SURVIVAL AND ANOXIA
The first reference to the unique ability of the neonate to withstand anoxia was by Boyle (1670)
who noted that kittens survived without oxygen much longer than mature animals of the same body
weight. In the late 1930's, Herman Kabat demonstrated that young animals could tolerate an
extended period of complete stoppage of brain circulation (typically achieved by ligating the carotid
arteries) to a much greater extent than could adults. In addition, the return to normal function was
much faster in the newborn, even if the period of stasis was greater.
This correlated well with earlier findings of several other workers demonstrating the persistence of
respiratory efforts in the face of cephalic circulatory stasis or anoxia were greatly extended in the
young animal. Respiratory survival time during brain stasis was shown to be 20-30 seconds in the
adult dog and 5 minutes in puppies between 8-10 days of age. During asphyxia, respiratory efforts
persist for 27 minutes in 1-day-old puppies, while they cease within 2-4 minutes in the adult dog.
Submerging newborn rats in 37 water resulted in survival for long periods, with removal at 40
minutes allowing recovery and apparent normal development.
Changes in Heart Function
The survival time also varies with maturity at birth. Newborn rats will survive 50 minutes in pure
nitrogen compared to newborn guinea pigs that survive only 7 minutes. Guinea pigs are
comparatively mature animals at birth, exhibiting righting reflexes, coordinated locomotion, and
thermoregulatory mechanisms to a much greater extent than the rat.
Infant rats placed in nitrogen live 50 minutes, while adults stop respiring at 2-4 minutes. In nitrous
oxide or helium, results were similar, but in carbon dioxide, newborns succumbed within 25
minutes and in cyclopropane, they died within 15 minutes. By 12 days of age, survival rates were
the same as adults. Puppies behaved similarly, although survival rates for newborns ranged from
16-43 minutes. As soon as 5 minutes after initiation of treatment, oxygen was eliminated from the
blood. The heart continued to beat after cessation of respiration, however, electrocardial changes
were noted in 4-5 day old puppies breathing pure nitrogen. The first alteration was a sinus
arrhythmia, followed by a depressed heart rate and disappearance of the P wave within 2 minutes.
Then, possibly due to a diminution of vagospasm, the P wave returns and, within 5 minutes of the
initiation of anoxia, the rate becomes more regular and faster than the first 2-3 minutes. Eventually,
heart action weakens and cardiac arrest will occur. In the term fetus, constriction of umbilical veins
will produce an immediate bradycardia and decrease in arterial blood pressure, however,
constricting arterial flow or severing the cord will induce bradycardia with an increase in arterial
pressure and increases in carotid blood flow. Prior to delivery, about 50% of fetal cardiac output is
directed towards the placenta. In bovine fetuses shortly prior to parturition that were subjected to
anoxia by clamping the umbilical cord, survival time was only about 4 minutes. Again, heart
activity continued for a prolonged period (6-21 minutes) after cessation of respiratory attempts.
Autopsy revealed hemorrhages throughout the body; always on the heart, usually in the thymus and
spleen, and occasionally on other sites throughout the body.
Changes in Regional Blood Flows
In sheep, regional blood flows are altered during anoxia, so that initially whole body oxygen
consumption is preserved at the expense of blood flow to the hind limbs. In fetal animals, asphyxia
results in preferential flows to the heart, brain, and adrenal at the expense of placental and
pulmonary flows, perhaps partially explaining the loss of respiratory reflexes prior to the loss of
heart function in the neonate. Brain flow preferentially maintains function in the midbrain,
brainstem, and cerebellum at the expense of the cerebral cortex. Blood flow may decrease to other
(non-essential) regions of the body to the extent that function of these systems may be permanently
impaired after reperfusion. Ischemia/reperfusion in the splanchnic bed (liver, stomach, small and
large intestine) results in hemorrhages and necrotic sites; this impaired blood flow during asphyxia
is thought to be the primary initiator for neonatal necrotizing enterocolitis.
Changes in Brain Function
Within the central nervous system, ischemic hypoxia results in neuron loss, gliosis, and abnormal
patterns of myelination in the neonatal striatum (within the basal ganglia). Dyskinetic cerebral
palsy, characterized by dystonia, is almost always associated with perinatal asphyxic events.
Myelination is especially delayed in infants with evidence of diffuse brain injury and
paraventricular leukomalacia.
Hypoxic/ischemic cell death appears to be mediated by excitatory amino acids (such as NMDA),
while the altered response of the infant to these excitatory amino acids is mediated by increased
concentrations of reactive oxygen metabolites. Actually, both hypoxia and hyperoxia have been
shown to reduce ascorbate concentrations in the adrenal gland; the detrimental effects of both
extremes of abnormal oxygen supply may be mediated by similar mechanisms. Not surprisingly,
pretreatment with free radical scavengers prior to asphyxic events improves brain function
following asphyxia. Pretreatment with dexamethasone also prevents cerebral infarction; however,
the treatment must precede the asphyxic event by 24 hours.
The basal metabolism of the newborn per unit weight is greater than the adult, however, per unit
body surface is smaller than the adult. In vitro oxygen consumption of brain slices per unit dry
weight is quite similar to the adult in either the presence or absence of substrate, although per unit
wet weight, the oxygen consumption is nearly 40% less than the adult. These results would suggest
that the reduced rate of oxygen utilization by the brain is a contributing factor in the greater
resistance to anoxia of the infant brain. Cerebral energy utilization rates in rats were calculated at
1.57 mmol/kg/min in the fetus, 1.33 mmol/kg/min in the neonate, and 2.58 mmol/kg/min in 7-dayold rats. It has also been demonstrated that the last gasp is closely correlated with the onset of an
increase in extracellular potassium in the brain (suggestive of a loss of electrical potential across
cell membranes and depolarization of nerve cells).
Reduced ratios of phoshocreatine:inorganic orthophosphate (normal ~1.7, asphyctic ~0.2 to 1.0) in
infant brains (determined by MRI) are indicative of severely impaired oxidative phosporylation and
highly predictive of multiple serious impairments. If the ratio of ATP:total phosphorus is reduced,
death is almost inevitable.
Changes in Energy Status
The ability of the animal to obtain energy in the absence of oxygen appears to be critical to the
survival of anoxic neonates. In 1931, Reiss observed that the whole body lactate content of
asphyxiated neonates was 460% higher than baseline as compared to a 23% increase in asphyxiated
adults. He also noted that a large carbohydrate reserve was still available to the asphyxiated
newborn, and that while heat stress increased the speed of death, that lactate levels were equivalent
at death. He concluded that the cause of death was due to accumulation of lactate. Evidence of
anaerobic metabolism appears when arterial oxygen content decreases below 4 volume percent, as
evidenced by increases in both lactate and hypoxanthine. At this point, however, adequate
myocardial oxygenation is still maintained by shifts in regional blood flows.
The resistance to hypoxia is reduced by approximately 50% when complicated by hypoglycemia,
and supplemental glucose will substantially increase the survival time of anoxic young rats.
Newborn rats injected with 10 units of insulin resisted coma and survived from 5-10 hours while all
adults receiving the same dose of insulin became comatose and sometimes died. Note that the
dosage of insulin on a body weight basis was at least ten times greater in the infants. The rise in
glucose seen in response to anoxia in the newborn can be minimized or in many cases abolished by
section of the splanchnic nerves.
Newborn rats injected with iodoacetate (inhibits glycolysis at the level of glyceraldehyde-3phophate) prior to asphyxia survived only 3 minutes, while injection alone allowed survival times
of 50 minutes. Injection of fluoride (inhibits glycolysis at 1,3-bisphosphoglycerate) shortened
survival time to 16 minutes, while fluoride alone allowed survival for 50 minutes. Sodium fluoride
further decreased the gasping reflex of the isolated head to 7 minutes. A secondary observation is
that injection of either fluoride or iodoacetate prior to asphyxia results in heart stoppage
simultaneously with cessation of respiratory movements.
In vitro studies with rat liver slices have demonstrated that the aging process results in the loss of:
1) the high rate of glycogen deposition, 2) potential high rate of glycolysis, and 3) high rate of
lipogenesis which is evident both anaerobically and aerobically. Lactate production in fetal liver
slices is 90% greater in nitrogen than oxygen, while adult liver only increases 30%. Hypoxia in
neonatal rats also decreases ureagenesis by inhibiting the two major pathways that supply nitrogen
to the urea cycle (glutamate dehydrogenase and aspartate aminotransferase). Concentrations of
both urea and ammonia are therefore decreased under these conditions.
In adult rats, fructose has been shown to protect the liver against hypoxic cell death by increasing
the glycolytic production of ATP in the absence of oxygen. Fructose is readily converted to lactate
while supplemental glucose is not utilized as well. Whether or not fructose is capable of being
utilized by fetal animals in this manner is not known.