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.
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.
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.
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.
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.
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.
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.
Inflammatory Second Messengers
Brain injury also induces the inflammatory cascade with increased release of cytokines. These compounds are believed to exacerbate delayed injury, whether by direct neurotoxicity, triggering apoptosis, or promoting stimulation of leukocyte adhesion and infiltration into the ischemic brain. Experimentally, cooling can potently suppress this inflammatory reaction. For example, in vitro , hypothermia inhibits proliferation and superoxide and nitric oxide production by cultured microglia, and in adult rats, hypothermia suppresses the posttraumatic release of interleukin-1β and accumulation of polymorphonuclear leukocytes. Similarly, neuroprotection with postinsult hypothermia was associated with suppression of microglial activation in fetal sheep. , ,
Other receptor- and nonreceptor-mediated toxic factors are likely to contribute to neural injury in the latent phase. For example, there is some evidence from preterm fetal sheep of delayed production of oxygen free radicals after hypoxia-ischemia, which may be particularly associated with death of oligodendroglia.
Excitotoxicity After Hypoxia-Ischemia
In contrast with their role during the primary phase, the importance of excitotoxins after reperfusion is questionable given that extracellular levels rapidly return to baseline values. , Pathologically elevated levels of extracellular excitatory amino acids such as glutamate are seen in a biphasic pattern. The initial increase occurs during hypoxia-ischemia and resolves rapidly after reperfusion, to control values. Levels remain low throughout the latent phase and then secondarily rise many hours later, in association with delayed seizures and cytotoxic edema. , In near-term fetal sheep, for example, intense seizures are seen from approximately 9±2 hours to 30±3 hours after cerebral ischemia. It is important to appreciate that completely suppressing these large-amplitude seizures with a selective glutamate antagonist was associated with very limited reduction in neuronal damage in more mildly affected regions but with no effect on infarction of the parasagittal cortex and no improvement in recovery of EEG activity. Moreover, combined antiglutamate treatment and mild whole-body hypothermia after severe asphyxia did not show additive neuroprotection in preterm fetal sheep.
The preclinical studies of therapeutic hypothermia that involved subsequent clinical protocols were structured around these observations.
The Determinants of Neuroprotection With Therapeutic Hypothermia
Timing of Starting Hypothermia: The Earlier the Better
There is extensive preclinical evidence that hypothermia must be started as early as possible within the latent phase for optimal benefit. In turn, this pattern is highly consistent with progressive mitochondrial failure during the latent phase, demonstrated by magnetic resonance spectroscopy after moderate to severe hypoxia-ischemia in human infants, , piglets, and near-infrared spectroscopy in preterm fetal sheep. Immediate initiation of hypothermia is protective across species and many paradigms of hypoxia-ischemia. For example, in anesthetized piglets exposed to either hypoxia with bilateral carotid ligation or to hypoxia with hypotension, either 12 hours of mild whole-body hypothermia (35°C) or 24 hours of head cooling with mild systemic hypothermia started immediately after hypoxia prevented delayed energy failure, reduced neuronal loss, and suppressed posthypoxic seizures. ,
Increasing the duration of hypothermia until resolution of the secondary phase of injury after approximately 72 hours can enable neuroprotection despite delayed initiation. In near-term fetal sheep, cerebral hypothermia induced 90 minutes after reperfusion from a severe episode of cerebral ischemia, that is, in the early latent phase, and continued until 72 hours after ischemia prevented secondary cytotoxic edema and improved electroencephalographic recovery. There was a concomitant dramatic reduction in cortical infarction and improvement in neuronal loss scores in all regions. Comparable neuroprotection was seen when treatment was delayed until 3 hours after the end of ischemia. By contrast, when the start of hypothermia was delayed until just before the onset of secondary seizures (5.5 hours after reperfusion), only partial neuroprotection was seen. With further delay until after seizures were established (8.5 hours after reperfusion), there was no electrophysiological or overall histologic protection with cooling.
Similar results have been reported in other paradigms. In nonanesthetized 21-day-old rat pups, mild hypothermia (a 2°C to 3°C decrease in brain temperature) for 72 hours after hypoxia-ischemia prevented cortical infarction, whereas cooling delayed until 6 hours after the insult had an intermediate, nonsignificant effect. More recently, in 7-day-old rat pups, hypothermia induced either immediately or at 3 hours was neuroprotective after a “moderate” duration of hypoxia-ischemia (90 minutes). By contrast, even immediate hypothermia did not improve outcomes after very prolonged hypoxia-ischemia (150 minutes). This illustrates that the window of opportunity for therapeutic hypothermia is critically dependent on the severity of the primary period of hypoxia-ischemia.
How Cold Is Too Cold?
The critical depth of hypothermia required for protection may be affected by multiple factors such as the delay before initiation and the severity and nature of the insult. There is some evidence from studies of moderate to severe ischemia that when cooling is delayed until 6 hours in both adult rodents and fetal sheep, greater functional and histologic neuroprotection may be seen with a 5°C reduction in brain temperature than with a 3°C reduction. , By contrast, in 7-day-old rat pups, there was no additional protection with cooling after hypoxia-ischemia to rectal temperatures below 33.5°C. Similarly, in neonatal piglets exposed to global cerebral ischemia, whole-body hypothermia with a reduction in body temperature of either 3.5°C or 5°C was associated with significant (and highly similar) overall neuroprotection, whereas a reduction of 8°C was detrimental.
If Some Is Good, Is More Better?
There is now compelling preclinical evidence that continuing cooling for approximately 72 hours provides optimal neuroprotection. , Broadly, and critically for clinical practice, the greater the delay before starting cooling or the more severe the insult, the greater the duration of cooling required for protection. For example, in adult gerbils, when the delay before initiating a 24-hour period of cooling was increased from 1 to 4 hours, neoronal survival in the CA1 region of the hippocampus after 6 months of recovery fell from 70% to 12%. Subsequent studies demonstrated that protection could be restored by extending the duration of moderate (32°C to 34°C) hypothermia to 48 hours or more, even when the start of cooling was delayed until 6 hours after reperfusion. Similarly, in near-term fetal sheep, cooling that started after 5.5 hours and continued until 72 hours was still partially protective. Finally, in the same paradigm, although delayed cooling from 3 hours after ischemia until 48 hours was partially protective, it was substantially less effective for both recovery of EEG power and neuronal survival than cooling for 72 hours.
Given this compelling evidence that hypothermia must be continued for at least 72 hours in large animals and humans, there has been interest in whether further prolonging the duration of hypothermia may be associated with greater benefit. However, in near-term fetal sheep, when delayed hypothermia starting 3 hours after ischemia was continued for 5 days compared with 3 days, there was no further improvement in electrophysiological recovery or neuronal survival or further reduction in cortical microglial induction. Indeed, post-hoc analysis suggested that extended cooling was associated with a small reduction in neuronal survival in the parasagittal cortex and the dentate gyrus.
Clinical Evidence for Therapeutic Hypothermia
The large body of experimental evidence discussed above supported the development of large randomized controlled trials of mild, induced hypothermia for moderate to severe neonatal HIE.
Evidence From Randomized Controlled Trials
A systematic meta-analysis of 11 randomized controlled trials of either selective head cooling or whole-body cooling initiated within 6 hours of birth and involving 1505 term and late preterm infants with moderate/severe HIE found consistent beneficial effects after hypothermia. Mild hypothermia was associated with reduced mortality or severe neurodevelopmental disability by 18 months of age (relative risk [RR], 0.75; 95% confidence interval [CI], 0.68–0.83). Cooling reduced mortality (RR, 0.75; 95% CI, 0.64–0.88; 11 studies, 1468 infants), with reduced neurodevelopmental disability in survivors (typical RR, 0.77; 95% CI, 0.63–0.94; 8 studies, 917 infants).
Long-term follow-up of these studies is ongoing; the available evidence suggests a similar improvement in outcomes in middle childhood after mild induced hypothermia for HIE. For example, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY) showed that significantly more children in the mild hypothermia group survived with an IQ score of 85 or more compared with the control group (52% versus 39%; RR, 1.31; P = .04) and that more children in the hypothermia group survived without neurologic abnormalities than in the control group (45% versus 28%; RR, 1.60; 95% CI, 1.15–2.22). Further, there was a significant reduction in the risk of cerebral palsy (21% versus 36%, P = .03) and of moderate or severe disability (22% versus 37%; P = .03). Moreover, recent cohort studies of infants cooled for HIE showed a lower incidence of epilepsy at 2 years of age compared with the cooling trials, as well as reduced severity of cerebral palsy. The reader should note that it is not possible to exclude the possibility that infants with less severe HIE were recruited once therapeutic hypothermia became standard care. Nevertheless, these studies used the same criteria for hypothermia as the original cooling trials, including amplitude integrated EEG (aEEG) monitoring.
Is It Possible to Further Optimize Therapeutic Hypothermia?
Although therapeutic hypothermia significantly reduces the risk of death or disability, current protocols for therapeutic hypothermia were partially neuroprotective in meta-analysis, with a number needed to treat of about 7 (95% CI, 5–10; 8 studies, 1344 infants). As already discussed, the experimental efficacy of hypothermia is highly dependent on the timing of initiation , depth , and duration of cooling. Thus potentially, it may be possible to further optimize regimens for therapeutic hypothermia.
Although there have been no randomized trials of early initiation of hypothermia, in a cohort study, infants who were treated within 3 hours after birth had significantly better motor outcomes than those treated after 3 hours. Few infants were started within that time frame in the large randomized controlled trials and thus there was limited power to assess the effect of earlier treatment. For example, in the CoolCap trial, hypothermia was started in only 12% of infants within 4 hours of birth, and many infants were already showing electrographic seizures. This is an earlier onset of seizures than is typically seen in preclinical studies. The likely reason is that many hypoxic-ischemic insults evolve over time before birth and thus the timing of the insult is often not clearly known. This strongly suggests that there is considerable potential to further improve outcomes by starting hypothermia earlier than in the original trials.
There is encouraging emerging evidence that outcomes may have improved further now that therapeutic hypothermia is routine care for moderate to severe HIE. For example, in a large randomized controlled trial of 347 infants with follow-up data who were randomized to different cooling protocols, the rate of death or disability at 18 months of age in infants treated with cooling to 33.5°C for 72 hours was 29.3% compared with 44% in infants receiving the same cooling protocol and recruited using the same criteria in a previous trial from the National Institute of Child Health and Human Development (the NICHD trial). The factors behind this apparent improvement are unclear. In part, it might be related to recruiting infants with slightly less severe HIE, but it might also be related to earlier initiation of cooling, with increasing use of passive cooling while infants are assessed for active cooling.
These studies suggest that current protocols of whole-body cooling to 33.5°C for 72 hours are reasonably close to optimal; thus the most effective way to further improve outcomes from therapeutic hypothermia in infants with HIE is to initiate cooling earlier, as soon as possible in the first 6 hours after birth. Alternatively, cooling plus other pharmacologic neuroprotective agents may enable further improvements in outcome. There is currently considerable interest in such options, based on the endogenous induction of potentially neuroprotective compounds in the body as well as exogenous agents.
Is More Better?
A large, randomized clinical trial of 364 infants with moderate to severe HIE who were randomized either to prolonged duration (120 hours versus 72 hours), increased depth of therapeutic hypothermia (32°C versus 33.5°C), or both was abandoned due to lack of effect and safety concerns. , The adjusted risk ratio for death in the neonatal intensive care unit after cooling for 120 hours compared with 72 hours was 1.37 (95% CI, 0.92–2.04), and for cooling to 32°C compared with 33.5°C, it was 1.24 (95% CI, 0.69–2.25). Furthermore, there was no significant overall effect of longer or deeper cooling on death or disability at a mean age of 18 months. These consistent clinical and preclinical findings suggest that there is a relatively broad range of temperatures that are beneficial for the brain after hypoxia-ischemia and that, reassuringly, it should not be necessary to reduce core temperatures by more than approximately 3.5°C.
Is There Benefit From Cooling Started More Than 6 Hours After Birth?
The preclinical and clinical studies reviewed above consistently suggest that hypothermia should be started as early as possible in the first 6 hours of life to achieve optimal outcomes. However, some infants are unable to be started within this time window because of late diagnosis or being born in areas that cannot provide support for cooling. Even though it is not optimal, should these infants be offered therapeutic hypothermia after 6 hours of life? A recent randomized controlled trial conducted by the Neonatal Research Network centered in the United States compared 83 term infants who were cooled starting at 6 to 24 hours after birth (at a mean of 16±5 hours) with 85 noncooled infants (range, 36.5°C to 37.3°C). Death or moderate to severe disability were seen in 24.4% of cooled infants, compared with 27.9% of noncooled infants ( P = .23). Thus, although very delayed treatment was not harmful, this trial strongly suggest that it is critical to focus on initiating treatment as early as possible within the first 6 hours after birth.
Should We Cool Infants With “Mild” HIE?
The large, randomized controlled trials of therapeutic hypothermia excluded infants who had “mild” HIE in the first 6 hours of life in order to increase the rates of unfavorable outcome, so the potential benefit of treating these infants with therapeutic hypothermia is unknown. In cohort studies, some infants with mild HIE as defined using the trial criteria in the first 6 hours of life have material risk of disability. The exact results have been rather variable, likely because of variable criteria for “mild,” retrospective identification, less formal neurologic examinations than used in the prospective trials, or not using aEEG criteria. The definition of “mild” HIE varies markedly between studies. The CoolCap and TOBY studies simply specified the clinical Sarnat criteria on a gestalt basis but also required that infants had moderate to severe changes on an aEEG recording before randomization. , The NICHD trial used only clinical criteria and excluded infants who did not have three or more criteria for moderate/severe HIE ; thus infants with one or two moderate or severe criteria were defined as having “mild” HIE. This suggests that some of these infants actually had “moderate” HIE even though they were excluded from the trial and raises the important possibility that it may be possible to refine the clinical criteria to more reliably identify infants who are at risk of disability.
A meta-analysis of studies with well-defined HIE grading at birth and standardized neurodevelopmental assessment at 18 months or older suggested that 86 of 341 infants (25%) with “mild” HIE in the first 6 hours of life had an adverse outcome, defined as death, cerebral palsy, or neurodevelopmental test scores that were more than 1 standard deviation below the mean. Although most of these studies recruited infants solely on clinical criteria, a prospective cohort study of infants who were not treated with therapeutic hypothermia found that infants with mild HIE, determined by both early EEG and clinical examination, had adverse cognitive and neuromotor outcomes at 5 years of age compared with healthy controls. Although survival was much greater after mild than moderate or severe HIE, survivors with mild HIE showed no significant difference in cognitive outcomes compared with those who had had moderate HIE.
Given that this population of infants with “mild” HIE in the first 6 hours is heterogeneous, the balance of clinical risk and benefit is unclear. Treating all cases of “mild” HIE would lead to a considerable increase in the number of infants being separated from their parents for at least 3 days and receiving invasive treatments such as central lines, invasive respiratory support, sedation, and delayed oral feeding. It is reasonable to reflect that there is evidence from young rodents that therapeutic hypothermia seems to be more protective after milder hypoxia-ischemia. Taken as a whole, it is likely that established protocols for therapeutic hypothermia will also reduce cell loss in infants with milder clinical HIE in the first 6 hours of life. Given that there are roughly as many infants with mild HIE as there are with moderate to severe HIE, it is critical that the benefits of treatment for this group are now formally tested.
Therapeutic hypothermia is now established as standard care to partially improve neurologic recovery in infants with moderate to severe HIE. Further improvements in neurodevelopmental outcomes are likely to come from combining hypothermia with endogenous or exogenous neuroprotective agents. Tantalizingly, autologous or external stem cells may have potential to promote long-term neurorepair through reducing neural inflammation and promoting release of trophic factors. , While awaiting the results of further research, it is important not to forget that the most effective ways to optimize treatment with hypothermia are to avoid hyperthermia during resuscitation and to identify infants with HIE and start treatment as soon as possible after birth. EEG recordings and other early biomarkers can help identify patients who would benefit from treatment in such a limited time frame.
The authors’ work reported in this review was supported by grants from the Health Research Council of New Zealand (17/601, 18/225, 22/559), the Lottery Health Board of New Zealand, and the Auckland Medical Research Foundation.