Therapeutic Hypothermia for Hypoxic–Ischemic Brain Injury Is More Effective in Newborn Infants than in Older Patients: Review and Hypotheses

Abstract

Posthypoxic therapeutic hypothermia has been tested in newborn infants, with seven randomized trials showing consistent evidence of reduction in death, cerebral palsy, and cognitive impairment at school age. In contrast, randomized trials of hypothermia after cardiac arrest in adults have not shown consistent evidence of lasting neurological protection. The apparently greater effectiveness of therapeutic hypothermia in newborns may be due to important biological and clinical differences. One such difference is that adults are heavily colonized with microbes, and many have active inflammatory processes at the time of arrest, but few newborns are heavily colonized or infected at the time of birth. Inflammation can interfere with hypothermia's neuroprotection. A second difference is that apoptosis is more commonly the pathway of neuronal death in newborns than in adults. Hypothermia inhibits apoptosis but not necrosis. Newborns have a larger endogenous supply of stem cells (which reduce apoptosis) than adults and this may favor regeneration and protection from hypothermia and regeneration. A third difference is that immature oligodendroglia are more sensitive to free radical attack then mature oligodendroglia. Hypothermia reduces free radical release. In addition, immature brain has increased N-methyl-D-aspartate receptor subunits compared with adults and hypothermia reduces excitotoxic amino acids. Adults suffering cardiac arrest often have comorbidities such as diabetes, hypertension, and atherosclerosis, which complicate recovery, but newborn infants rarely have comorbidities before asphyxia. Adult hypothermia treatment may have been too short as no trial has cooled for longer than 48 hours, some only 24 or 12 hours, but neonatal therapeutic hypothermia has routinely lasted 72 hours. We hypothesize that this combination of differences favors the effectiveness of therapeutic hypothermia in newborn infants compared with adults.

Introduction

Out-of-hospital cardiac arrest in adults has features in common with birth asphyxia, in that an individual suddenly experiences global (brain and body) hypoxia–ischemia resulting in substantial mortality and with many of the survivors suffering hypoxic–ischemic brain injury and disability.

Despite the apparent similarities, there is a striking difference between adults and newborns in the quantity and consistency of the evidence for benefit from therapeutic hypothermia. This short review considers the laboratory and clinical evidence and suggests possible biological and clinical reasons why newborns may benefit more than adults from therapeutic hypothermia.

It has been known for centuries that being cold during hypoxia could protect the brain and this knowledge helped the early development of open-heart surgery. More recently, evidence emerged that mild cooling after hypoxia–ischemia can also reduce brain injury. Busto et al. (1989) showed in adult rats that postischemic hypothermia to a temperature of 30°C, 5 minutes after bilateral carotid artery occlusion and hypotension protected the CA1 region of the hippocampus. Chopp et al. (1991) showed in adult rats that 2 hours of hypothermia at 34°C after experimental forebrain ischemia reduced injury. Hoffmann et al. (1991) showed that 1 hour of postischemic hypothermia at 34°C reduced brain injury in an adult unilateral stroke model.

Further work in adult rats showed that hypothermia reduced the accumulation of excitotoxic amino acids and that the protective effect of cooling was greater in transient ischemia than with permanent arterial occlusion. Hypothermia improved behavioral tests as well as histopathology in adult animals. Cooling adult dogs to 34°C very soon after cardiac arrest reduced cerebral injury (Sterz et al., 1991; Weinrauch et al., 1992). However, cooling to 29°C was deleterious in cats, dogs, and primates (Steen et al., 1980; Steen et al., 1979).

Clinical Trials in Adults After Out-of-Hospital Cardiac Arrest

Two randomized trials of therapeutic hypothermia to 33°C in unconscious adult survivors after out-of-hospital cardiac arrest reported in 2002. The larger trial (Hypothermia After Cardiac Arrest Study Group, 2002) (n = 275) cooled for 24 hours and reported better gross neurological categories at 6 months as well as reduced mortality. Detailed cognitive testing of the survivors at 6 months did not show a statistically significant difference (Tiainen et al., 2007). The smaller trial (Bernard et al., 2002) (n = 77) cooled for 12 hours and reported better outcomes at hospital discharge.

Since then, larger numbers of patients have been recruited to randomized trials. A meta-analysis of six randomized trials of therapeutic hypothermia after out-of-hospital cardiac arrest (Shrestha et al., 2022) concluded that cooling to around 33°C did not reduce mortality at 6 months, odds ratio (OR) 0.88 (confidence interval [CI] 0.67–1.16; n = 3243). Hypothermia did not increase favorable neurological outcome measured as Cerebral Performance Category or Modified Rankin Scale (OR 1.31 [0.93–1.84]; n = 3091). Pneumonia was not significantly increased (OR 1.13 CI 0.98–1.31, n = 3056).

A more extensive systematic review of randomized trials of therapeutic hypothermia after in-hospital and out-of-hospital cardiac arrest in adult and pediatric patients included 17 trials (Colls Garrido et al., 2021). The review concluded that therapeutic hypothermia did not improve the survival rate or neurological status in adult or pediatric patients. Recently, a large trial of targeted temperature management (Dankiewicz 2021) reported 1850 patients with out-of-hospital arrest randomized to 33°C or normothermia. Fifty percent of the hypothermia group died and 48% in the normothermia group. Fifty-five percent of survivors in each group were assessed as moderately severely disabled (or worse). Although there have been concerns raised over the time taken to reach target temperature and the criteria for withdrawing life support, it seems fair to say that extensive testing has not confirmed that therapeutic hypothermia in the real clinical world following cardiac arrest in adults improves outcome.

Early Laboratory Evidence for Postischemic Hypothermia in Newborn Animals

Reducing body temperature from 38.5°C to 35°C for 12 hours in a newborn pig model of transient cerebral ischemia prevented secondary energy failure (Thoresen et al., 1995) and apoptotic cell death (Edwards et al., 1995). Thoresen et al. (1996) developed a whole-body hypoxia–ischemia model in newborn pigs, more similar to birth asphyxia, and showed that hypothermia reduced neuropathological injury (Haaland et al., 1997; Tooley et al., 2003).

Gunn et al. (1997), working with transient hypoxia–ischemia by umbilical cord occlusion in fetal lambs, showed that selective head cooling by 5° reduced cortical cytotoxic edema and infarction as well as preserving EEG. Starting hypothermia later than 5.5 hours after resuscitation was not protective. They showed that rewarming after cooling for 48 hours was associated with deterioration, but cooling for 72 hours was protective (Gunn et al., 1997). This work led to 72 hours being chosen as the duration of hypothermia for trials in human infants.

Hypothermia was shown to reduce infarct size in a 7-day-old rat pup carotid occlusion/hypoxemia model (Thoresen et al., 1996). Importantly, the rat pup model showed that the hypothermia effect lasted until age 6 weeks, which is adolescence in rats (Bona et al., 1998). Thus, by 1998, a range of experiments in three different species of newborn animals had shown that cooling by only a few degrees reduced brain injury and protected brain function without major adverse effects.

Clinical Trials in Neonatal Hypoxic–Ischemic Encephalopathy

In 1998, safety and feasibility studies of selective head cooling with rectal temperature maintained at 34.5°C for 72 hours for term infants with hypoxic–ischemic encephalopathy (HIE) had started in Auckland, Bristol, and London (Azzopardi et al., 2000; Gunn et al., 1998; Thoresen and Whitelaw, 2000). These studies showed that the physiological changes resulting from mild hypothermia in encephalopathic infants could be safely managed within an environment of closely monitored neonatal intensive care.

The CoolCap Trial, the first large multicenter randomized trial, started in 1999 and used selective head cooling and rectal temperature 34–35°C for 72 hours (Gluckman et al., 2005). Two large multicenter trials of total body cooling with rectal temperature 33–34°C for 72 hours followed (Azzopardi et al., 2009; Shankaran et al., 2005). These three trials reported a reduction in disability or death. In 2010, the American Heart Association (AHA), the European Resuscitation Council (ERC), and the International Liaison Committee on Resuscitation (ILCOR) issued new guidelines on newborn resuscitation, which included therapeutic hypothermia (Perlman et al., 2010). By 2012, seven methodologically adequate randomized trials of therapeutic hypothermia in 1214 term infants with HIE had reported outcome to age 18 months. Meta-analysis showed significant reductions in disability or death and significant reductions in death, major disability, cerebral palsy, developmental delay, and visual impairment (Tagin et al., 2012).

The results of the individual trials were similar. In meta-analysis, death or major disability relative risk was 0.76 (CI 0.69–0.84) and the number needed to treat was 7. Not only was there neurological benefit at 18 months, but the two large trials with the longest follow-up found neurodevelopmental benefit at school age (Shankaran et al., 2012, Azzopardi et al., 2014,).

It has been suggested (Moler et al., 2017) that the neonatal trials showed benefit from hypothermia because the control groups were hyperthermic. The temperatures of the control groups were tightly monitored and Shankaran et al. (2005) used equipment that servo-controlled on esophageal temperature. Mean core temperature in the normothermia group was 37.2°C (±standard deviation [SD] 0.6°C) in Shankaran et al. (2005) and just under 37.0°C (±SD 0.5°C) in Azzopardi et al. (2009). Thus, they were not “hyperthermic” in the accepted sense of the word. However, without intervention, body temperature falls in newborn infants after hypoxia (Burnard and Cross, 1958), and so, a temperature of 37°C could be regarded as too high after birth hypoxia.

Therapeutic hypothermia has been tested in other types of acute brain injury in adults, but, as yet, there is no consistent evidence of efficacy and safety in stroke, brain trauma, subarachnoid hemorrhage, or meningitis. However, these types of brain injury are substantially different from birth asphyxia and out-of-hospital cardiac arrest, which are both characterized by sudden transient global hypoxia–ischemia without hemorrhage or trauma.

Therapeutic hypothermia shows so much more convincing evidence of brain protection in newborn infants with hypoxia–ischemia than in older patients with hypoxia–ischemia in cardiac arrest, and we hypothesize that the following biological differences between newborns and adults may help to explain the difference: (1).

Inflammation worsens hypoxic–ischemic brain injury (Eklind et al., 2001) and there is evidence that lipopolysaccharide may block the protective effect of hypothermia (Osredkar et al., 2014). In the developed world, only a small percentage of infants are infected at the time of birth and the vast majority of newborn infants at the time of term delivery are neither infected nor heavily colonized with microbes and their immune systems are still immature. C-reactive protein (CRP) is synthesized in the liver mainly in response to interleukin-6 and is therefore a useful indicator of systemic inflammation over the previous 12–24 hours.

Using a highly sensitive radioimmunoassay, Wasunna et al. (1990) found that median cord blood CRP value in noninfected newborns was 0.1 mg/L and this increased to median 1 mg/L at 24 hours, and then 2 mg/L at 48 hours. The 10-fold rise in the first 24 hours coincided with microbial colonization of the gut and upper respiratory tract. Using the same highly sensitive radioimmunoassay, healthy blood donors had a median CRP of 0.8 mg/L (Shine et al., 1981). Newborns with encephalopathy are routinely treated with two intravenous antibiotics, usually a penicillin and aminoglycoside, thus further limiting bacterial colonization and invasion. Patients at all other ages are heavily colonized at the time of hypoxia–ischemia and have mature immune systems. We hypothesize that a lower level of bacterial colonization and inflammation in birth asphyxia than in older individuals with cardiac arrest favors hypothermic protection in newborns.

Furthermore, as hypothermia reduces the body's antimicrobial defenses, older heavily colonized individuals are more likely to develop pneumonia if hypothermia continues for days, particularly if sedated.

(2).

Chavez-Valdez et al. (2012) presented evidence that neuronal apoptosis is more readily induced than necrosis in the immature brain. Posthypoxic hypothermia reduces apoptosis but not necrosis (Edwards et al., 1995). This difference favors hypothermic protection after birth asphyxia rather than after adult cardiac arrest.

(3).

White matter injury is more apparent after perinatal hypoxic–ischemic injury than after adult cardiac arrest. The full-term newborn brain is relatively unmyelinated and late precursor and immature oligodendroglial cells are more sensitive to hypoxia–ischemia than are mature oligodendroglia (Back et al., 2001) and more vulnerable to oxidative stress-induced death caused by glutathione depletion (Back et al., 1998). Black et al. (1995) showed that newborn rat basal ganglia have increased neuronal nitric oxide synthase, which contributes to free radical toxicity. Microdialysis in newborn pigs has shown that posthypoxic hypothermia reduces nitric oxide in the cerebral cortex (Thoresen et al., 1997).

(4).

Excitotoxicity via N-methyl-D-aspartate (NMDA) glutamate receptors is another important mechanism of posthypoxic neuronal injury. Jantzie et al. (2015) showed increased NMDA receptor subunits in immature white matter and gray matter and hypothesized “intrinsic prenatal vulnerability to glutamate-mediated injury.” Thoresen et al. (1997) showed that posthypoxic hypothermia in newborn pigs reduced excitotoxic amino acids in the cerebral cortex.

(5).

Umbilical cord blood at term is particularly rich in mesenchymal stem cells (Haase et al., 2009) and human umbilical cord-derived stem cells can reduce apoptosis in posthypoxic neuronal cell culture (Boltze et al., 2012; Hau et al., 2008). Newborns have, in proportionate to body size, a much larger endogenous supply of stem cells than have adults. Furthermore, umbilical cord stem cells support regeneration and reduce apoptosis more than necrosis thus favoring the newborn brain.

(6).

Body (and therefore brain) temperature can be lowered much faster in newborns, having a larger surface area-to-weight ratio than adults. Thus, after the decision to cool has been made, target temperature can be achieved within a few minutes. However, this advantage may be counteracted by intrapartum hypoxia–ischemia having started hours before delivery. Thus, neonatal cooling may, in some cases, be applied after a longer time interval than in adults surviving cardiac arrest.

(7).

Adults with cardiac arrest tend to have established, sometimes advanced, vascular disease, which has already injured vital organs, whereas newborns do not have an established vascular disease. The circulatory changes with therapeutic hypothermia may further compromise adult organs that are already vulnerable.

(8).

Trials in adults may not have applied hypothermia for long enough to be protective. All seven neonatal trials of therapeutic hypothermia in the (Tagin et al., 2012) meta-analysis treated for 72 hours, but the adult trials treated for maximum 48 hours, some for only 24 hours. The shorter duration of treatment in adults was likely due to the concern that adult patients did not tolerate longer periods of hypothermia.

Conclusion

We suggest that the much stronger evidence for benefit in newborns from therapeutic hypothermia is not because of a lack of trials in the adult intensive care environments but because of a number of important biological and clinical differences that favor hypothermic cerebral protection in newborn infants more than in adults.

Footnotes

Authors' Contributions

A.W.: conceptualization, literature search, and writing the first draft and editing. M.T.: conceptualization, literature search, and writing and editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This article required no separate external funding beyond the authors' regular support from their positions in the Universities of Bristol and of Oslo.

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