PERINATAL ADAPTATION

John K. House

At birth the fetus must successfully make a series of structural and physiologic changes to survive. Perinatal mortality is often attributable to cardiovascular, pulmonary, thermoregulatory, or metabolic physiologic abnormalities. Dystocia and severe birth asphyxia compromises physiologic transitions, increasing the risk of neonatal mortality. Compromised neonates that survive the birth process are less likely to consume adequate colostrum and are subsequently more likely to die of hypothermia and infectious diseases. A good review of physiologic mechanisms of adaptation at birth is presented by Kasari.¹

The placenta functions as the respiratory organ of the developing fetus; efficiency of oxygen transfer to the fetus is increased by the high oxygen affinity of fetal vs. adult hemoglobin.² In utero the potential spaces of alveoli and the tracheobronchial tree are distended with fluid secreted by pulmonary tissue.³ Oxygenated blood is delivered to the fetus via the umbilical vein, which anastomoses with the portal vein near the liver, and approximately two thirds of the blood flow is shunted via the ductus venosus directly into the caudal vena cava.¹ The caudal vena cava drains into the right atrium, where over 50% of the volume shunts directly into the left atrium via the foramen ovale.¹ The relatively hypoxic in utero environment causes constriction of pulmonary vessels and dilation of the ductus arteriosus.¹ Because pulmonary arterial resistance is higher than systemic arterial resistance, nearly 70% of pulmonary artery flow is shunted via the ductus arteriosus into the aorta, with the remainder perfusing the lung.⁴ Left ventricular output is distributed to the systemic circulation via the aorta. The two umbilical arteries arise from the aorta in the region of the last lumbar vertebra to carry predominantly venous blood back to the placenta via the umbilicus.

At birth some of the lung fluid is evacuated through the trachea during spontaneous delivery.⁵ When the umbilicus ruptures, asphyxia triggers reflex gasping, respiratory movements, and increased peripheral vascular resistance.⁴ The majority of lung fluid is absorbed through alveolar walls in the initial stages of ventilation.⁵ This mechanism is prompted by activation of adrenaline-mediated β-adrenergic receptors in the pulmonary epithelium.⁶ The rapidity of lung fluid absorption by the body is optimized at thoracic pressures between 35 and 40 cm H₂O.⁵ Pulmonary ventilation reduces pulmonary vascular resistance, promoting perfusion of the ventilated alveolar tissue.¹ The increased O₂ saturation of blood stimulates closure of the ductus arteriosus within 4 to 5 minutes of birth.⁴ The foramen ovale functionally closes within 5 to 20 minutes of birth when increased pulmonary venous return raises blood pressure in the left atrium, reversing the right-to-left shunt.⁴ The septum secundum, a thin fold of tissue that lies in close apposition to the foramen, acts as a valve closing the opening. Healthy calves have mean pulmonary arterial pressures ranging from 40 to 82 mm Hg immediately after birth, declining to 22 to 25 mm Hg by 2 weeks of age.⁷ Systemic arterial pressure is approximately 100 mm Hg, and arterial saturation is greater than 90%.¹ Transient mild metabolic and respiratory acidosis is observed after rupture of the umbilical cord as a result of anaerobic glycolysis in poorly perfused tissues during the transition between placental oxygen delivery and establishment of respiratory function. The mild acidosis is normally corrected within 1 to 4 hours of birth.⁸ Anatomic closure of the foramen ovale and ductus arteriosus may take several weeks.⁴ Normal blood gas values for the calf during the immediate postpartum period are presented in Table 16-1.

Table 16-1 Arterial and Venous Blood Gas Values for Newborn Calves

Dystocia is commonly associated with prolonged hypoxia and acidosis. Hypoxia and acidosis maintain constriction of pulmonary arterioles, and the subsequent maintenance of high pulmonary vascular resistance favors continuation of in utero right-to-left vascular shunts, which contributes to systemic hypoxia. After dystocia neonates are less active, slow to stand, slow to nurse, and prone to hypothermia and hypogammaglobulinemia. The normal duration of stage 2 labor (from appearance of fetal membranes at the vulva to delivery of the fetus) in ruminants is generally shorter in multiparous animals (approximately 30 minutes) than primiparous animals (approximately 60 minutes).⁹ Fetal viability is improved with early intervention; multiparous animals should be assisted after 30 to 60 minutes of stage 2 labor, and primiparous animals after 60 to 90 minutes.¹⁰

The range in ambient temperatures over which newborn animals are able to maintain homeothermy is much narrower than in growing or adult animals. Neonates are more susceptible to fluctuations in environmental temperature because of their large surface area—to-mass ratio, evaporation of amniotic fluid, and limited caloric reserves. Starvation and hypothermia is the second leading cause of death of neonatal lambs.¹¹ Neonatal mortality increases with decreasing ambient temperature and with increasing precipitation on the day of birth.¹² Thermoneutrality is maintained by shivering and metabolism of brown adipose tissue. Normally at birth blood glucose concentration in calves ranges between 50 and 60 g/dL, rising to 100 mg/dL within the first 24 hours of life.¹ Lambs born in warm weather can survive for up to 4 days without supplemental nutrition. Severe weather stress may increase energy requirements by 500% and deplete the energy reserves of newborn lambs in 6 to 16 hours.¹³ Starvation exacerbates the effects of environmental stress by reducing the available substrates for heat production, and energy depletion leads to hypoglycemia. Administration of glucose to hypothermic neonates before and during warming is important to avoid deaths from cerebral hypoglycemia induced by increased use of glucose by peripheral tissues.¹⁴ Warming hypothermic lambs by immersion in 38 ° C water is more efficient than infrared lamps or wrapping them in cotton cloth.¹⁵

No intrauterine transfer of immunoglobulin (Ig) occurs in ruminants; hence, at birth, neonatal ruminants are agammaglobulinemic and immunologically naive. Infectious disease is the leading cause of morbidity and mortality in calves greater than 3 days of age.¹⁶ Failure of passive transfer (FPT) increases the risk of neonatal mortality.¹⁷ Colostrum provides a concentrated source of energy and immunoglobulins. Immunoglobulins are concentrated in colostrum by an active, receptor-mediated transfer of IgG₁ from the blood of the dam across the mammary gland secretory epithelium beginning several weeks before parturition.¹⁸ Colostral IgG₁ concentrations may be 5 to 10 times the maternal serum concentrations. IgM, IgA, and IgG₂ concentrations in colostrum are much lower.¹⁹ The large numbers of leukocytes also contribute to providing passive immunity to the newborn.²⁰ Methods of assessing passive transfer and management of FPT are discussed in detail in Chapter 53.

ACUTE ASPHYXIA IN THE NEONATE

Wendy E. Vaala

Guy D. Lester

Peripartum asphyxia can lead to encephalopathy, ischemic renal failure, and varying degrees of gastrointestinal (GI) dysfunction, the most severe form being necrotizing enterocolitis (NEC). The encephalopathy is most commonly referred to as hypoxic ischemic encephalopathy (HIE). The diagnosis of peripartum asphyxia syndrome relies on prepartum transabdominal ultrasonography of the fetoplacental unit, postpartum placental and neonatal foal examination, and immediate assessment of creatinine and presuckle glucose in the foal after delivery. Patient survival may depend on management of central nervous system (CNS), GI, and renal dysfunction.

Any process that results in impairment to placental blood flow or gas exchange can produce asphyxia. These changes in moderation are both normal and critical for postnatal adaptation through a phenomenon known as ischemic preconditioning. Essentially, brief episodes of ischemia, as can occur with myometrial contractions, induce partial protection against subsequent episodes of severe ischemia. This is likely mediated through inducible nitric oxide and can also be triggered by hypoxia and volatile inhaled anesthetic agents.²¹ Disease develops when episodes of ischemia and/or hypoxia are severe or prolonged. Asphyxia is a multifactorial disease process that develops when tissue oxygenation is disrupted. It is most commonly encountered when pregnancy and labor are complicated by problems resulting in impaired oxygen delivery to fetal tissues, on either a short-term or a long-term basis. Peripartum asphyxia has been associated with rapid, seemingly uncomplicated deliveries, dystocia, induced delivery, cesarean section, premature placental separation and other placental abnormalities, umbilical cord abnormalities, twinning, meconium staining, postdate pregnancy, and severe maternal illness.²² Asphyxia may also occur in the neonatal period; causes include severe hemorrhage, resulting in hypovolemia and shock, and severe cardiorespiratory dysfunction, as in severe pneumonia, cardiac malformations, pulmonary hypertension, and airway obstruction.

The overall incidence of the condition in the foal is not known, because of the high incidence of unmonitored and unobserved deliveries and the diagnostic confusion of asphyxial problems with other perinatal problems.²³ In a recent study of causes of equine perinatal death, complications of birth, including asphyxia, dystocia, and trauma, were listed as the second most common cause of death after infection (19% of 3527 cases). This figure does not include acute placental or umbilical cord abnormalities, problems that also could have caused acute fetal asphyxiation.²³

Peripartum asphyxia produces HIE, ischemic renal failure, and varying degrees of NEC. Diagnosis relies on prepartum transabdominal ultrasonography of the fetoplacental unit, postpartum placental and neonatal foal examination, and immediate assessment of creatinine and presuckle glucose in the foal after delivery. Patient survival depends on management of CNS, GI, and renal dysfunction.²⁴

Potential Postnatal Sequelae of Birth Asphyxia

The consequences of an episode of asphyxia can be far-reaching and profound. Many organ systems can be adversely affected and contribute to the commonly observed clinical signs of weakness and depression in the neonate. Management can be difficult and complex, but with good supportive care, dramatic recoveries can be made in even severely affected individuals. Unfortunately, it is virtually impossible at the onset of treatment to predict either the severity of injury or the prognosis. Chronic asphyxia in premature individuals or those with sepsis carries the poorest prognosis for intact neurologic survival.

Clinical signs related to the asphyxial injury may not appear until hours or days after the insult. Blood volume abnormalities, such as severe hypovolemia, occurring at delivery may not be obvious until several hours later. Blood pressure may actually be normal at first because capillary capacitance beds are constricted by substances such as catecholamines and angiotensin II. Then as the peripartum stresses decrease over time, circulating hormone levels fall and progressive hypotension and acidosis often develop.²³

Table 16-2 lists specific clinical conditions and organ system derangements that have been associated with asphyxial injury. Table 16-3 presents therapies for specific organ system dysfunction.

Table 16-2 Clinicopathologic Conditions Associated with Peripartum Asphyxia⁷⁴

Table 16-3 Drugs Used to Treat Foals with Peripartum Asphyxia⁷⁴

Organ System	Clinical Sign	Drug Therapy
CNS	Seizures	Diazepam: 0.11-0.44 mg/kg IV
		Phenobarbital: 2-10 mg/kg IV q12h; give slowly, monitor serum levels
		Pentobarbital: 2-10 mg/kg IV
	CNS edema	DMSO: 0.5-1 g/kg IV as 20% solution over 1 hr; can repeat q12h
		Mannitol: 0.25-1 g/kg IV as 20% solution over 15-20 min; q12-24h
	Antioxidants	N-acetylcysteine: 70 mg/kg IV as 10% solution; q6h
		Vitamin E: 20 IU/kg SC sid
		Thiamine: 10 mg/kg added to IV fluids sid
	NMDAantagonist	Magnesium sulfate: 0.05 mg/kg/h loading dose and then 0.025 mg/kg/hr as IV infusion
Renal	Oliguria, anuria	Dopamine infusion: 2-10 μg/kg/min; monitor blood pressure and pulse
		Furosemide infusion: 0.25-2 μg/kg/hr or 0.25-0.5 mg/kg IV q1-6h; monitor serum electrolytes and hydration status
		Mannitol: 0.5-1 g/kg IV as 20% solution over 15-20 min.
		Dobutamine infusion: 2-15 μg/kg/min; use if cardiac dysfunction is contributing to hypotension and poor renal perfusion
		Fenoldopam: 0.04 μg/kg/min
Gastrointestinal	Ileus, GI distention	Erythromycin: 1-2 mg/kg PO q6h; 1-2 mg/kg/hr as IV infusion q6h
		Cisapride: 10 mg PO q6-8h
		Metoclopramide: 0.25-0.5 mg/kg/hr infusion q6-8h
	Ulcers	Sucralfate: 20-40 mg/kg PO q6h
		Ranitidine: 5-10 mg/kg PO q6-8h, 1-2 mg/kg IV q8h
		Cimetidine: 15 mg/kg PO q6h; 6.6 mg/kg IV q6h
		Omeprazole: 2 mg/kg PO q24h
Cardiac	Hypotension	Dopamine infusion: 2-10 μg/kg/min
		Dobutamine infusion: 2-15 μg/kg/min
		Digoxin: 0.02-0.035 mg/kg PO q24h if cardiac failure is suspected
Respiratory	Hypoxemia	Intranasal, humidified oxygen: 2-10 LPM
	Apnea	Caffeine: loading dose, 10 mg/kg PO; maintenance dose, 2.5-3 mg/kg PO q24h
Endocrine	Hypocortisolemia	ACTH (depot): 0.26 mg IM q8-12h
Immune	FPT, leukopenia	Hyperimmune plasma: 10-20 mL/kg IV; monitor serum IgG and WBCs

ACTH, Adrenocorticotropic hormone; CNS, central nervous system; DMSO, dimethyl sulfoxide; FTP, failure of passive transfer; GI, gastrointestinal; IgG, immunoglobulin G; IM, intramuscular; IV, intravenous; LPM, liters per minute; NMDA, N-methyl-D-aspartate; PO, by mouth; SC, subcutaneous; sid, once per day; WBCs, white blood cells.

CENTRAL NERVOUS SYSTEM

Numerous terms are used in the literature to label foals with hypoxic ischemic brain injury. The term hypoxic-ischemic encephalopathy is preferred by some, but other terms include neonatal maladjustment syndrome; dummy, barker, or wanderer foals; and perinatal asphyxia syndrome. Risk factors for asphyxial injury are numerous and include placental insufficiency, placentitis, premature placental separation, maternal illness, umbilical cord diseases (e.g., torsion, funisitis, thrombosis), exogenous induction of labor, dystocia, caesarean section,³³ and a range of postnatal causes including airway obstruction and hemorrhage. Mild asphyxia produces transient tissue ischemia with potentially reversible damage. Prolonged ischemia results in disruption of tight junctions in the capillary endothelium and leakage of osmotic agents and fluid into surrounding brain interstitium, causing vasogenic edema.³⁴ Brain necrosis occurs and is accompanied by increased intracranial pressure, progressive brain swelling, reduced cerebral blood flow, and exacerbation of existing ischemia. In critically ill foals, cerebral edema has been associated with cerebellar herniation.³⁵

Additional brain injury occurs as a result of repeated seizures, which are common during severe encephalopathy. Repeated seizures cause brain injury through (1) hypoventilation and apnea resulting in hypoxemia and hypercapnia, (2) elevation in arterial blood pressure and cerebral blood flow, (3) progressive neuronal injury because of excessive release of excitatory amino acids such as glutamate, and (4) depletion of the brain’s limited energy stores to support seizure activity.

Neonatal foals suffering from HIE display a wide spectrum of neurologic signs that are mostly related to cerebral dysfunction. These include jitteriness, hyperalertness, stupor, somnolence, obtundation, lethargy, hypotonia, clonic seizures, extensor rigidity, hypertonia, subtle seizures, tonic posturing, coma, death, aimless wandering, head pressing, loss of affinity for the dam, inability to find the udder, abnormal vocalization (barking, high-pitched cry), loss of suckle, dysphagia, decreased tongue tone, odontoprisis, blindness, anisocoria, mydriasis, nystagmus, eye deviation, head tilt, head and neck turn, irregular respiration, apnea, abnormally slow respiratory rate, proprioceptive deficits, and spastic dysmetric gait. Blindness is a relatively common complication of perinatal asphyxia and postnatal anoxia from seizure activity and results in extensive gray and white matter injury affecting optic radiations and the visual cortex.³⁶ In a smaller number of affected foals there may be signs of brainstem or spinal cord involvement. Foals with HIE exhibit a variety of seizure-like activities. Seizures can vary in clinical severity from subtle, which may not be recognized as seizure activity, to generalized and severe (see Seizures, Chapter 19). Jitteriness is associated with mild hypoxia and is not a true seizure but a movement disorder consisting of tremors that can be stopped by gentle restraint. Subtle seizures are called motor automatisms and are characterized by paroxysmal events including eye blinking, eye deviation, nystagmus, pedaling movements, a variety of oral-buccal-lingual movements such as intermittent tongue protrusion (so-called “chewing gum fits”), sucking behavior, purposeless thrashing, and other vasomotor changes such as apnea, abnormal breathing patterns, and changes in heart rate. Tonic posturing is another subtle seizure activity characterized by symmetric limb hyperextension or flexion and may be accompanied by abnormal eye movements and apnea. Clonic seizures are true epileptiform seizures with a distinct electroencephalogram (EEG) signature and are characterized by rigid jerky motions that cannot be suppressed by restraint.

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Not all neurologic abnormalities in large animal neonates are the result of peripartum asphyxia. Other causes of neonatal neurologic disease include the following:

Metabolic disorders: hypocalcemia, hypomagnesemia, hyponatremia, hypernatremia, hyperosmolality (e.g., hyperlipidemia, hyperglycemia), severe azotemia, hepatoencephalopathy

Infectious conditions: septic meningitis, septicemia or endotoxemia, equine herpesvirus 1 (EHV-1) infection

Malformation: hydrocephalus, agenesis of the corpus callosum, vertebral and spinal cord malformations, cerebellar abiotrophy, occipitoatlantoaxial malformation

Cranial or vertebral trauma

Toxins

The diagnosis of HIE is unfortunately often done by exclusion. In foals in which there is a clear history of an asphyxial insult, such as dystocia or prolonged stage 2 labor, or that were delivered through cesarean section, the accuracy of the diagnosis should be extremely high. In foals with signs of neurologic disease when there has been no obvious asphyxial insult and when other known causes of brain dysfunction have been ruled out, a diagnosis of HIE should be made with some degree of skepticism. It has been suggested that the term neonatal encephalopathy may be more appropriate than HIE for such foals, as the cause may be unclear.

An important but uncommon cause of neurologic signs in neonatal foals is bacterial meningitis. A normal leukogram or the absence of severe leukopenia, neutropenia, and toxic neutrophil changes help rule out septic conditions. A cerebrospinal fluid (CSF) tap is indicated to rule out meningitis in foals in which signs of infection coexist with neurologic signs. Septic meningitis produces an increased nucleated cell count, protein concentration, and IgG index in the CSF. Hypoxic brain damage may result in an increased albumin quotient in the CSF compatible with increased blood-brain barrier permeability. It is also important to remember that foals with postasphyxial encephalopathy are susceptible to infection and that the two conditions often coexist without bacterial involvement of the CNS. The differentiation between HIE and congenital brain anomalies can be very difficult. The most common anomalies include hydrocephalus and hydranencephaly and are presumptively diagnosed on the basis of persistence of neurologic abnormities or definitively through computed tomography (CT) or magnetic resonance imaging (MRI). Normal serum chemistries help rule out metabolic disturbances.

Currently, suggested treatment of CNS dysfunction in asphyxiated large animal neonates includes seizure control, nursing care to prevent self-trauma, and judicious fluid therapy to avoid overhydration and hypoglycemia or hyperglycemia. Maintenance of effective perfusion and oxygen delivery is the central component of management. Diazepam is used initially to control seizures because of its rapid onset of action. Phenobarbital is used to control severe or repeated seizures. Foals receiving high doses of anticonvulsants should have their vital signs monitored closely because the combination of diazepam and phenobarbital can produce respiratory depression, loss of thermoregulatory control, and hypotension.

A large number of additional therapies are used in the management of foals with suspected postasphyxial brain injury. These therapies are used in the absence of efficacy data and may add little to the principles of therapy described previously. Interstitial cerebral edema is a pathologic feature in a small number of foals. Intravenous dimethyl sulfoxide (DMSO; 0.5 to 1 g/kg of a 10% to 20% solution, slowly over 1 to 2 hours) has been advocated for its ability to reduce brain swelling, intracranial pressure, and inflammation and to act as a diuretic.²² The osmotic agent mannitol has also been used to reduce cerebral edema and to act as a free radical scavenger. These drugs likely exert little benefit in the control of intracellular edema. To prevent exacerbation of cerebral edema, fluid therapy should be conservative, and sudden changes in osmolality should be avoided. Controversy surrounds the benefits of glucose administration. Hyperglycemia immediately after prolonged hypoxic ischemic injury has been associated with severe neonatal brain injury.³⁷ Other studies suggest that glucose administration after global hypoxic injury may offer neuroprotection by stimulating insulin release and by reducing glycolysis, free radical formation, and glutamine-mediated injury.³⁸ Therefore the safest recommendation is to maintain serum glucose concentration within a normal range. N-acetylcysteine is a potent antioxidant and antiinflammatory agent that has also been shown to be of benefit in experimental models of neonatal brain injury.³⁹ A dose rate of 70 mg/kg (as a 10% solution) IV every 6 hours has been suggested in affected neonatal foals. Thiamine is a required cofactor for several important mitochondrial enzymes involved with neuronal metabolism and can attenuate oxygen free radical damage in experimental ischemic brain damage.⁴⁰ Thiamine (10 mg/kg sid) is commonly used in foal practice but again in the absence of efficacy data. Other vitamin treatments used by some include vitamin E and vitamin C.

Magnesium sulphate infusion is yet another therapy used to attenuate postasphyxial brain injury in foals. Magnesium is recognized as an inhibitor of NMDA receptor—mediated calcium entry into cells and a membrane stabilizer preventing the persistent membrane depolarization that occurs as a consequence to disruption of the Na/K ATPase pump.⁴¹ Experimental and clinical data regarding the use of magnesium sulphate are conflicting. A recent report not only failed to demonstrate any neurologic benefit of magnesium in postasphyxiated human neonates, but raised the possibility that the therapy could have unexpected cardiovascular and neuromuscular complications.⁴¹ As with many of these agents, any potential effect may be realized only if the treatment is administered before or immediately after the insult.

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CARDIOPULMONARY EFFECTS

The response of pulmonary vasculature to hypoxia and acidemia includes increased pulmonary vascular resistance, pulmonary hypertension, increased atrial pressure, and persistent right-to-left flow of blood across fetal pathways (e.g., patent ductus arteriosus, foramen ovale). The neonatal pulmonary circulation reflexively constricts in response to hypoxemia and acidosis.⁴² This pulmonary vasoconstriction results in increased pulmonary vascular resistance, pulmonary hypertension, and increased right atrial pressure. If pulmonary arterial pressure exceeds systemic pressure, right-to-left blood flow may result in the reestablishment of fetal circulation (right-to-left flow through the ductus arteriosus and foramen ovale). Persistent fetal circulation (PFC) is associated with severe hypoxemia unresponsive to oxygen therapy owing to severe right-to-left shunting of unoxygenated blood away from the lungs.

When PFC patterns exist, hypoxemia is exacerbated. During asphyxia-induced pulmonary vasoconstriction, substrate delivery to the pneumocytes is impaired and surfactant production decreases with secondary pulmonary atelectasis. Perinatal asphyxia may adversely affect the respiratory control centers of the brain and result in hypoventilation (increased carbon dioxide), secondary to periods of apnea or abnormal breathing patterns.

Adequate surfactant production is dependent on adequate function of the type II pneumocytes and the ongoing delivery of lipid precursors by the blood. If pulmonary blood flow is compromised, surfactant production may stop, and a secondary surfactant deficiency may result.^23,43 The altered permeability characteristics of the lung that have been associated with asphyxial injury also interfere with the function of surfactant, predisposing to atelectasis.⁴⁴

If asphyxia induces in utero passage of meconium, then the fetus may aspirate meconium. Meconium can cause mechanical obstruction of airways, resulting in suffocation or regional lung atelectasis. Partial obstruction produces a ball-valve phenomenon with distal air trapping, ventilation-perfusion mismatching, alveolar overdistention and possible rupture, interstitial emphysema, and pneumothorax.⁴⁵ Meconium also induces chemical pneumonitis accompanied by alveolar collapse and edema.⁴⁶ The free fatty acids in meconium displace surfactant, resulting in additional atelectasis and decreased lung compliance.⁴⁷ See Chapter 19, Respiratory Distress, for further information. Adverse effects of asphyxia on myocardial function include reduced myocardial contractility, left ventricular dysfunction, tricuspid valve insufficiency, and cardiac failure. As a result of cardiac insufficiency the foal may develop systemic hypotension, further impairment of renal blood flow, and decreased pulmonary perfusion. In the human infant, perinatal asphyxia has been associated with myocardial and papillary muscle ischemia and infarction, with decreased myocardial contractility, tricuspid valve insufficiency, and congestive heart failure often resulting. Cardiac isoenzymes may be increased. Treatment is directed at correcting hypoxemia, acidosis, and hypoglycemia and maintaining cardiac output and blood pressure. Inotropic drugs, such as dopamine and dobutamine, are commonly used.

If pulmonary hypertension develops, thoracic radiographs show diminished vascular markings as a result of pulmonary hypoperfusion. Surfactant dysfunction produces diffuse lung atelectasis and a diffuse reticulogranular parenchymal pattern with air bronchograms. Meconium aspiration may produce perihilar infiltrated and focal atelectasis. Echocardiography helps identify arrhythmias.

Support of the respiratory system involves maintenance of oxygenation and ventilation of the patient. Mild to moderate hypoxemia can be treated by increasing the amount of time the foal spends in sternal recumbency or standing and by administering modest flows of humidified intranasal oxygen (2 to 8 L/min [LPM]). Foals with severe hypoxemia and hypercapnia (PaO₂ <40 mm Hg; PaCO₂ <65 mm Hg) require positive pressure ventilation. Respiratory stimulants are used to treat periodic apnea and abnormally slow breathing patterns associated central depression of the respiratory center. Caffeine is used most frequently to stimulate the respiratory neuronal activity and increase receptor responsiveness to elevated carbon dioxide concentrations. Overdosing with respiratory stimulants leads to excessive CNS, myocardial, and GI stimulation resulting in agitation, seizures, tachycardia, hypertension, colic, and diarrhea. Caffeine is the safest of the methylxanthines to use.

RENAL EFFECTS

During asphyxia, redistribution of blood flow away from the kidneys frequently results in decreased renal perfusion and acute tubular necrosis. The renal effects of asphyxia in foals are likely underreported, as overt signs of failure are rare. Transient changes in urine output are often overlooked, particularly when the foals are on fluid therapy. In human infants, oliguria (<1 mL of urine per kilogram of body weight per hour) is the most common clinical sign of acute renal failure; it has also been observed in asphyxiated foals.^22,23 Other signs of renal ischemic damage include peripheral edema, elevated concentrations of serum creatinine and urine γ-glutamyltransferase (GGT), and electrolyte disturbances such as hypocalcemia, hyponatremia, and hypochloremia resulting from renal tubular damage. The oliguric animal should be identified by careful monitoring of fluid intake and output to avoid fluid overload and edema formation. Based on studies in other neonates, renal blood flow and urine output may be increased by the use of low to moderate doses of dopamine (2 to 10 μg/kg/min infusion) or dobutamine (2 to 10 μg/kg/min infusion). Higher doses of dopamine are contraindicated to avoid peripheral vasoconstriction and a decrease in renal blood flow.²² Therefore, blood pressure and urine output should be carefully monitored during infusion of these substances. The dopamine-1 receptor agonist, fenoldopam, when administered at a low dose (0.04 μg/kg/min infusion) has no effect on system hemodynamics but did cause an increase in urine output in healthy neonatal foals.⁴⁸ Diuretics, such as furosemide (0.5 to 2.5 mg/kg/hr as an infusion, or 1 mg/kg intramuscularly [IM] or intravenously [IV] q12h) and mannitol (0.25 to 1 g/kg as 20% solution, infused slowly IV over 1 to 2 hours), have also been successfully used to improve urine output in asphyxiated foals.²²

GASTROINTESTINAL EFFECTS

Hypoxia results in reduced mesenteric and splanchnic blood flow and varying degrees of intestinal ischemia. The most severe form of intestinal dysfunction is NEC. (See the discussion of abdominal distension in Chapter 19.) 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.⁴⁹ Reflux and feces may be positive for blood. Generalized sepsis often accompanies NEC. As a result of varying degrees of intestinal dysmotility, some foals develop intussusceptions that can be imaged with ultrasound.

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Many asphyxiated foals demonstrate mild signs of GI malfunction, including meconium impactions and intolerance to enteral feeding (delayed gastric emptying, abdominal distension, diarrhea, and colic). Colic, bloody diarrhea, and sudden death have been observed secondary to extensive intestinal mucosal sloughing in severe cases. Ileus associated with hypoxic gut damage can result in bowel distention and colic. Nasogastric decompression relieves proximal gut distention. Enema administration stimulates distal colonic function and encourages passage of gas. Metoclopramide and erythromycin may improve gastric emptying and upper GI function. Metoclopramide infusion (0.25 to 0.3 mg/kg infusion, qid) has been suggested to improve gastric emptying and improve small intestinal motility.²² Cisapride and erythromycin have been used to stimulate small and large intestinal motility. Be certain to allow adequate time for healing of damaged bowel before using prokinetics in a compromised foal. Sonographic examination of the abdomen helps rule out the presence of intussusceptions and other obstructive lesions before motility modifiers are administered. Severe large bowel distention may require percutaneous trocarization. Alternatively, exploratory celiotomy may be performed, but the multisystemic derangements often make such animals poor surgical risks.

To reduce the risk of NEC, asphyxiated foals should have enteral feeding reduced or withheld until intestinal motility has returned. Reassuring signs include manure passage, normal borborygmi, and stable vital signs (temperature, blood pressure). Enteral feeding should be started cautiously with fresh mare’s milk or colostrum. Foals with severe GI dysfunction should have enteral feeds withheld and should be started on parenteral nutrition. Because intestinal ischemia may predispose to ulceration, histamine-2 (H₂) blockers (cimetidine, ranitidine), proton pump inhibitors (omeprazole), or cytoprotective agents (sucralfate) are recommended.

HEPATIC AND ENDOCRINE FUNCTION

Hypoxic liver damage produces an increase in hepatocellular and biliary enzymes. Affected neonates are usually icteric. Impaired hepatic function renders the neonate more susceptible to alteration in glucose homeostasis and can result in decreased hepatic defense mechanisms and increased susceptibility to sepsis. Endocrine organ damage associated with hypoxia includes adrenal gland hemorrhage and necrosis with hypocortisolemia. Parathyroid damage may result in hypocalcemia. Pancreatic injury and abnormal insulin activity can occur.

IMMUNE DYSFUNCTION

Maladjusted foals are at increased risk for FPT because of their abnormal nursing behavior. Serum IgG levels should be evaluated, and colostrum and/or plasma administered to treat FPT.

RESUSCITATION OF THE NEONATE

John K. House

Assisted deliveries are usually associated with moderate to severe fetal stress. Survival of the compromised fetus is facilitated by prompt initiation of supportive care. Prior preparation of a “crash box” or “crash cart” (Fig. 16-1) expedites location of the necessary supplies and equipment. Passage and subsequently aspiration of meconium often accompany fetal stress. Suction, if available, is useful for clearing the airway but should be used judiciously as prolonged pharyngeal and tracheal aspiration induces vagally mediated bradycardia.⁵⁰ Vigorously rubbing the skin over the legs stimulates a somatic-respiratory reflex and may help initiate respiratory effort.⁵¹ Thermoregulation is important, as recovery from acidosis is delayed by hypothermia.⁵² Cold stress leads to increased metabolic needs and produces hypoxia, hypercarbia, metabolic acidosis, and potentially hypoglycemia—metabolic sequelae that resuscitation is aimed at correcting.⁵³ Weak fetuses are often born with strongly beating hearts but have difficulty initiating adequate inspiratory efforts to expand their lungs. Positive pressure ventilation is required to overcome surface tension in alveoli and the elastic recoil of lung tissue. Fluid within alveolar spaces and the lumen of the tracheobronchial tree is absorbed into the pulmonary interstitium most efficiently at thoracic pressures between 35 and 40 cm H₂O.⁵ Less pressure is usually needed for succeeding breaths. Intrathoracic pressure that exceeds 40 cm H₂O increases the risk of damaging the alveolar epithelium. Observation of chest wall movement is a more reliable sign of appropriate inflation pressures than pressure readings from a manometer. Nasal insufflation with oxygen does not facilitate resorption of lung fluid and is largely ineffective.

Fig. 16-1 Supplies for a “crash box.”

If an endotracheal tube and a laryngoscope are available the fetus should be intubated. Placing a rigid stylet in the endotracheal tube and positioning the neonate in sternal recumbency with head and neck extended makes intubation easier. Calves may also be intubated blindly via palpation of the larynx. Ventilation of asphyxiated newborn neonates with 100% oxygen is usually recommended, but experimental work with newborn pigs and a study in humans suggest room air may be as effective.^54,55 Ventilation with a pulmonary resuscitation bag (Ambu bag) with a pressure relief valve set at 42 cm H₂O avoids inadvertent overinflation.⁵⁶ If a laryngoscope and an endotracheal tube are not available, positive pressure ventilation can be achieved using an esophageal feeding tube. The tube is passed into the esophagus with the fetus in right lateral recumbency. The distal end of the tube is located approximately one third of the distance “down” the neck. The esophagus is compressed distal to the end of the tube, with one hand taking care not to trap the trachea, and the muzzle is gripped with the other hand to seal the nares. The operator then blows into the tube and, providing the esophageal and muzzle seals are good, air is delivered into the lungs.⁵⁷ Direct mouth-to-mouth resuscitation is unhygienic and delivers air mainly into the abomasum. Respiratory stimulant (analeptic) drugs, such as doxapram hydrochloride, may be used to stimulate respiration in neonates but should be used judiciously, as the stimulatory action of the drug is nonselective. Convulsions may be observed with repeated administration, increasing the demand for O₂ in an already hypoxic neonate.⁵⁸ Analeptics should not be used as a substitute for ventilatory support.

Progressive hypoxia and tissue acidosis lead to bradycardia, decreased cardiac contractility, and eventually cardiac arrest. If apnea progresses to cardiopulmonary arrest, artificial circulation in the form of cardiac massage needs to be provided, along with positive pressure ventilation. Cardiac massage in lambs and kids is performed by compressing the ventral thorax behind the elbows between the thumb and two fore fingers. Cardiac compressions in calves is achieved by placing the patient in lateral recumbency and compressing the ventral thorax behind the elbows against a sandbag placed under the calf in a position opposite the resuscitator’s hands. Effectiveness of cardiac compressions may be monitored by checking for a palpable pulse and by observing changes in mucous membrane color. When available, an electrocardiograph is useful to monitor the electrical activity of the heart. Abdominal wrapping is used in human and small animal medicine during cardiopulmonary resuscitation to improve myocardial perfusion by returning pooled venous blood from the abdomen and limbs to the central compartment and by reducing the runoff of arterial blood to the caudal periphery.⁵⁹ Treatment with epinephrine is recommended for asystole or if the heart rate stays below 60 beats/minute. Epinephrine increases systemic vascular resistance, redistributing circulation away from the periphery to the cerebral and myocardial circulation, and increases myocardial contractility, heart rate, and cardiac output. Epinephrine is initially administered at a dose of 0.02 mg/kg either intravenously or intratracheally (via the endotracheal tube). There are reports of cases in the human literature in which there was no response to this dose but responses were observed to doses as high as 0.2 mg/kg.⁶⁰ High-dose epinephrine therapy may increase the risk of acute renal failure and intracranial hemorrhage and is not recommended as a primary treatment.⁵³ Peak plasma concentrations of epinephrine are achieved 60 seconds after endotracheal administration. Plasma concentrations of epinephrine after endotracheal administration are approximately 10 times lower than those achieved with intravenous administration, so intravenous access should be established as soon as possible.⁶¹ Administration of large doses of epinephrine endotracheally to compensate for the reduced absorption is associated with prolonged hypertension and is not recommended.⁶² In an emergency the endotracheal route of drug administration may be used for other lipid-soluble drugs such as lidocaine or atropine but should not be used for non—lipid-soluble drugs.⁶³ When drugs are administered by the endotracheal route, they should be instilled as deeply as possible into the tracheobronchial tree using a catheter inserted beyond the tip of the endotracheal tube.⁶⁴ Dilution of the drug in 1 to 2 mL of saline may aid drug delivery. Rapid intravenous infusion of warm isotonic fluid (lactated Ringers 20 to 40 mL/kg) increases the circulating fluid volume and may help to compensate for the increased vascular volume. The use of sodium bicarbonate, atropine, and calcium chloride in cardiopulmonary resuscitation of neonates is controversial. A basic protocol for resuscitation of the newborn is presented in Fig. 16-2.

Fig. 16-2 Resuscitation of the neonate.

The rationale for sodium bicarbonate administration in the presence of lactic acidosis is to increase extracellular pH and thereby improve cardiac function, perfusion and oxygenation of peripheral tissues, intracellular pH, and lactate metabolism.⁶⁵ Sodium bicarbonate administration is associated with production of carbon dioxide; correction of the acidosis requires removal of the CO₂, which is dependent on adequate ventilation and pulmonary blood flow. If pulmonary ventilation or pulmonary blood flow is inadequate, administration of sodium bicarbonate will result in hypercarbia. Excessive administration of sodium bicarbonate causes alkalemia and a right shift in the oxygen-hemoglobin dissociation curve, reducing oxygen availability to tissues. Paradoxic CNS acidosis has been documented in association with bicarbonate administration during cardiopulmonary resuscitation,⁶⁶ and acute intracellular potassium shifts secondary to sodium bicarbonate therapy may be associated with an increased incidence of cardiac arrhythmias.⁶⁷ Administration of sodium bicarbonate is recommended only if adequate ventilation has been established and when all other measures have not been successful.⁶⁸ The dose is 1 to 2 mEq/kg administered by slow intravenous injection. Because catecholamines are inactivated by bicarbonate and because calcium will precipitate when mixed with bicarbonate, intravenous catheters should be flushed between infusions of drugs.⁶⁴

Use of atropine in resuscitation is based on its peripheral effects as a competitive antagonist of acetylcholine, reducing vagal tone and increasing conduction through the atrioventricular node. The effect of atropine is dependent on the degree of vagal stimulation that is causing the bradycardia. Vagal stimulation is not the cause of bradycardia in hypoxic newborns; therefore a response is unlikely. Possible deleterious effects of atropine administered at therapeutic doses are increased myocardial oxygen consumption and precipitation of atrial and ventricular tachyarrhythmias.⁶⁹ In low doses atropine stimulates the medullary vagal nuclei, causing paradoxic bradycardia with slowing of atrioventricular conduction.⁷⁰

The belief that increasing the availability of calcium during cardiac arrest might improve myocardial function led to inclusion of calcium chloride in cardiopulmonary resuscitation protocols. Calcium has been implicated as a cause of postresuscitation cerebral ischemia, as high levels of calcium promote prolonged vasoconstriction, exacerbating cerebral and myocardial hypoperfusion.⁷¹ Currently administration of calcium chloride is recommended only in cases of known hypocalcemia and hyperkalemia.