Immediate care of the compromised foal for the field practitioner (Proceedings)

Perinatal Asphyxia Syndrome produces hypoxic ischemic encephalopathy (HIE) resulting in neurological deficits ranging from hypotonia to grand mal seizures. Foal's affected with perinatal asphyxia also experience gastrointestinal disturbances ranging from mild ileus and delayed gastric emptying to severe, bloody diarrhea and necrotizing enterocolitis (NEC). Renal compromise accompanied by varying degrees of oligouria is also a sequela to asphyxia.

Any discussion of the pathogenesis of perinatal HIE requires the definition of certain terms regarding variations in blood or tissue concentration of oxygen. Hypoxia is the partial (hypoxemia) or complete (anoxemia) lack of oxygen in the brain or blood. If the hypoxemia is severe enough, initially peripheral tissues and ultimately brain tissue will develop an oxygen debt, leading to anaerobic glycolysis and the production of lactacidosis. Asphyxia is the state in which placental or pulmonary gas exchange is compromised or ceases which typically progresses to hypoxemia. Ischemia is a reduction in or cessation of blood flow to an organ (brain), which compromises not only oxygen delivery to tissue but substrate delivery as well.

In utero the fetus adapts to a relatively hypoxic environment by increased oxygen affinity of fetal hemoglobin, increased ability to extract oxygen from the blood and a greater tissue resistance to acidosis. Similar to the redistribution of blood flow in a diving seal, the severely asphyxiated fetus and neonate are able to redistribute oxygenated blood away from less vital organs (lungs, kidneys, skin and bowel) to more vital organs (heart, brain and adrenals). As a result of this protective mechanism, multiple organs may sustain injury. The equine fetus appears to have an oxygen demand "reserve" in that, under conditions of reduced oxygen availability, it decreases its rate of growth and decreases it's oxygen consumption. This form of in utero growth retardation (IUGR) is termed disproportionate. The fetus is stunted and presents with a disproportionately large head, little muscle mass, small frail body and little to no fat. If the in-utero asphyxia is severe the fetus will not be able to sufficiently compensate and the CNS will be compromised. The compromise of the fetal CNS will lead to sequential loss of fetal reflexes with the most complex, oxygen demanding fetal activities affected first which begins with the fetal heart rate, followed by fetal breathing, generalized fetal movements, and fetal tone. Many factors including gestational age of the fetus, severity of hypoxia and duration determine the severity of clinical signs and CNS lesions.

In utero passage of meconium could be normal or during hypoxia. In a hypoxic-ischemic event fetal reflex redistribution of cardiac output away from less vital organs such as the bowel results in intestinal ischemia followed by transient hyperperistalisis, anal sphincter relaxation, and meconium passage.

In the intact perinatal animal, and presumably in the human fetus or newborn, uncomplicated hypoxemia, no matter how severe, never causes brain damage.This is largely due to a redistribution of blood flow to the heart and brain during hypoxemia and also because of the preservation of cardiac function by the heart's high endogenous stores of glucose and glycogen. Studies in fetal animals do however support the notion that brain damage does occur when cerebral ischemia, secondary to systemic hypotension is superimposed on the hypoxemia.

Adenosine triphosphate (ATP) is the primary energy modulator of all cells including neurons. In tissue hypoxia ATP production by oxidative phosphorylation is curtailed, with concurrent increases in cellular adenosine disphosphate (ADP) and adenosine monophosphate (AMP). Of necessity, the loss of cellular ATP during hypoxia-ischemia severely compromises those metabolic processes that require energy for their completion. Thus, ATP-dependent NA+ efflux through the plasma membrane in exchange for potassium is curtailed with a resultant intracellular accumulation of sodium and chloride as well as water (cytotoxic edema). Intracellular sodium and chloride ions and water continue to accumulate, resulting in electrochemical gradients that cannot be re-established. Prolonged hypoxia-ischemia can also result in cell death of the capillary endothelium and tight junctions. Potentially this results in extracellular edema (vasogenic edema). How long a cell can survive in this situation is not known, as other factors are called into play that influence the ultimate cellular integrity. The role of extracellular edema and increased intracranial pressure in foals with HIE is still currently being debated with no consensus at this time.

Recent in vitro and in vivo studies have revealed that the excitatory amino acid neurotransmitter glutamate is a major factor in the production of HIE injury. Under normal conditions, most of the glutamate remains within neuronal and glial cell bodies, where it is prevented from activating the glutamate receptors. There are at least four glutamate receptors. (Figure 1.) . Three of these receptors have been named KA, NMDA and AMPA. All three of these receptors are coupled to ion channels and gate flux of cations when activated. The uptake pumps transport synaptically released glutamate back across the cell membrane so that the concentration of free glutamate is low. Under conditions of prolonged hypoxia-ischemia the energy dependent uptake pumps gradually fail. Neurons depolarize and leak glutamte, which cannot be removed rapidly from the extracellular space. Once activated these glutamate receptors activate the sodium and potassium ion channels. More critical however, is the influx of calcium that passes through glutamate-gated channels, especially the NMDA receptor. Calcium, in turn, sets in to motion a cascade of biochemical events that cause the death of a neuron.

Figure1

Excessively excited by high levels of glutamate, neurons and other cells with appropriate receptors can be sent into a death spiral. The mitochondria are the major buffers of intracellular calcium and will become overloaded during cytoplasmic calcium flooding from the opening of the NMDA calcium channels. The diminished mitochondrial function can lead to decreased energy to maintain ion gradients, potentially perpetuating a viscous cycle of membrane depolarization and NMDA receptor channel opening. The increased free cytosolic concentrations of calcium activates numerous intracellular reactions that in excess can seriously compromise the viability of the neuron. These reactions include the activation of lipases, proteases and endonucleases, which disrupt the structural integrity of the cell. Calcium also contributes to the formation of oxygen free radicals via the formation of xanthine and prostaglandins.

At present, a rational approach to the management of hypoxic-ischemic encephalopathy in the fetus or newborn does not exist. The problem of preserving brain function during neonatal asphyxia is that we do not know the therapeutic window for intervention. In the term human infant the therapeutic window would be short and no longer than 4 to 8 hours. In this regard, the therapeutic window for immature animals may be even smaller. The treatment of HIE in foals should involve the treatment of other damaged organ systems. Because the preservation of brain function in neonatal asphyxia is urgent, a novel strategy must be implemented. The strategy would employ a combination of therapies because of the multifaceted nature of hypoxic-ischemic brain injury.

Allopurinol: 40 mg/kg PO within 2-3 hours of birth. Mechanism of action has been explained primarily by its ability to inhibit xanthine oxidase.

Ascorbic acid: 100mg/kg/day IV Inhibits neurotransmitter binding to NMDA receptors. In the fetus, ascorbic acid is one of the principal antioxidant systems. Plasma Ascorbic acid concentrations in the brain are approximately 10 fold-those in plasma. The optimal dosage of ascorbic acid for neuroprotection is not known. In high-risk human premature infants a dose of 100mg/kg/day was found to be safe.

Vitamin E: 4,000 IU PO SID (Neonate) or 10,000 IU PO SID (DAM) Vitamin E is an antioxidant that is synergistic with ascorbic acid. While ascorbic acid is the principal antioxidant in the aqueous environment, vitamin E decreases the amount of lipid peroxidation and is the principal antioxidant in the lipid environment. The main problem with vitamin E is that it is lipid soluble; for an effective dose to reach the brain or circulation, vitamin E needs to be given for some days before the ischemic insult. There may be a role in the setting of early fetal distress and vitamin E supplementation given to the mare.

Magnesium sulfate 50mg/kg IV infusion for 1st hour then 25mg/kg CRI Mg2+ has a normal blockade of the NMDA receptor current that is noted to be reduced (voltage-dependant) in mechanically injured neurons. The Mg2+ blockade can be partially restored by increasing extracellular Mg2+ concentration There is a lack of consensus in human medicine regarding the use of magnesium in the treatment of infants with HIE. The current dose regime has been noted to be safe in foals when infused over 3 days. At this time no beneficial conclusions can be drawn from the use of this treatment in HIE.

Thiamin 1 gram IV in 1 L of Fluids SID. Thiamine is thought to be neuroprotective due to its action of increasing activity of the adenosine triphosphate dependent sodium pump, thereby regulating ion uptake and decreasing cellular water.

DMSO 0.25 to 1 gram /kg IV Q6 to Q12 hour as 10% solution (100ml per liter) It has been used for specific treatment for cerebral edema and suspected increase in intracranial pressure (osmotic diuretic). DMSO also is a hydroxyl radical scavenger and may theoretically prevent some cellular damage attributed to oxygen radical generation.

Mannitol 0.25 to 1 gram as 20% solution Q6 to Q12 hour as an IV bolus over 15-20 minutes. Osmotic agent, which has been specifically used for the treatment of cerebral edema. It also has some neuroprotective properties.

Diazepam 0.11 to 0.44 mg/kg IV or Phenobarbitol 12mg/kg IV Loading dose then 2-7mg/kg IV Q 12h. Give slowly, monitor serum concentrations (maintain serum levels 15-40 mcg/ml) Use for seizure activity

Hyperbaric Oxygen Therapy 1.5 to 2 ATM for 45min to 1 hour SID/BID