [12, 14, 311. It would appear, therefore, that differences in energy demands,
not blood flow, may explain the selective vulnerability
of the perinatal brain to asphyxia, as Himwich [321
suggested many years ago from in vitro measurements
of regional cerebral oxygen consumption.
Supported in part by US Public Health Service Grant NS-03346.
Dr Duffy is an Established Investigator of the American Heart
Association.
We thank Ms Nancy F. Cruz, Susan J. Kohle, Joan W. Wolf, and Mr
Emil Abdel-Malek for technical assistance.
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