Management of Neonatal Neurologic Injury: Evidence-based Outcomes

Mihaela Podovei

Bhavani Shankar Kodali

Neonatal neurologic injuries can be due to a variety of perinatal events, such as intrauterine hypoxic–ischemic episodes (cord prolapse, placental abruption, or uterine rupture), birth trauma (shoulder dystocia, instrumental vaginal deliveries), or maternal trauma. However, many of the injuries do not have a recognizable cause. This chapter will focus on the evidence-based management of neonatal neurologic injury.

Neonatal Encephalopathy

Neonatal encephalopathy is a relatively common condition. Nelson and Leviton define it as a clinical syndrome of “disturbed neurologic function in the earliest days of life in the term infant, manifested by difficulty with initiating and maintaining respiration, depression of tone and reflexes, subnormal level of consciousness, and often by seizures” (1). Kurinczuk et al. recently analyzed data on incidence and estimated it to be 3/1,000 live births, with a 95% Confidence Interval (CI) 2.7 to 3.3 (2), with earlier studies placing it between 2 and 6/1,000 live births (1). Neonatal encephalopathy was considered to be the result of an intrapartum event, and different terms were used to define the process: Hypoxic–ischemic encephalopathy, birth asphyxia, postasphyxial encephalopathy, and perinatal asphyxia. In modern thinking, neonatal encephalopathy describes a set of clinical symptoms without assumptions of either etiology or pathogenesis. Hypoxic–ischemic encephalopathy is a subgroup of neonatal encephalopathy, where there is evidence of a recent, usually intrapartum, ischemic event. A recent meta-analysis estimated the incidence of hypoxic–ischemic encephalopathy to be 1.5/1,000 live births (95% CI, 1.3 to 1.7) (2), with previous reports ranging from 1 to 8/1,000 live births.

To differentiate within the spectrum of the clinical syndrome, most investigators use modifications of the criteria Sarnat and Sarnat originally used to characterize 21 cases of neonatal encephalopathy (3):

Mild/Stage 1: Hyperalertness, hyperreflexia, tachycardia, dilated pupils, absence of seizures;
Moderate/Stage 2: Lethargy, hyperreflexia, miosis, bradycardia, hypotonia with weak suck and Moro, seizures;
Severe/Stage 3: Flaccidity, stupor, small to mid-point pupils with poor reaction to light, decreased stretch reflexes, hypothermia, absent Moro.

The presence of neonatal encephalopathy has serious consequences for many infants, including death, cerebral palsy, epilepsy, significant cognitive, developmental, and behavior problems.

Williams et al. studied the extracellular space changes after transient cerebral ischemia in fetal sheep and observed a biphasic distribution of intracellular edema, with early edema resolving slowly and incompletely in (mean +/- SD) 28 +/- 12 minutes and secondary swelling beginning 7 +/- 2 hours later and peaking at 28 +/- 6 hours (4). It is widely accepted today that after a hypoxic–ischemic insult in the newborn, the same biphasic natural course can be identified.

There is immediate neuronal death due to hypoxia. Neuronal injury results from primary energy failure, acidosis, glutamate release, intracellular calcium accumulation, lipid peroxidation, and nitric oxide neurotoxicity all of which disrupt essential components of the cell resulting in cell death (5,6,7). The severity and the duration of the insult influence the progression of cellular injury after hypoxia/ischemia.
After initial resuscitation, oxygenation and circulation are restored. The infant brain goes through a latent period of at least 6 hours, before secondary damage and further neuronal death occurs. There is a window of opportunity between the initial event and the secondary phase of injury, when therapeutic interventions may effectively improve the neurologic outcome.
Delayed neuronal death occurs due to hyperemia, cytotoxic edema, mitocondrial failure, cytotoxic actions of activated mitochondria, accumulation of excitotoxins, active cell death, nitric oxide synthesis, and free radical damage (4,8,9,10,11). Circulating endogenous inflammatory cells and mediators also contribute to ongoing brain injury. Expression of interleukin 1-β and tumor necrosis factor (TNF) α messenger RNA has been demonstrated hours after hypoxia–ischemia, along with induction of α and β chemokines followed by neutrophil invasion of the area of infarction (12,13).

The severity of the secondary stage has been associated with severe neurodevelopmental outcomes at 1 and 4 years (5,14). Significant effort has been concentrated on the identification of interventions that may minimize the neuronal damage and improve the outcome of infants with hypoxic–ischemic encephalopathy (hypothermia, oxygen-free radical inhibitors and scavengers, excitatory amino acid antagonists, growth factors, prevention of nitric oxide formation, and blockage of apoptotic pathways) (5).

Management of infants with hypoxic–ischemic encephalopathy includes (1) identification, (2) supportive care, and (3) interventions against ongoing brain injury. Basic concepts of identification and supportive care, and a summary of interventions designed to lessen further injury are outlined in Table 17-1. Additional discussions of the possible therapeutic interventions are discussed in the sections that follow.

Table 17-1 Management of Infants with Hypoxic-ischemic Encephalopathy

Identification
Evidence of a sentinel event during labor, e.g., fetal heart rate abnormality Severely depressed infant (low-extended Apgar score) Need for resuscitation in the delivery room Evidence of severe fetal acidemia Early abnormal neurologic examination (neonatal encephalopathy) and/or abnormal assessment of cerebral function (amplitude-integrated electroencephalogram) Amplitude-integrated electroencephalography, head ultrasound, computer tomography, and magnetic resonance imaging can be used to assess the severity and the progression of hypoxic–ischemic encephalopathy (15,16,17,18).
Supportive Care
Maintain adequate ventilation Avoid hypotension Avoid hypoglycemia. A retrospective review of 185 infants admitted to NICU with acidosis suggests that initial hypoglycemia (BG < 40 mg/dL) is an important predictive factor for perinatal brain injury (19), and may accentuate brain damage (20). Treat seizures. Hypoxic–ischemic cerebral injury is the most common cause of early onset neonatal seizures (6). Seizure activity may contribute to ongoing injury: Repetitive seizures disturb the brain growth and development as well as increase the risk for subsequent epilepsy (21,22).
Interventions Against the Ongoing Brain Injury
Cooling Oxygen-free radical inhibitors and scavengers Excitatory amino acids antagonists Growth factors Prevention of nitric oxide formation Blockage of apoptotic pathways

Interventions Against Ongoing Brain Injury

Therapeutic Hypothermia

Over the last decade, significant efforts went into studying the effects of hypothermia on infants with hypoxic–ischemic encephalopathy. Therapeutic hypothermia had been employed in the 1950s and 1960s, but ignored for decades (23,24,25,26). Hypothermia re-emerged as a promising intervention in late 1990, and over the last 5 or 6 years, five large randomized-controlled trials (RCTs) with follow-up data at 18 months have been published, all showing some benefit from the intervention (Table 17-2).

Table 17-2 Primary Outcome (Death or Severe Disability at 18 Months) in Therapeutic Hypothermia Randomized Controlled Trials

Study	Number of Patients	Primary Outcome in the Intervention Group	Primary Outcome in the Control Group	Odds Ratio	95% CI	P Value
Cool Cap	218	55%	66%	0.61	0.34–1.09	0.1
NICHD	205	44%	62%	0.72	0.54–0.95	0.01
Toby	325	45%	53%	0.86	0.68–1.07	0.17
The China Study	194	31%	49%	0.47	0.26–0.84	0.01
Neo.nEURO. Network	111	51%	83%	0.21	0.09–0.54	0.001

Therapeutic hypothermia may improve neurologic outcome after ischemic injury by several mechanisms:

Inhibition of glutamate release
Reduction of cerebral metabolism which preserves high-energy phosphates
Decreasing intracellular acidosis and lactic acid accumulation
Preservation of endogenous antioxidants
Reduction of NO production
Prevention of protein kinase inhibition
Improving protein synthesis
Reduction in leukotriene production
Prevention of blood–brain barrier disruption and brain edema
Inhibition of apoptosis (5,27,28)

Before instituting hypothermia, several protocol details need to be considered:

Time from the insult to the initiation of therapy
Method of achieving hypothermia (total body cooling vs. selective head cooling)
Degree of hypothermia, site of temperature measurement
Duration of hypothermia (48 to 72 hours)

All RCTs of hypothermia in infants with hypoxic–ischemic encephalopathy attempted to initiate the intervention during the latent phase after a hypoxic–ischemic injury, before the onset of the secondary metabolic failure. Universally, the infants were enrolled and cooled within the first 6 hours after birth or an identifiable ischemic event. Most trials belong to one of the two methods of achieving hypothermia—selective head cooling or total body cooling. In selective head cooling, a cap that circulates water at 10°C is placed over the head, while the body is warmed as needed to maintain the rectal temperature at 34°C to 35°C (29,30,31,32,33,34). In total body cooling, ice or gel packs are used to induce hypothermia, and two cooling blankets above and below the infant are used to maintain the temperature at 33°C to 34°C (35,36,37,38).

As noted, the target temperature may vary slightly depending on the cooling method used.

Selective head cooling: The first safety study on therapeutic hypothermia in infants was on selective head cooling (29). The subjects were divided into groups cooled to different target temperatures, as low as 35.5°C, and the study proved hypothermia to be safe and well tolerated (29). Subsequent
studies of selective head cooling used a target temperature of 34°C to 35°C rectal temperature (17,30,31,32,33,34,39).

Total body cooling: Shankaran et al. published a pilot study to evaluate the reliability and safety of whole body hypothermia to 34°C to 35°C (esophageal temperature), for 72 hours (40). The heart rate decreased with cooling and remained lower than in controls, but was well tolerated; no greater hazards have been identified in the cooled group. Blood pressure, renal failure, persistent pulmonary hypertension, hepatic dysfunction, and need for pressors were similar, and mortality rate was similar between the intervention and the control groups. The same group published a few years later the results of a large RCT using the same cooling methods to an esophageal temperature of 33.5 +/- 0.5°C (41,42). Other RCTs of whole body hypothermia also cooled the infants to 33°C to 34°C rectal temperature and found no major adverse events from the intervention (35,36,37).

However, Eicher et al. published a safety study of systemic hypothermia, with cooling to a rectal temperature of 33 +/- 0.5°C (38). In this study, the hypothermia group had frequent bradycardia, lower heart rates during the period of hypothermia, longer dependence on pressors, higher prothrombin times, decreased platelet counts, increased plasma and platelet transfusion requirements, and more frequent clinical seizures and electroencephalographic abnormalities.

All observed side effects were considered mild to moderate in severity and manageable with minor interventions.

Between 2005 and 2010, there were five large RCTs and a meta-analysis pertaining to therapeutic hypothermia in infants with hypoxic–ischemic encephalopathy, with over 1,000 infants enrolled. In each trial, the primary outcome was death or severe disability at 18 months.

The Cool Cap Trial was an RCT of selective head cooling with mild systemic hypothermia to a rectal temperature of 34°C to 35°C for 72 hours versus standard treatment. The study enrolled 234 term infants and data was available for 218 infants. Inclusion criteria included amplitude-integrated electroencephalography (aEEG) data in addition to clinical, biochemical, and neurologic criteria of moderate and severe asphyxia. The study reported a 66% prevalence of the primary outcome in the conventional treatment group and 55% in the intervention group, OR 0.61 (0.34 to 1.09), p = 0.1. After adjustment for the severity of aEEG changes the odds ratio for hypothermia treatment was 0.57 (0.32 to 1.01, p = 0.05). A subgroup analysis showed that head cooling had no benefits in infants with the most severe aEEG changes, but was beneficial in infants with less severe aEEG changes (number needed to treat [NNT], 6 [CI, 3 to 27]) (33).

A secondary analysis of the Cool Cap Trial examining factors that may determine the efficacy of treatment found a significant interaction of treatment and birth weight. Larger infants (weight ≥25 percentile) showed a lower frequency of favorable outcomes in the control group but a greater improvement with cooling (34). For larger infants, the NNT was 3.8. Also pyrexia in the control group (≥38°C) was associated with marked increase in adverse outcomes, controlled for the severity of encephalopathy. Out of the 34 control patients that had rectal temperatures above 38°C at any time during the 76 hours monitoring period, 28 had unfavorable outcomes (OR 3.2, 95% CI, 1.2 to 8.4, p = 0.028) (34).

The second large randomized control study was performed by the National Institute of Child Health and Human Development (NICHD) Neonatal Network, referred as NICHD trial (41). The study enrolled 208 infants, and data were available for 205. Hypothermia was obtained using cooling blankets to maintain an esophageal temperature of 33°C to 34°C for 72 hours, and the results were compared against the conventional treatment. Unfavorable primary outcome (death or moderate to severe disability at 18 months) was observed in 62% of controls and 44% of the cooled infants, with a risk ratio of 0.72, 95% CI, 0.54 to 0.95, p = 0.01, NNT = 6. Both moderate and severe encephalopathy group had a trend toward decrease for all adverse outcomes in hypothermia group (41).

The third large study—the TOBY trial (36) enrolled 325 infants with moderate to severe hypoxic–ischemic encephalopathy at 42 centers worldwide. The intervention was whole body cooling. Gel packs were used to initiate hypothermia, and cooling blankets were used to maintain the temperature at 33°C to 34°C for 72 hours. Unfavorable outcomes were present in 53% of controls and 45% of cooled infants (RR 0.86, 95% CI, 0.68 to 1.07). The difference in primary outcome (death or moderate to severe disability) did not reach statistical significance, but among survivors, infants in the cooled group had increased rate of survival without neurologic abnormality (44% in the cooled group vs. 28% in the standard treatment group, RR 1.57, 95% CI, 1.16 to 2.12, p = 0.003). Also the intervention reduced the risk of cerebral palsy among survivals (RR 0.67, 95% CI, 0.47 to 0.96, p = 0.03), improved scores on the Mental Developmental Index and Psychomotor Index of the Bayley Scales of Infant development II (p = 0.03 for each) and the Gross Motor Classification System (p = 0.01). The study concluded that the induction of moderate hypothermia for 72 hours in infants with perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors (36).

A meta-analysis of the previous randomized control trials of therapeutic hypothermia was published in 2010 (43). The three large trials with 18 months follow-up information, including 767 infants, were analyzed. Seven other trials with mortality information but without appropriate neurodevelopmental data were identified. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability at 18 months: Risk ratio 0.81, 95% CI, 0.71 to 0.93, p = 0.002; risk difference -0.11, 95% CI 0.18 to 0.04, with NNT = 9 (95% CI, 5 to 25).

Hypothermia increased survival with normal neurologic function, reduced the rates of severe disability, cerebral palsy, and mental psychomotor developmental index less than 70 (43).

Since the meta-analysis, two other large RCTs published their results (37,39). A group of investigators from China published the results of a multicenter, randomized control trial of selective head cooling within 6 hours after birth to a nasopharyngeal temperature of 34ºC and rectal temperature of 34°C to 35ºC for 72 hours. 194 neonates were enrolled. The primary outcome was death and severe disability at 18 months and the prevalence was 31% in the cooling group versus 49% in the control group (OR 0.47, 95% CI, 0.26 to 0.84, p = 0.01). The severe disability prevalence was 14% versus 28%, OR 0.4, 95% CI, 0.17 to 0.92, p = 0.01 (39).

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