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Equine April 2009 (Vol 4, No 3)

Perinatal Asphyxia Syndrome in Foals

by Wendy Vaala, VMD, DACVIM

    The most common effects of perinatal asphyxia are:

    • Neurologic deficits ranging from hypotonia to grand mal seizures
    • Gastrointestinal (GI) disturbances ranging from mild ileus and delayed gastric emptying to severe, bloody diarrhea and necrotizing enterocolitis
    • Renal compromise accompanied by varying degrees of oliguria

    Based on the neurologic deficits (including loss of affinity for the dam, seizures, impaired sucking and swallowing reflexes, and abnormal vocalization), affected foals have been called dummies, convulsives, barkers, and wanderers. Neonatal encephalopathy, neonatal maladjustment syndrome, and hypoxic-ischemic encephalopathy are commonly used to describe this condition. Central nervous system (CNS) disturbances associated with this condition ultimately result from necrosis and occasional hemorrhage.

    During severe in utero compromise, there is sequential loss of fetal reflexes, with the most oxygen-demanding fetal activities disappearing first. Fetal reflexes are lost in the following order:

    1. Fetal heart rate reactivity (the ability to increase heart rate in response to fetal activity)
    2. Fetal breathing
    3. Generalized fetal movements
    4. Fetal tone

    These biophysical events, in addition to amniotic fluid volume estimation and placental integrity, can be evaluated in late pregnancy using transabdominal ultrasonography.

    Diagnostic Criteria

    Historical Information

    • No sex or breed predilection.
    • Signs of peripartum asphyxia during the first 24 to 72 hours of life.
    • Delivery may be outwardly normal in cases in which prepartum asphyxia is due to some form of unrecognized placental insufficiency and in utero hypoxia. Events during delivery that are associated with hypoxia include the following: — Dystocia
      — Premature placental separation ("red-bag" delivery)
      — Twinning
      — Meconium staining of fetal fluids, placenta, and/or foal
      — Evidence of diffuse placental pathology, including an unusually heavy or edematous placenta (e.g., placental weight >10% to 11% of the foal's birth weight).
    • Mares with reproductive tract disease (e.g., placentitis, hydrops allantois, hydrops amnii, prepubic tendon rupture) are more likely to deliver affected foals. Severe maternal illness accompanied by anemia, hypoproteinemia, or endotoxemia can alter uteroplacental blood flow, resulting in fetal asphyxia. Postterm pregnancies have been associated with varying degrees of placental insufficiency and the birth of small, underweight, maladapted foals.
    • Foals may appear normal at birth and then develop a host of behavioral abnormalities, including the loss of coordinated swallowing and sucking reflexes, the inability to locate the udder, the tendency to wander from the mare and walk into walls, generalized hypotonia, and seizures.

    Physical Examination Findings

    • Mildly affected foals exhibit jitteriness and hyperexcitability.
    • Moderately affected foals exhibit stupor, somnolence, lethargy, and hypotonia, which may be accompanied by epileptiform seizures and extensor rigidity. Additional clinical signs include dysphagia, decreased tongue tone, odontoprisis, central blindness, mydriasis, anisocoria, nystagmus, head tilting, and loss of the suckle reflex.
    • Premature foals are more likely to experience "subtle seizures" characterized by paroxysmal events, including eye blinking, eye deviation, nystagmus, pedaling movements, a variety of oral-buccal-lingual movements (e.g., intermittent tongue protrusion, sucking behavior), whole body thrashing, and other vasomotor changes (e.g., apnea, abnormal breathing patterns, changes in heart rate). Tonic posturing is another subtle seizure activity characterized by symmetric limb hyperextension or flexion and is often accompanied by abnormal eye movements and apnea.
    • Severely affected foals exhibit marked CNS depression, coma, and loss of central regulation of respiration, blood pressure, and temperature, ultimately leading to death.
    • Limb deficits and generalized spasticity are less common.
    • Signs of renal compromise include decreased urine production with subsequent peripheral edema formation.
    • The GI tract is often affected. Mild cases may involve transient ileus, constipation, and mild colic. The most severe form of intestinal dysfunction is necrotizing enterocolitis. During GI ischemia, mucosal cell metabolism diminishes and production of the protective mucous layer ceases, allowing proteolytic enzymes to begin autodigestion of the mucosal barrier. Bacteria within the lumen can then colonize, multiply, and invade the bowel wall. Intramural gas is produced by certain species of bacteria, and pneumatosis intestinalis develops. Possible complications include intestinal rupture, pneumoperitoneum, severe bacterial peritonitis, and septicemia.

    Laboratory Findings

    TABLE 1  lists clinical signs associated with specific organ system dysfunction and the laboratory abnormalities to anticipate.

    • Metabolic acidosis: pH <7.3; bicarbonate concentration <20 mEq/L.
    • Prepartum placental insufficiency may be associated with neonatal azotemia: creatinine concentration >3.5 mg/dL.
    • Foals experiencing respiratory depression may develop hypoxemia and respiratory acidosis: Po2 <60 mm Hg; Pco2 >65 mm Hg.

    Other Significant Diagnostic Findings

    Transabdominal ultrasonography of the pregnant mare should be used to evaluate fetal well-being and placental integrity:

    • The mare's ventral midline must be cleaned and clipped from the level of the umbilicus caudally to the mammary gland, and a viscous coupling gel should be applied.
    • Minimal maternal restraint is usually required. Chemical sedation should be avoided because drugs such as xylazine and detomidine induce fetal bradycardia and decrease fetal movement.
    • A 2.5- to 3.5-MHz transducer is used.

    Signs suggestive of fetal or placental compromise during the last month of gestation include the following:

    • Persistent fetal bradycardia: fetal heart rate <50 to 60 bpm; loss of fetal heart rate variability
    • Reduced or absent fetal movement for prolonged periods (>30 min)
    • Decreased volume of fetal fluids: maximum ventral fetal fluid pocket depths average 8 cm for amniotic fluid and 13 cm for allantoic fluid
    • Large areas of placental separation
    • Generalized placental thickening: combined uteroplacental thickness >15 mm

    Transrectal measurements of uteroplacental thickness around the cervical star should not exceed 12 mm after day 330 of gestation.

    Foals with necrotizing enterocolitis have generalized ileus and thickening of the bowel wall with or without intramural gas accumulation visible on transabdominal ultrasonography when a 5- to 7.5-MHz transducer is used.

    Summary of Diagnostic Criteria

    • History of abnormal periparturient events, including fetal compromise on ultrasonography, gross placental abnormalities, or delivery complicated by dystocia; premature placental separation; or meconium staining.
    • Development of neurologic deficits in the newborn foal within the first 24 to 72 hours of life; the most common CNS disturbances include hypotonia, loss of suckle reflex, loss of affinity for the dam, and focal or grand mal seizures.
    • No other obvious cause of CNS disease, including septic meningitis, electrolyte disturbances, and trauma.
    • Hemogram and serum chemistries are often normal, except for azotemia associated with placental compromise and metabolic acidosis.
    • Foals experiencing severe dystocia often have elevated serum concentrations of the muscle-specific enzyme creatine kinase.
    • The neonatal pancreas and liver can also sustain injury.
      — Foals with pancreatic damage may demonstrate insulin-responsive hyperglycemia.
      — Neonates sustaining hepatic injury may have elevated concentrations of the hepatocellular enzyme sorbitol dehydrogenase.
    • Computed tomography and magnetic resonance imaging are newer modalities being used to evaluate CNS lesions.

    Differential Diagnosis

    Seizures during the first few days of life can be congenital or acquired. Causes of acquired seizures include the following:

    • Metabolic disorders: Hypocalcemia, hypomagnesemia, hyponatremia, hypernatremia, hypoglycemia
    • Hyperosmolality: Hyperlipemia, hyperglycemia
    • Severe azotemia
    • Hepatoencephalopathy: Elevated liver enzyme (aspartate aminotransferase, g-glutamyltransferase, sorbitol dehydrogenase), serum ammonia, and bilirubin levels concurrent with low blood glucose and blood urea nitrogen levels
    • Infectious conditions:
      — Bacterial meningitis
    • Spinal fluid analysis: leukocytes >5 to 10 cells/µL; total protein >150 mg/dL
    • Positive blood culture result
    • Abnormal hemogram results: leukopenia, neutropenia, toxic granules in neutrophils
      — Viral meningitis associated with equine herpesvirus 1 infection
    • Positive presuckle viral titers
    • Virus isolation from buffy coat
    • Polymerase chain reaction testing using nasal swabs and buffy coat samples
    • Cranial trauma
      Congenital causes of seizures include CNS malformations, including hydrocephalus, corpus callosum agenesis, cerebellar abiotrophy (most common in Arabians), hydranencephaly, and lavender foal syndrome (observed in Arabian foals of Egyptian lineage that have diluted coat color).
      — Normal serum chemistry results help rule out metabolic disturbances.
      — A normal leukogram or the absence of severe leukopenia, neutropenia, and toxic neutrophil changes may help rule out septic conditions.
      — Cerebrospinal fluid (CSF) analysis is indicated if septic meningitis is a possible differential. Septic meningitis produces an increased nucleated cell count, protein concentration, and IgG index in the CSF. Brain damage may result in an increased albumin quotient in the CSF compatible with increased blood-brain barrier permeability.

    Treatment Recommendations

    (TABLE 2)

    Initial Treatment

    Seizure Control

    • Diazepam (0.11 to 0.44 mg/kg IV)
      — Can repeat dose in 30 minutes
      — Rapid onset of action, but short duration of effect
      — Inactivated by plastic and sunlight
      — Avoid repetitive doses to reduce risk of respiratory depression
    • Phenobarbital (2 to 10 mg/kg slowly IV q8-12h)
      — High doses and rapid rate of administration are associated with respiratory depression.
      — Infuse slowly over 15 to 20 minutes. Expect peak effect within 45 minutes.

    Possible Treatments for CNS Cellular Damage

    • Mannitol (0.25 to 1.0 g/kg IV given as a 20% solution over 20 to 30 min q4-12h).
      — May exacerbate severe intracranial hemorrhage.
      — Excessive administration may induce significant alterations in plasma osmolality. Monitor hydration status.
    • Dimethyl sulfoxide (DMSO; 0.5 to 1.0 g/kg IV given as a 20% solution slowly over 1 hr q12-24h).
      — Use cautiously in hypotensive neonates.
      — Alternative route of administration is via nasogastric intubation but is not usually recommended in critically ill neonatal foals.

    Therapy for Central Respiratory Center Depression and Periodic Apnea

    • Caffeine (10 mg/kg PO or per rectum as initial loading dose, followed by maintenance dose of 2.5 to 3.0 mg/kg PO q24h).
      — Helps increase carbon dioxide sensitivity of central respiratory center, leading to an increased respiratory rate
      — Most effective when hypercapnia has produced significant acidosis
    • In certain cases of persistent hypercapnia, positive pressure ventilation may be necessary.

    Broad-Spectrum, Bactericidal Antimicrobials to Treat and Prevent Secondary Sepsis

    • Amikacin (20 to 28 mg/kg IV q24h) and potassium penicillin (22,000 to 40,000 IU/kg IV q6h) or ampicillin sodium (20 to 50 mg/kg IV q6h); if amikacin is used, peak and trough monitoring is recommended.
    • Ceftiofur (5 to 10 mg/kg IV q6-12h)

    Alternative/Optional Treatments

    • Seizure control: Pentobarbital (2 to 10 mg/kg IV q4-8h or to effect) is an alternative to phenobarbital. Long-term use is not recommended.
    • Midazolam (2 to 5 mg IM for a 110-lb [50-kg] foal) can be given IV, but hypotension and apnea may occur following rapid IV administration. Use lowest effective dose.
    • Naloxone (0.01 to 0.02 mg/kg IV), an opiate antagonist, has been used to diminish CNS depression.
    • Low doses of magnesium sulfate (50 mg/kg/hr diluted to 1% solution and given slowly IV as a constant-rate infusion for 1 hr, then decreased to 25 mg/kg/hr as a constant-rate infusion for up to 24 hr) may be considered. Magnesium acts as an NMDA-receptor antagonist and may reduce the hypoxia-induced increase in oxygen free radical generation.
    • Ascorbic acid (vitamin C) has been advocated as an antioxidant. It is believed to act as a neuromodulator that inhibits neurotransmitter binding to NMDA receptors. The optimal dose for neuroprotection has not been determined. Oral doses vary from 50 to 100 mg/kg/day.
    • a-Tocopherol (vitamin E) has also been advocated for its antioxidant effect. Peroxyl radicals liberated during hypoxia-induced lipid peroxidation react with a-tocopherol instead of a free fatty acid, thereby terminating a potentially destructive process. The optimal dose of vitamin E has not been established. I have used 500 to 1000 U/day PO.

    Supportive Treatment

    • Protect the foal from self-trauma during seizures.
      — Provide a padded environment and soft, absorbent bedding.
      — Wrap limbs.
      — Apply artificial tears to the eyes to prevent secondary corneal ulceration.
    • Ensure adequate passive transfer of colostral antibodies.
      — The foal's serum IgG should be >800 mg/dL by 18 to 24 hours of age. If IgG is <800 mg/dL:
    • Give a minimum of 10 mL/kg of hyperimmune plasma IV if the foal is >18 to 24 hours of age or gut function is compromised.
    • Give a minimum of 40 g/kg IgG PO by bottle or nasogastric tube using good-quality colostrum or an artificial IgG supplement if the foal is <12 to 18 hours of age and has a functional gut (e.g., no signs of colic or reflux).
    • Provide adequate nutrition and monitor glucose level until the foal can nurse normally from the mare.
      — Minimal nutritional requirement = 10% of the foal's body weight per day as milk fed as small meals every 1 to 2 hours (e.g., a 110-lb [50-kg] foal would require a minimum of 5 L or 11 pints of milk per day divided into 10 to 12 feedings per day).
      — Offer milk by bottle if the foal has a strong suckle reflex and a coordinated swallow reflex.
      — Tube feed by nasogastric intubation if the suckle or swallow reflexes are ineffective.
      — Consider IV fluids supplemented with dextrose if the foal is inappetent; however, use parenteral nutrition if the foal is critically ill or has severe necrotizing enterocolitis.
      — Continue to milk the mare every 2 to 3 hours until the foal can nurse normally.
    • Maintain cerebral perfusion, tissue perfusion, and blood pressure by administration of IV crystalloid fluids.

    Patient Monitoring

    • Perform serial neurologic evaluations to assess the response to treatment.
    • Monitor vital signs (including blood pressure), manure and urine production, and peripheral pulses. If respiratory depression is present, check the arterial blood gases to assess pulmonary function and the need for oxygen therapy.
    • Frequently monitor the blood glucose level.

    Milestones/Recovery Time Frames

    • Expect to see stabilization of CNS signs within the first 48 to 72 hours following delivery.
    • Expect to observe gradual improvement in neurologic signs within the first 3 to 5 days.
    • Some foals may not regain the ability to nurse from the mare for 7 to 10 days.

    Treatment Contraindications

    • Avoid acepromazine because it lowers the seizure threshold.
    • Avoid xylazine because it causes transient hypertension that can exacerbate CNS hemorrhage.

    Prognosis

    With proper support, 70% to 80% of foals with this condition recover. Most foals recover completely, and many "survivors" perform successfully as racehorses and other athletes.

    Foals with the poorest prognosis develop sepsis, fail to show any signs of neurologic improvement within the first 5 days of life, remain comatose and difficult to arouse, and experience severe, recurrent seizures. Dysmature and premature foals with prolonged in utero insult are more likely to have refractory hypotension and persistent subtle seizure activity than are full-term foals. Rare, long-term CNS sequelae include unusual docility as an adult, vision impairment, residual gait spasticity, and recurrent seizures.

    Favorable Criteria

    • A full-term foal experiencing a brief in utero or peripartum insult
    • Minimal or mild GI and renal involvement
    • A foal that is normal at birth, with CNS deficits developing within 12 to 24 hours of delivery

    Unfavorable Criteria

    • Advanced prematurity in addition to an in utero or peripartum insult
    • Concurrent septicemia
    • Severe necrotizing enterocolitis
    • Nonresponsive hypotension and oliguria
    • Persistent seizures that continue past 5 days of age despite anticonvulsive therapy
    • A foal that is abnormal immediately following delivery and remains comatose and nonresponsive
    • Signs of severe brainstem damage: loss of thermoregulatory control, profound apnea, marked increase in intraocular pressure suggestive of increased intracranial pressure.

    Updated by the author and reprinted with permission from Standards of Care: Equine Diagnosis and Treatment 2002;2.1:1-7.

    Downloadable PDF

    Dr. Vaala discloses that she is employed by Intervet/Schering-Plough Animal Health.

    NEXT: The Final Diagnosis —You Might Be a Mixed Animal Practitioner If . . .

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