Hypoxic-ischemic encephalopathy (perinatal asphyxia or neonatal maladjustment syndrome) is one of the most common diseases affecting neonatal foals. The incidence of this disease among equine neonates is reported to be 1% to 2% of all births.1 Hypoxicischemic encephalopathy in foals is commonly associated with adverse peripartum events, such as dystocia and premature placental separation, that may result in brain hypoxia or ischemia. Typically, affected foals are apparently normal at birth but develop signs of CNS abnormalities within hours after delivery. The spectrum of clinical signs in affected foals ranges from mild behavioral abnormalities to multiorgan failure with various neurologic deficits, including central blindness, coma, and seizure.2 As a result of CNS damage, affected foals often have an abnormally low respiratory rate or periods of apnea, resulting in severe respiratory acidosis from loss of sensitivity to carbon dioxide within the chemosensitive area of the respiratory center. Hypercapnia causes cerebral acidosis and cerebral vasodilation.3 Cerebral vasodilation may cause increased blood flow in uninjured areas, with relative ischemia to damaged areas.3 This excess blood flow to uninjured areas may result in intracranial hemorrhage.3
Treatments for foals with hypoxic-ischemic encephalopathy that develop severe hypercapnia include mechanical ventilation or pharmacologic stimulation of respiration. Mechanical ventilation of foals is possible but is expensive and labor intensive. Pharmacologic stimulation of respiration via administration of methylxanthines or doxapram markedly decreases the need for mechanical ventilation in human neonates with apnea of prematurity.4 Although apnea of prematurity in human infants has a completely different pathogenesis from hypoxic-ischemic encephalopathy in foals, both conditions are clinically associated with apnea and abnormal respiratory control. Caffeine, a methylxanthine, often represents the first line of treatment in infants with apnea.4 Mechanisms by which methylxanthines decrease apnea and improve ventilation include stimulation of the respiratory center, improvement of diaphragmatic contractility, and antagonism of adenosine (a neurotransmitter that causes respiratory depression).4,5 Adverse effects of caffeine in infants are rare but include tachycardia, signs of gastrointestinal dysfunction, agitation, and irritability.5 Caffeine has also been reported to alter cerebral and intestinal flow velocity in preterm infants.6
Doxapram improves ventilation through direct stimulation of the medullary respiratory centers and through reflex activation of aortic and carotid body chemoreceptors.7 In human neonates, adverse effects of doxapram are similar to those reported for caffeine. Doxapram substantially reduces the frequency of apnea, bradycardia, and hypoxemia in infants with caffeineresistant apnea.8,9 In a meta-analysis of the human medical literature, doxapram and methylxanthines were similar in their short-term effects on respiratory function and adverse effect profiles.10 As a result, doxapram is recommended for administration to infants who are unresponsive to methylxanthines alone.7
Despite the lack of data regarding the efficacy and safety of caffeine and doxapram for the treatment of hypercapnia in equine neonates, the use of those agents as a respiratory stimulant is recommended in many equine textbooks and review articles, with dosage regimens extrapolated from studies11-13 in infants. The objective of the study reported here was to determine and compare the short-term effects of caffeine and doxapram on respiratory function, cardiovascular performance, and cerebral blood flow velocity in clinically normal foals by use of an anesthetic technique that results in hypercapnea but not hypoxemia. Our hypothesis was that caffeine and doxapram would be effective in decreasing PaCO2 in foals with hypercapnea.
End-tidal carbon dioxide
Inspiration-to-expiration time ratio
Systolic arterial pressure
Diastolic arterial pressure
Mean arterial pressure
Lithium dilution cardiac output
Alveolar dead space ventilation
Systemic vascular resistance
Oxygen extraction ratio
Peak systolic blood flow velocity
End-diastolic blood flow velocity
Time-averaged mean velocity
High-performance liquid chromatography
DVM Stat, Corporation for Advanced Applications, Newburg, Wis.
Mila International Inc, Florence, Ky.
Abbott Laboratories, North Chicago, Ill.
VetaKet, Phoenix Scientific Inc, St Joseph, Mo.
IsoFlo, Abbott Laboratories, North Chicago, Ill.
S/5, Datex-Ohmeda Division, Madison, Wis.
DOT-34 NRC 300/375 M1014, Datex-Ohmeda Division, Madison, Wis.
Airway Module M-CAiOV, Datex-Ohmeda Division, Madison, Wis.
Plasmalyte 148, Baxter Healthcare Corp, Deerfield, Ill.
LiDCO cardiac computer CM 31-01, LiDCO Ltd, London, UK.
Flow-through cell electrode assembly, LiDCO Ltd, London, UK.
ABL System 605/600 and OSM3 Hemoximeter, Radiometer Medical, Copenhagen, Denmark.
LiDCO Ltd, London, UK.
Bedford Laboratories, Bedford, Ohio.
Cafcit, MeadJohnson & Co, Evansville, Ind.
Medfusion Model 2010i syringe pump, MedexInc, Duluth, Ga.
Vivid 3 Expert, GE Medical Systems, Milwaukee, Wis.
United Chemical Technologies, Bristol, Pa.
HP1100 system, Hewlett Packard, Wilmington, Del.
Adsorbosphere C18 column (4.6 × 250 mm; 5 μm), Alltech, Deerfield, Ill.
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Formulas used for calculated variables in a study of the effects of doxapram, caffeine, and saline (0.9% NaCl) solution in anesthetized neonatal foals with isoflurane-induced respiratory acidosis.