Hypoxic-Ischemic Encephalopathy Treatment & Management

Following initial resuscitation and stabilization, treatment of hypoxic-ischemic encephalopathy (HIE) is largely supportive and should focus on adequate ventilation and perfusion, careful fluid management, avoidance of hypoglycemia and hyperglycemia and treatment of seizures.^{[49, 50]} Intervention strategies aim to avoid any further brain injury in these infants.^[51]

Delivery room management follows standard Neonatal Resuscitation Program (NRP) guidelines. Close attention should be paid to appropriate oxygen delivery, perfusion status, and avoidance of hypoglycemia and hyperthermia.

A lot of attention is currently focused on resuscitation with room air versus 100% oxygen in the delivery room. Several clinical trials indicate that room air resuscitation for infants with perinatal asphyxia is as effective as resuscitation with 100% oxygen. In addition, infants resuscitated with room air have a lower level of circulating markers of oxidative stress. However, studies indicating that time to return to spontaneous circulation is equivalent with room air resuscitation are lacking. Given these limitation, current International Liaison Committee on Resuscitation (ILCOR) recommendations include initiating neonatal resuscitation with concentrations of oxygen between 21-100%.^[52] Updated ILCOR guidelines are set to be published October 2010; updated NRP guidelines are expected in February 2011.

Most infants with severe hypoxic-ischemic encephalopathy need ventilatory support during first days of life. Although animal data suggest that permissive hypercapnia may be neuroprotective, no such evidence is available in newborn. Therefore, the role of mechanical ventilation is to maintain the blood gases and acid-base status in the physiological ranges and prevent hypoxia, hyperoxia, hypercapnia, and hypocapnia. Hypocapnia in particular may lead to severe brain hypoperfusion and cellular alkalosis and has been associated with worse neurodevelopmental outcomes.

Infants with hypoxic-ischemic encephalopathy are also at risk for pulmonary hypertension and should be monitored. Nitric oxide (NO) may be used according to published guidelines.^[53]

Studies indicate that a mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid decreased cerebral perfusion. Hypotension is common in infants with severe hypoxic-ischemic encephalopathy and is due to myocardial dysfunction, capillary leak syndrome, and hypovolemia; hypotension should be promptly treated. Dopamine or dobutamine can be used to achieve adequate cardiac output in these patients. Avoiding iatrogenic hypertensive episodes is also important.

Because of the concern for acute tubular necrosis (ATN) and syndrome of inappropriate antidiuretic hormone (SIADH) secretion, fluid restriction is typically recommended for these infants until renal function and urine output can be evaluated. However, this recommendation is not based on evidence from randomized controlled trials.^[54] Therefore, fluid and electrolyte management must be individualized on the basis of clinical course, changes in weight, urine output, and the results of serum electrolyte and renal function studies.

The role of prophylactic theophylline, given early after birth, in reducing renal dysfunction after hypoxic-ischemic encephalopathy has been evaluated in 3 small randomized controlled trials.^{[55, 56, 57]} In these studies, a single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in (1) decreased severe renal dysfunction (defined as creatinine level >1.5 mg/dL for 2 consecutive days); (2) increased creatine clearance; (3) increased glomerular filtration rate (GFR); and (4) decreased b2 microglobulin excretion. The clinical significance of these findings remains unclear. Larger studies are warranted to confirm the safety of adenosine inhibitor use following hypoxic-ischemic encephalopathy.

Fluid and glucose homeostasis should be achieved. Avoid hypoglycemia and hyperglycemia because both may accentuate brain damage. Hypoglycemia in particular should be avoided. In a retrospective study, Salhab et al showed that initial hypoglycemia (< 40 mg/dL) is significantly associated with adverse neurological outsomes.^[58]

Hyperthermia has been shown to be associated with increased risk of adverse outcomes in neonates with moderate-to-severe hypoxic-ischemic encephalopathy.^[59] In this observational secondary study, the risk of death or moderate-to-severe disability was increased 3.6-fold to 4-fold for every 1°C increase in the mean of the highest quartile of skin or esophageal temperature.

Hypoxic-ischemic encephalopathy is the most common cause of seizures in the neonatal period. Seizures are generally self-limited to the first days of life but may significantly compromise other body functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, studies suggest that seizures, including asymptomatic electrographic seizures, may contribute to brain injury and increase the risk of subsequent epilepsy.^{[60, 61, 62]}

Current therapies available to treat neonates with seizures include phenobarbital, phenytoin, and benzodiazepines. Phenobarbital has been shown to be effective in only 29-50% of cases,^{[63, 64, 65]} Phenytoin only offers an additional 15% efficacy. Benzodiazepines, particularly lorazepam, may offer some additional efficacy.^{[66, 67]}

Extensive experimental data suggest that mild hypothermia (3-4°C below baseline temperature) applied within a few hours (no later than 6 h) of injury is neuroprotective. The neuroprotective mechanisms are not completely understood. Possible mechanisms include (1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to hypoxic-ischemic encephalopathy; and (4) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.^{[68, 69]} The clinical efficacy of therapeutic hypothermia in neonates with moderate-to-severe hypoxic-ischemic encephalopathy has been evaluated in 7 randomized controlled trials.^{[18, 70, 19, 71, 72, 73, 74, 75]} Inclusion criteria varied slightly. Criteria from the larger trials (NICHD, CoolCap, and TOBY) are summarized as follows:

• Near-term infants born at 36 weeks' gestation or more with birth weight of 1800-2000 g or more, younger than 6 hours at admission
• Evidence of acute event around the time of birth - Apgar score of 5 or less at 10 minutes after birth (In the study by Shankaran et al, this needed to be in conjunction with either evidence of acute perinatal event or need for assisted ventilation for at least 10 min.^[19] ), severe acidosis, defined as pH level of less than 7 or base deficit of 16 mmol/L or less (cord blood or any blood gas obtained within 1 h of birth), continued need for resuscitation at 10 minutes after birth
• Evidence of moderate to severe encephalopathy at birth - Clinically determined (at least 2 of the following: lethargy, stupor, or coma; abnormal tone or posture; abnormal reflexes [suck, grasp, Moro, gag, stretch reflexes]; decreased or absent spontaneous activity; autonomic dysfunction [including bradycardia, abnormal pupils, apneas]; and clinical evidence of seizures), moderately or severely abnormal amplitude-integrated electroencephalography (aEEG) background or seizures (CoolCap and TOBY)

See the image below.

These clinical studies have been reassuring thus far regarding safety and applicability of hypothermia therapy.^[76] Many theoretical concerns surround hypothermia and its side effects, which include coagulation defects, leukocyte malfunctions, pulmonary hypertension, worsening of metabolic acidosis, and abnormalities of cardiac rhythm, especially during rewarming.

Therapeutic hypothermia when applied within 6 hours of birth and maintained for 48-72 hours is a promising therapy for mild-to-moderate cases of hypoxic-ischemic encephalopathy.^{[77, 78]} Although many components of its implementation remain to be optimized, hypothermia therapy is increasingly offered to infants with moderate-to-severe hypoxic-ischemic encephalopathy. Some even argue that not discussing hypothermia therapy as an option with parents is unethical.^{[79, 80]}

The remaining questions regarding optimal implementation of hypothermia therapy for hypoxic-ischemic encephalopathy include the following:^{[77, 81]}

What is the optimal timing of initiation of hypothermia therapy?

Cooling must begin early, within 6 hours of injury. However, experimental evidence strongly suggest that the earlier the better.

Reports on the feasibility and safety of cooling on transport indicate that initiation of hypothermia therapy at referring centers is possible, provided that ongoing education is in place.^[82] The recently published ICE trial confirmed that a simplified method using widely available icepacks is an effective way to provide hypothermia therapy in referring centers while awaiting transfer to a tertiary NICU.^[72]

On the other hand, a favorable outcome may be possible if the cooling begins beyond 6 hours after injury. A current National Institute of Child Health and Human Development (NICHD) study is evaluating the efficacy of delayed hypothermia therapy for infants presenting at referral centers beyond 6 hours of life or with evolving encephalopathy.

What is the optimal duration of hypothermia therapy?

The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal neuroprotection.

The optimal duration of brain cooling in the human newborn has not been established.

What is the best method?

Two methods have been used in clinical trials: selective head cooling and whole body cooling.

In selective head cooling, a cap (CoolCap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34-35°C for 72 hours.

In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours.

The relative merits and limitations of these 2 methods have not been established.

What is the optimal rewarming method?

Rewarming is a critical period. In clinical trials, rewarming was carried out gradually, over 6-8 hours.

Can the use of aEEG improve candidates selection?

Predefined subgroup analysis in the CoolCap trial suggested that head cooling had no effect in infants with the most severe aEEG changes.

The findings were beneficial only in infants with less severe aEEG changes.

Does hypothermia therapy result in long-term benefits?

Establishing long-term benefits by providing long-term follow-up of all infants undergoing hypothermia therapy is critical in the ongoing evaluation of this therapy. Further studies are needed.

Several meta-analysis have been conducted and indicate that that therapeutic hypothermia is beneficial to term newborns with hypoxic-ischemic encephalopathy. In a Cochrane review, Jacobs et al found that therapeutic hypothermia results in significant reduction in the following:^[43]

• Combined outcome of mortality or major neurodevelopmental disability at age 18 months (relative risk [RR], 0.76; 95% confidence interval [CI], 0.65-0.89), with a number needed to treat (NNT) of 7 (95% CI, 4-14)
• Mortality (RR, 0.74; 95% CI, 0.58-0.94) and an NNT of 11 (95% CI, 6-50)
• Neurodevelopmental disability in survivors (RR, 0.68; 95%, CI 0.51-0.92), with an NNT of 8 (95% CI, 4-33).

They also found a significant increase in thrombocytopenia, although it was not clinically significant.

Schulzke et al found a significant effect of therapeutic hypothermia on the following:^[83]

• The composite outcome of death or disability (RR, 0.78; 95% CI, 0.66-0.92) with an NNT of 8 (95% CI: 5-20)
• Mortality (RR, 0.75; 95% CI, 0.59-0.96)
• Neurodevelopmental disability at age 18-22 months (RR, 0.72; 95% CI, 0.53-0.98)
• Benign sinus bradycardia (RR, 7.42; 95% CI, 2.52-21.87)
• Thrombocytopenia (RR, 1.47; 95% CI, 1.07-2.03) with an NNH of 8

Shah et al also found a reduction in the combined outcome of death or neurodevelopmental disability (RR, 0.76; 95% CI, 0.65-0.88) and an NNT of 6 (95% CI, 4-14), as well as death and moderate-to-severe neurodevelopmental disability when separately analyzed^[84] .

Despite the methodological differences between trials, wide CIs, and the lack of follow-up data beyond the second year of life, the consistency of the results is encouraging.

Azzopardi et al recently reported the results of the TOBY trial.^[75] Entry criteria were similar to that of the NICHD whole body hypothermia trial and the CoolCap trial. In this prospective trial of 325 infants with a gestational age of at least 36 weeks and a history of perinatal hypoxic encephalopathy, subjects were randomized to either intensive cooling plus whole body cooling or intensive cooling alone by age 6 hours. No difference in composite outcome of death or severe disability were noted between the groups. However, the study found that moderate hypothermia for 72 hours improved neurologic outcomes in survivors. Surviving infants who were cooled were more likely to be free of neurologic abnormalities (relative risk, 1.57; 95% confidence interval [CI], 1.16-2.12; P=0.003), had reduced risk of cerebral palsy (relative risk, 0.67; 95% CI, 0.47-0.96; P=0.03), and had higher scores on tests of mental and psychomotor development (P=0.03) and gross motor function (P=0.01).

Hypothermia therapy should be conducted under strict protocols and reserved to regional referral centers offering comprehensive multidisciplinary care and planning to conduct long-term neurodevelopmental follow-up. Further implementation requires thorough and ongoing education to avoid complications such as overcooling.^[85] Ideally, all infants should be registered in national registry whenever possible.

Several groups are investigating other neuroprotective strategies whether alone or in combination with hypothermia therapy (summarized in the image below).^[86]

Promising avenues include the following:

• Prophylactic barbiturates: In a small randomized trial, high-dose phenobarbital (40 mg/kg) was given over 1 hour to infants with severe hypoxic-ischemic encephalopathy. Treated infants had fewer seizures (9 of 15) than untreated control infants (14 of 16). Treated infants also had fewer neurological deficits at age 3 years (4 of 15) than untreated infants (13 of 16).^[87] In another small study, thiopental given within 2 hours and over 24 hours, did not result in improved rate of seizures or neurodevelopmental outcomes at 12 months.^[88] Hypotension was more common in infants who received thiopental. Thus, the role of prophylactic barbiturate remains unclear. Further studies are needed.^[89]
• Erythropoietin: In a recent study, low-dose erythropoietin (300-500 U/kg) administered for 2 weeks starting in the first 48 hours of life decreased the incidence of death or moderate and severe disability at age 18 months (43.8% vs 24.6%; P < 0.05) in infants with moderate-to-severe hypoxic-ischemic encephalopathy. Subgroup analysis indicated that only infants with moderate disability benefited from this therapy.^[90]
• Allopurinol: Slight improvements in survival and cerebral blood flow (CBF) were noted in a small group of infants tested with this free-radical scavenger in one clinical trial.^[91]
• Excitatory amino acid (EAA) antagonists: MK-801, an EAA antagonist, has shown promising results in experimental animals and in a limited number of adult trials. However, this drug has serious cardiovascular adverse effects.

In cases of posterior cranial fossa hematoma, surgical drainage may be lifesaving if no additional pathologies are present.

A pediatric neurologist should help assist in the management of seizures, interpretation of EEG, and overall care of the infant with hypoxic-ischemic encephalopathy. The neurologist should also work with the primary care physician to address long-term disabilities. A developmental specialist can also help plan for long-term assessments and care.

In most cases (particularly in moderately severe and severe hypoxic-ischemic encephalopathy), the infant is restricted to nothing by mouth (NPO) during the first 3 days of life or until the general level of alertness and consciousness improves. In addition, infants undergoing hypothermia therapy should remain NPO until rewarmed. Enteral feeds should be carefully initiated and the use of trophic feeds is initially advisable (about 5 mL every 3-4 h). Infants should be monitored carefully for signs and symptoms of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk. Individualize increments in feeding volume and composition.