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Hypoxic Ischemic Encephalopathy: Neonatal Encephalopathy
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Hypoxic ischemic encephalopathy (HIE), also known as neonatal encephalopathy (NE), is one systemic manifestation of a broader syndrome of perinatal asphyxia syndrome (PAS). Management of foals presenting with signs consistent with a diagnosis of HIE requires the clinician to fully examine other body systems and provide therapy directed at treating other involved systems [1]. While PAS primarily manifests as HIE, the gastrointestinal tract and kidneys are frequently affected by peripartum hypoxia/ischemia/asphyxia and complications associated with these systems should be expected. The cardiovascular and respiratory systems may also be affected and endocrine disorders are not uncommon.
HIE has been recognized as one of the most common diseases of the equine neonate for decades [2-4]. It has been known in the past as dummy foal syndrome and as neonatal maladjustment syndrome (Fig. 1).
Figure 1. Foal with uncomplicated hypoxic ischemic encephalopathy (HIE). This foal is receiving intranasal oxygen insufflation and intravenous fluids, including parenteral nutrition. It is partially covered by a circulating warm air blanket. The mattress is covered with a synthetic "sheepskin" to protect against skin abrasions. It is wearing a soft cloth halter with loop-and-hook closures.
The designation HIE, while not perfect, attempts to describe the syndrome in terms of the suspected underlying pathophysiology, while the term neonatal encephalopathy is broader. Neonatal encephalopathy is clinically defined as a syndrome of disturbed neurologic function in an infant at or near term during the first week after birth, manifested by difficulty with initiating and maintaining respirations, depression of reflexes, altered level of consciousness, and often seizures [5]. A wide spectrum of clinical signs are associated with HIE and range from mild depression with loss of the suck reflex to grand mal seizure activity. Typically, affected foals are normal at birth but show signs of central nervous system (CNS) abnormalities within a few hours following birth (Fig. 2). Some foals are obviously abnormal at birth and some will not show signs until 24 to 36 hours of age. HIE is commonly associated with adverse peripartum events, including dystocia (Fig. 3) and premature placental separation, but a fair number of foals have no known peripartum period of hypoxia, suggesting that HIE in these foals results from unrecognized in utero acute or chronic hypoxia (Table 1).
Figure 2. Foal with HIE complicated by effects of asphyxia on other body systems. This foal is receiving parenteral nutrition, inopressor support, intravenous fluid support supplemented with thiamine, intravenous plasma, intravenous magnesium constant rate infusion, and is being mechanically ventilated.
Figure 3. Dystocia. The mare has been anesthetized and its hindlimbs elevated in an effort to deliver the foal vaginally. The foal was delivered vaginally but did not survive.
Table 1. Causes of hypoxia in the fetus and neonate*. |
Maternal Causes
|
Placental Causes
|
Intrapartum Causes
|
Neonatal Period Causes
|
* Adapted from: JE Palmer, Perinatal Hypoxic-Ischemic Disease, Proceedings IVECCS VI, 1998; pp717-718.
Severe maternal illness may also result in foals born with PAS. Ascending placental infection is now suspected to be a major contributor to NE in infants and the incidence of NE is increased with the presence of maternal fever, suggesting a role for maternal inflammatory mediators [6-8].
The underlying pathophysiologic details of HIE in the foal are unknown and, to date, accurate experimental models of HIE and PAS in the foal have not been described. However, a great deal of attention has been paid to peripartum hypoxia/asphyxia by our human counterparts, as the effects of adverse peripartum events in the human neonate have far ranging implications for the affected human neonate and for society. Therefore, equine neonatologists have long looked to human studies and models of the human disease for understanding of the syndrome in the equine neonate.
Perinatal brain damage in the mature fetus usually results from severe uterine asphyxia due to an acute reduction of uterine or umbilical circulation. The fetus responds to this challenge by activation of the sympathetic adrenergic nervous system causing a redistribution of cardiac output that favors the central organs - brain, heart and adrenal glands [9,10]. If the hypoxic insult continues, a point is reached beyond which the fetus cannot maintain this centralization of circulation, cardiac output falls and cerebral circulation diminishes [10]. The loss of oxygen results in a substantial decrease in oxidative phosphorylation in the brain with concomitant decreased energy production. The Na+/K+ pump at the cell membrane cannot maintain the ionic gradients, and the membrane potential is lost in the brain cells. In the absence of the membrane potential, calcium flows down its large extra/intracellular concentration gradient through voltage dependent ion channels into the cell. This calcium overload of the neuron leads to cell damage by activation of calcium dependant proteases, lipases and endonucleases. Protein biosynthesis is halted. Calcium also enters the cells by glutamate-regulated ion channels as glutamate, an excitatory neurotransmitter, is released from pre-synaptic vesicles following anoxic cellular depolarization. Once the anoxic event is over, protein synthesis remain inhibited in specific areas of the brain and returns to normal in less vulnerable areas of the brain. Loss of protein synthesis appears to be an early indicator of cell death due to the primary hypoxic/anoxic event [11].
A second wave of neuronal cell death occurs during the "reperfusion" phase and is thought to be similar to classically described "post-ischemic reperfusion injury" in that damage is due to production of and release of oxygen radicals, synthesis of nitric oxide (NO) and inflammatory reactions [12]. Additionally, an imbalance between excitatory and inhibitory neurotransmitters occurs [11]. Part of the secondary cell death that occurs is thought to be due to apoptosis, a type of programmed cell death termed "cellular suicide". Secondary cell death is also thought be due to the neurotoxicity of glutamate and aspartate resulting, again, from increased intracellular calcium levels [13,14]. In human infants, the distribution of lesions with hypoxic-ischemic brain damage following prenatal, perinatal or postnatal asphyxia fall into distinct patterns depending on the type of hypoxia-ischemia, rather than post-conceptual age at which the asphyxial event occurs [14]. Periventricular leukomalacia is associated with chronic hypoxia-ischemia while the basal ganglia and thalamus are primarily affected in patients experiencing acute profound asphyxia, providing direct evidence that the nature of the event determines the severity and distribution of neurologic damage in humans. These very selective patterns of injury in children, with variability in the damage caused to regions anatomically located within millimeters of each other, resulted in the hypothesis that location within neurotransmitter specific circuitry loops is important. This hypothesis has important implications in the design of neuroprotective strategies and therapies for neonates experiencing hypoxic-ischemic-asphyxial events. There is now overwhelming evidence that the excitotoxic cascade that evolves during HIE extends over several days from the time of insult and is modifiable [13,14].
In brain injury, traumatic or hypoxic, the mechanisms underlying delayed tissue injury are still poorly understood. It is believed by many that neurochemical changes, including excessive neurotransmitter release, are crucial to the development of secondary neuronal death. Excitatory aminoacid neurotransmitters and magnesium are known to play at least a minimal role in secondary cell death following brain injury; a fair body of literature regarding these factors has been generated over the last 10 - 12 years. The activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is implicated in the pathophysiology of traumatic brain injury and is suspected to play a role in HIE [13-15]. Mechanically injured neurons demonstrate a reduction of voltage-dependant Mg2+ blockade of NMDA current that can be partially restored by increasing extracellular Mg2+ concentration or by pretreatment with calphostin C, a protein kinase C inhibitor [16]. This finding suggested that administration of Mg2+ to brain injured patients could lead to improved outcome. Subsequently, intravenous administration of magnesium sulfate was shown to dramatically improve the immediate recovery of rats from hypoxia [17]. However, while pretreatment with magnesium sulfate protected against hypoxic ischemic brain injury, postasphyxial treatment worsened brain damage in seven-day-old rats, suggesting an age related response in the rat [18]. Delayed magnesium treatment of mature rats following severe traumatic axonal brain injury improved motor outcome when administered up to 24 hours after injury, with early treatments providing the most benefit [19]. Obviously, the role of magnesium needs further attention.
Maternal seizure in rats is associated with fetal histopathologic changes that are abolished by maternal administration of magnesium sulfate which has been demonstrated to protect the fetal brain from severe maternal hypoxia [20]. Clinical trials investigating the efficacy of magnesium treatment following hypoxia in infants are underway, with few reports currently in the medical literature. Magnesium sulfate was used to treat 9 infants after perinatal asphyxia in one study, there was no control group, and all children were neurologically normal at 1 year of age. Seizure did not occur in any of these children nor were any adverse side effects noted [21]. Magnesium sulfate administration failed to delay the global impairment in energy metabolism after hypoxia-ischemia, characteristic of severe brain damage, in newborn piglets and at 48 hours post-hypoxia-ischemia no difference could be found in the severity of injury in magnesium-treated piglets compared to placebo-treated piglets, suggesting magnesium may not be protective with severe acute injury, at least in non-precotial species [22].
In developing countries, birth hypoxia is frequently associated with HIE and while this finding is most frequently attributed to inadequate obstetrical care, poor nutrition may also play a role. Red blood cell magnesium levels were measured in over 500 women in labor at a teaching hospital in South Africa [23]. Fifty five of the women delivered infants with HIE and had significantly lower levels of magnesium than controls; the infants with HIE also had significantly lower magnesium levels than controls. The large majority (54/55) of the women giving birth to HIE infants were from poor social circumstances, suggesting nutrition might play a role in some cases of HIE, with maternal magnesium levels affecting outcome in the infants. The authors suggested an early pregnancy intervention study may help determine the role of magnesium in the pathogenesis of HIE in human infants born to at risk mothers. In a separate study, the cord blood of asphyxiated infants developing severe HIE had significantly lower ionized magnesium concentration than the cord blood of asphyxiated infants not developing HIE, or showing only mild HIE symptoms [24].
Therapy for the various manifestations of hypoxia-ischemia involves control of seizures, general cerebral support, correction of metabolic abnormalities, maintenance of normal arterial blood gas values, maintenance of tissue perfusion, maintenance of renal function, treatment of gastrointestinal dysfunction, prevention/recognition/early treatment of secondary infections and general supportive care. It is important that seizures be controlled as cerebral oxygen consumption increases five-fold during a seizure. Diazepam can be used for emergency control of seizures (Table 2).
Table 2. Drugs used to control or prevent seizures in HIE. | ||||
Drug | Dose | Route | Frequency | Comment |
Diazepam | 5 - 10 mg/foal | IV | PRN | Seizure control short term |
Phenobarbital | 2 - 3 mg/kg | IV | Bolus to effect | Bolus over 15 - 20 min. |
Phenytoin | 5 - 10 mg/kg loading | IV | Q 4 hr 1st 24 hours | Seizure control |
Magnesium sulfate | loading* | IV | CRI- 1 hour | Constant rate infusion. Discontinue if muscle tremors, hypotension occur. Treat for 24 - 48 hours after hypoxic insult |
Gabapentin | 8 mg/kg | PO | BID - TID | Seizure control |
* To make up magnesium CRI, remove 20 ml from a 100 ml bag of normal saline. Add 20 ml of 50% magnesium sulfate solution. Initial rate for 50 kg foal is 25 ml/hr. Give this as a 1-hour infusion. Maintenance dose becomes 12.5 ml/hr after 1 hour loading dose is completed.
If the seizure is not readily stopped with diazepam, or more than two seizures are recognized, then diazepam should be replaced with phenobarbital given to effect [25]. The half-life of phenobarbital can be quite long in the foal (more than 200 hours) and this should be kept in mind when monitoring neurologic function in these cases after phenobarbital administration (JE Palmer, personal communication). Early stage, pre-seizure, administration of phenobarbital has been advocated by some investigators for prevention of NE. However, one recent study in asphyxiated human infants demonstrated that early phenobarbital treatment was associated with a three-fold increase in the incidence of subsequent seizures, and, consequently, a trend towards increased mortality. Seizures per se were associated with almost a twenty-fold increase in mortality. These findings suggest that early phenobarbital administration may produce adverse rather than beneficial effects following asphyxia. Because this was an observational study the results need to be confirmed by appropriate randomized trials in similar clinical settings [26]. Phenobarbital administration is not without deleterious effects and alteration in ventilation may be seen, as may changes in blood pressure regulation, after its administration. Foals receiving phenobarbital should be closely monitored and sequential, frequent blood pressure determinations and arterial blood analyses should be obtained. If phenobarbital fails to control seizures, phenytoin therapy may be attempted. In cases of HIE, ketamine and xylazine have historically been avoided because of their association with increased intracranial pressure. However, there is evidence that ketamine infusion may be beneficial in controlling grand mal seizure uncontrolled by phenobarbital [27]. This author has also used midazolam for control of seizures in these patients. It is important to protect the foal from injury during a seizure and also to ensure airway patency to prevent the onset of occlusive hypercapnia, negative pressure pulmonary edema [28] or aspiration pneumonia.
Probably the most important therapeutic interventions are aimed at maintaining cerebral perfusion. This is achieved by careful titration of intravenous fluid support, neither too much nor too little, and judicious administration of inotropes and pressors in order to maintain adequate perfusion pressures. Cerebral interstitial edema is only truly present in the most severe cases [29,30] in most cases the lesion is intracellular edema and the classic agents used to treat cerebral interstitial edema, mannitol and dimethylsulfoxide (DMSO), are minimally effective treating cellular edema. We also use thiamine supplementation in the intravenous fluids to support metabolic processes, specifically mitochondrial metabolism and membrane Na+/K+/ATPases, involved in maintaining cellular fluid balance [31,32]. This therapy is rational and inexpensive but unproven in efficacy. Drugs such as mannitol and dimethylsulfoxide (DMSO) are indicated only when cellular necrosis and vasogenic edema are present, and again, these cases are usually the most severely affected. In our clinic we rarely use DMSO and have recognized no change in outcome by discontinuing its use. When we use intravenous DMSO, it is reserved for use within the first hour after an acute asphyxial insult primarily for its hydroxyl radical scavenging effects and its theoretical modulation of post-ischemic reperfusion injury [33].
Naloxone has been advocated for the treatment of HIE in humans and in foals, perhaps based on a study suggesting that post-asphyxia blood-brain barrier disruption was causally related to poor neurological outcome in a lamb model of HIE, and that naloxone prevented both disruption, and neurological dysfunction among those survivors with intact blood-brain barrier [34,35]. However, other studies have demonstrated that naloxone exacerbates hypoxic-ischemic brain injury in 7 day-old rats subjected to unilateral common carotid artery ligation and hypoxia. Moreover, systemic acidosis and cellular edema were not different in naloxone-treated animals compared to animals treated with saline solution. The authors concluded that high doses of naloxone may, in fact, reduce the resistance of the fetus to hypoxic stress [36]. The use of naloxone in human neonatal resuscitation remains controversial, as whether the contradictory effects are related to a reduction in acute neuronal swelling by osmotic effects or by a more direct receptor mediated mechanism is currently unknown [37]. Naloxone is most effective in resuscitation of compromised human infants born to drug addicted mothers. GABAergic agonists are being used by some practitioners in the managements of HIE in foals, based on evidence showing neuroprotection when used in ischemia, both alone and in combination with NMDA antagonists [38-40]. We currently have no experience with these compounds in our neonatal intensive care unit (NICU) and cannot comment regarding their efficacy in foals. Regional hypothermia is also being investigated as a potential therapy for global hypoxia/ischemia, published data are consistent with the theory that cooling must be continued throughout the entire secondary phase of injury (~3 days) to be effective [41]. Experimentally, this approach has resulted in dramatic decreases in cellular edema and neuronal loss; its practical application remains to be demonstrated.
Despite a lack of consensus regarding the use of magnesium in the treatment of infants with HIE, we have used magnesium sulfate infusion as part of our therapy for selected HIE foals for the past several years. Our rationale is based primarily in the evidence demonstrating protection in some studies and a failure of any one study to demonstrate significant detrimental effects. Our clinical impressions to date suggest that the therapy is safe and may decrease the incidence of seizure in our patients. We administer magnesium sulfate as a constant rate infusion after a loading dose is given over 1 hour. The author has continued the infusion for up to 3 days without demonstrable negative effect beyond some possible trembling, but given the current evidence, a 24-hour course of treatment may be effective and all that is necessary. Post-asphyxial treatment may certainly be beneficial in foals with HIE and maternal magnesium therapy may be beneficial in certain high-risk pregnancy patients.
Foals with PAS often have a variety of metabolic problems including hypo- or hyperglycemia, hypo- or hypercalcemia, hypo- or hyperkalemia, hypo- or hyperchloremia and varying degrees of metabolic acidosis. While these problems need to be addressed, the normal period of hypoglycemia that occurs postpartum should not be forgotten and should not be treated aggressively for fear of worsening the neurologic injury. Foals suffering from PAS will also have recurrent bouts of hypoxemia/desaturation of hemoglobin and occasional bouts of hypercapnia. Intranasal oxygen insufflation is generally needed in these cases both as a preventative therapy and as direct treatment, as the appearance of the abnormalities can be sporadic and unpredictable (Fig. 4).
Figure 4. Foal receiving intranasal oxygen insufflation. Note that the intranasal cannula is taped in place rather than being sewn in place. This method of cannula attachment is well tolerated by the foal and changing the cannula is simplified.
Additional respiratory support, particularly in those foals with centrally mediated hypoventilation and periods of apnea or abnormal breathing patterns, include caffeine (per os or per rectum) and positive pressure ventilation. Caffeine is a central respiratory stimulant and has minimal side effects at the dosages used (10 mg/kg loading dose; 2.5 mg/kg prn) [42]. We purchase whatever oral form of caffeine is available at the local convenient or drug-store and administer it dissolved in a small volume, 5 ml, of warm water per rectum. Foals treated with caffeine have an increased level of arousal and are more reactive to the environment. Adverse effects are generally limited to restlessness, hyperactivity and mild to moderate tachycardia. Mechanical ventilation of these patients can be very rewarding and is generally required for less than 48 hours (Fig. 5).
Figure 5. HIE foal being mechanically ventilated secondary to central respiratory depression.
It is important that blood pH be monitored and maintained within the normal range. Metabolic alkalosis can develop in some of these cases that requires clinician tolerance of some degree of hypercapnia. When evaluating these cases and considering alternatives for treatment, pH is important. If the respiratory acidosis is not so severe as to adversely affect the patient (generally > 70 mmHg), and the pH is within normal limits, hypercapnia may be tolerated [43]. The therapeutic goal is to normalize pH. Foals with respiratory acidosis as compensation for metabolic alkalosis will not respond to caffeine. Metabolic alkalosis in critically ill foals is frequently associated with electrolyte abnormalities creating differences in strong ion balance. This pH perturbation is best handled by correction of the underlying electrolyte problem.
Maintaining tissue perfusion and oxygen delivery to tissues is a cornerstone of therapy for PAS in order to avoid additional injury. Oxygen carrying capacity of the blood should be maintained; some foals will require whole blood transfusions to maintain a PCV > 20% (Fig. 6).
Figure 6. Foal with HIE receiving a blood transfusion to maintain oxygen carrying capacity. This foal is also receiving intranasal oxygen insufflation and having its ECG monitored; note intranasal oxygen cannula and ECG leads attached to foal.
Adequate vascular volume is important, but care should be taken to avoid fluid-overloading the foal. Early evidence of fluid overload is subtle accumulation of ventral edema between the front legs and over the distal limbs. Fluid overload can result in cerebral edema, pulmonary edema and edema of other tissues, including the gastrointestinal tract. This edema interferes with normal organ function and worsening condition of the patient. Perfusion is maintained by supporting cardiac output and blood pressure by judicious use of intravenous fluid support and inotrope/pressor support (Fig. 7).
Figure 7. Indirect blood pressure monitoring of a foal with HIE. Tail cuffs are used most commonly in recumbent foals.
We do not aim for any "magic" systolic, mean or diastolic pressure. Instead we monitor urine output, mentation, limb perfusion, gastrointestinal function and respiratory function as indicators that perfusion is acceptable. It is not unusual for these patients to require inopressor therapy but in some cases the hypoxic damage is sufficiently severe to blunt the response of the patient to the drugs.
Outcome of foals with HIE is generally good. Early reports suggested that foals with HIE have a fair to good short-term survival, barring complications such as sepsis or significant musculoskeletal abnormalities [44,45]. Foals with HIE surviving the initial neonatal period without significant complications, have a fair to good prognosis for future athletic performance and, once racing, have performance similar to their age-matched cohort [44-46].
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New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pennsylvania, USA.
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