Management of Hypoxic-Ischemic Encephalopathy Using Therapeutic Hypothermia

KEY POINTS

1.
A healthy fetus has considerable aerobic and anaerobic reserves to successfully adapt to transient or mild hypoxia. Prolonged or repeated severe asphyxia results in failure of adaptation and progressive hypotension and hypoperfusion. The severity of brain injury is consistently related to the severity and duration of hypotension.
2.
There is no intrinsic, physiologic relationship between the amount of systemic anaerobic metabolism (as reflected by metabolic acidosis) and the development of neuronal injury. The crude clinical correlation between acidosis and encephalopathy simply reflects that hypoxic-ischemic damage occurs under anaerobic conditions.
3.
Hypoxia-ischemia can trigger multiple intracellular, apoptotic, and necrotic pathways and secondary inflammation in a latent phase after reperfusion that ultimately lead to delayed cell death. Many of these pathways are effectively suppressed by mild hypothermia.
4.
Optimally, therapeutic hypothermia needs to be induced as soon as possible in first 6 hours after hypoxia-ischemia; brain temperature should be reduced by approximately 3.5°C, and cooling should be continued for approximately 72 hours. It is important to avoid pyrexia during or after resuscitation, before initiation of treatment.
5.
It is likely but unproven that further improvements in outcome will arise from combining therapeutic hypothermia with other neuroprotective strategies. For now, clinical care should focus on timely identification and early treatment of infants who may benefit from therapeutic hypothermia.

Introduction

Impaired placental oxygen and glucose delivery can occur before or during birth at any gestational age and lead to moderate to severe acute, evolving hypoxia-ischemia and disturbed brain function (i.e., hypoxic-ischemic encephalopathy [HIE]). In the developed world it occurs in approximately 1 to 3 per 1000 live births. ^, HIE is associated with high rates of adverse outcomes. For example, the Western Australian Cerebral Palsy register reported that approximately 15% of infants with cerebral palsy born at term had had acute encephalopathy at birth. Rates are even higher in low- and middle-income countries, so that HIE at birth and during the first 28 days of life is estimated to contribute one-tenth of all disability-adjusted life-years. HIE is of course only one cause of neonatal encephalopathy. Nevertheless, HIE is the single most common cause of neonatal seizures. The key link between exposure to hypoxia-ischemia as shown by metabolic acidosis and subsequent neurodevelopmental impairment is early onset of evolving encephalopathy.

Therapeutic hypothermia is now well established in clinical practice, based on compelling evidence from large randomized controlled trials that it improves survival without disability in infancy and into middle childhood. ^, This improvement is partial; standard protocols were shown to reduce the combined risk of death and severe disabilities at 18 months of age by approximately 12%, from 58% to 46%. The key challenge is now to further improve outcomes after treatment. We will dissect the known mechanisms of action of hypothermia and the evidence that current protocols for therapeutic hypothermia are essentially optimal.

The Pathogenesis of Brain Cell Death

In a fetus, hypoxia-ischemia is commonly secondary to profound hypoxemia, which leads to cardiac compromise with secondary hypotension and hypoperfusion. Compared with hypoxia alone, hypoperfusion reduces delivery of substrate as well as oxygen and thus accelerates depletion of cerebral high-energy metabolites, dramatically increasing the risk of subsequent injury. These concepts help explain the consistent observation that most cerebral injury after acute perinatal insults occurs in association with hypotension and consequent tissue hypoperfusion. By contrast, although asphyxial brain injury involves anaerobic metabolism, there is only a crude correlation between the severity of systemic acidosis and subsequent injury across experimental models. Notably, this very weak relationship between severity of acidosis and injury is also seen clinically. For example, in a large, single-center cohort study, 412 of 27,028 infants had an arterial cord blood pH ≤7.10. Of these, just 35 of 85 infants who developed HIE had an arterial cord blood pH <7.00, compared with 34 of 327 infants with pH between 7.00 and 7.10.

This reflects, at least in part, that the effects of asphyxia depend on the nature and pattern of the insult and the condition of the fetus. The fetus is highly adapted to hypoxia, and injury occurs only in a very narrow window between intact survival and death. Immediate, catastrophic asphyxia due to events such as cord prolapse and placental abruption contribute to approximately 25% of cases of HIE. The impact of the profound hypoxia on the fetus can be greatly potentiated by fetal blood loss leading to hypotension, as occurs during abruption. Approximately two-thirds of cases of HIE at term are associated with repeated, short periods of deep hypoxia, reflecting the inherent intermittent reduction in utero-placental blood flow during contractions and reduced placental and intervillous perfusion. Finally, approximately 10% of cases of moderate to severe HIE have been reported to be associated with abnormal fetal heart rate recordings before the start of labor, suggesting that the fetus had already been exposed to hypoxia-ischemia. ^,

As well as the pattern of hypoxia-ischemia, not surprisingly, maternal condition can affect outcomes. For example, maternal hyperthermia was independently associated with neonatal morbidity, including risk of death, HIE, and stroke, in multiple studies.

What Initiates Neuronal Injury?

At the most fundamental level, injury requires a period of insufficient delivery of oxygen and substrates such as glucose (and other substrates in the fetus) such that neurons and glia cannot maintain supplies of high-energy metabolites and thus cannot sustain homeostasis. When this happens, the energy-dependent mechanisms of intracellular homeostasis, such as the sodium/potassium adenosine triphosphate–dependent pump, fail, leading to neuronal depolarization. This creates an osmotic and electrochemical gradient that in turn favors cation and water entry, leading to cell swelling (cytotoxic edema). If sufficiently severe, this may lead to immediate lysis. Importantly, these edematous neurons may still recover, at least temporarily, if the hypoxic insult is reversed or the environment is manipulated. Multiple factors can cause cell injury during and after depolarization. These include the extracellular accumulation of excitatory amino acid neurotransmitters due to impairment of energy-dependent reuptake, which promotes further receptor-mediated cell swelling, excessive intracellular calcium entry, and the generation of oxygen free radicals and inflammatory cytokines. These excitatory factors are balanced by a disproportionate release of inhibitory neurotransmitters such as gamma-aminobutyric acid and adenosine. ^, These inhibitory factors suppress the metabolic rate (termed adaptive hypometabolism) and protect the brain by delaying the onset of cell depolarization. The duration of neuronal depolarization in turn critically determines the severity of neural injury.

Cerebral Injury Evolves Over Time

The central concept that enabled modern studies of neuroprotection is that although brain cell death can occur during sufficiently severe hypoxia-ischemia (termed the “primary” phase of injury), even after surprisingly severe events, many cells can initially reestablish oxidative metabolism in a so-called latent phase, followed by progressive secondary failure of oxidative metabolism and cell death over hours to days. ^, Studies using magnetic resonance spectroscopy demonstrated that many infants with evidence of moderate to severe asphyxia show initial, transient recovery of cerebral oxidative metabolism after birth, followed by secondary deterioration as shown by delayed cerebral energy failure from 6 to 15 hours after birth. The severity of the secondary deterioration is closely correlated with neurodevelopmental outcome at 1 and 4 years of age. Conversely, infants with HIE who did not show initial recovery of cerebral oxidative metabolism had extremely poor outcomes.

An identical pattern of initial recovery of cerebral oxidative metabolism followed by delayed (secondary) energy failure was confirmed after hypoxia-ischemia in piglets, rats, and fetal sheep and is closely correlated to the severity of neuronal injury. ^, ^, The timing of energy failure after hypoxia-ischemia is closely linked to the appearance of cell death on brain histology. Continuous measurements of cytochrome oxidase, the terminal electron acceptor in the mitochondrial transport chain, using near-infrared spectroscopy demonstrated that after severe asphyxia in fetal sheep, there was initial recovery of cytochrome oxidase to sham control values, followed by a progressive fall that started after approximately 3 to 4 hours and continued until approximately 48 to 72 hours after asphyxia. Delayed loss of mitochondrial activity was associated with a marked increase in relative intracerebral oxygenation, strongly indicating impaired ability to use oxygen. This evidence of a “latent” phase of transient recovery during oxidative recovery offered the tantalizing possibility that therapeutic intervention after hypoxia-ischemia might be possible.

The timing and physiologic events during these phases of injury are now well described in preclinical studies. After restoration of circulation and oxygenation the initial hypoxic depolarization-induced suppression of cerebral oxidative metabolism, cytotoxic edema and accumulation of excitatory amino acids resolve over approximately 30 to 60 minutes. ^, Despite recovery of oxidative cerebral energy metabolism and mitochondrial activity, electroencephalographic (EEG) activity remains depressed. Cerebral blood flow initially recovers but typically shows a delayed, transient reduction below control values within hours after reoxygenation. ^, During the secondary deterioration from approximately 6 to 15 hours after moderate to severe hypoxia-ischemia, delayed seizures develop and then continue for several days, ^, accompanied by secondary cytotoxic edema, accumulation of excitotoxins, failure of cerebral mitochondrial activity, ^, and ultimately, cell death. Secondary edema and seizures are not seen after milder insults that do not cause cortical injury. By contrast, more severe hypoxia-ischemia typically accelerates the evolution of neuronal loss.

As well as evolving over time, cell death spreads outward from the most severely affected regions toward less severely affected regions. In piglets exposed to transient hypoxia-ischemia, the cerebral apparent diffusion coefficients normalized almost completely by 2 hours after resuscitation, followed by a fall in apparent diffusion coefficients beginning in the parasagittal cortex and then spreading through the brain. This pattern likely reflects both severity of injury and active mechanisms such as the opening of astrocytic connexin hemichannels on the cell surface, which can facilitate waves of spreading depression that can trigger cell death in less-injured tissues. The secondary phase resolves over approximately 3 days after severe hypoxia-ischemia into a tertiary phase of ongoing injury, involving chronic inflammation and epigenetic changes affecting repair and reorganization that may last weeks to months and even years.

These concepts—that an acute, global period of hypoxia-ischemia can trigger evolving cell death and that characteristic events are seen at different times after the insult—are central to understanding the causes and treatment of HIE. The initial triggers of the delayed death cascade during exposure to hypoxia-ischemia, including exposure to oxygen free radical toxicity, excessive levels of excitatory amino acids, and intracellular calcium accumulation down the concentration gradient due to failure of energy-dependent pumps during hypoxia and opening of channels linked to the excitatory neurotransmitters. However, these events rapidly resolve during reperfusion from the insult and thus cannot readily be related to the effects of postinsult interventions such as cooling. It is striking that in vitro neuronal degeneration can be prevented by cooling initiated well after exposure to an insult. Thus the key therapeutic targets must involve secondary consequences of hypoxia-ischemia, such as the intracellular progression of programmed cell death (apoptosis), the inflammatory reaction, and abnormal receptor activity.

Intracellular Mediators of Delayed Cell Death

Multiple factors are involved in delayed development of cell death despite initial recovery of oxidative metabolism after hypoxia-ischemia, including activation of cell death pathways, withdrawal of trophic factors, and secondary inflammation ( Fig. 46.1 ). The cell death pathways are stimulated by entry of calcium during anoxic depolarization, exposure to reactive oxidative species during reperfusion, and likely other factors.

Fig. 46.1, Flow Chart Illustrating the Relationship Between the Mechanisms Active in the Pathophysiologically Defined Phases of Cerebral Injury After Moderate to Severe Hypoxia-Ischemia.

There is good histologic evidence that activation of preexisting programmed cell death pathways contributes to posthypoxic cell death in the developing human brain. The pattern of cell death is not purely apoptotic but rather includes elements of apoptotic and necrotic processes, with one or the other being most prominent depending on factors such as maturity and the severity of insult. Consistent with the hypothesis that apoptotic processes are a key therapeutic target, postinsult hypothermia started after severe hypoxia-ischemia was reported to reduce apoptotic cell death but not necrotic cell death in the piglet. Similarly, protection with posthypoxic-ischemic hypothermia in fetal sheep has been closely linked with suppression of activated caspase-3.

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