Current controversies in hypothermic neuroprotection

doi:10.1016/j.siny.2007.09.004

Seminars in Fetal and Neonatal Medicine

Volume 13, Issue 1, February 2008, Pages 30-34

https://doi.org/10.1016/j.siny.2007.09.004 Get rights and content

Summary

In 2005, three randomised controlled trials (RCTs) showed that treating infants with hypoxic–ischaemic encephalopathy (HIE) with hypothermia decreased the combined outcome of death or disability at 12–18 months, although treatment effects were modest. More recently, the US Food and Drug Administration (FDA) approved a device for selective head cooling. In addition, the protocol from another of the three trials, using equipment available in many hospitals, has been in the public domain for over a year. Why has this not led to a consensus that hypothermia is the standard of care for HIE? This is explored. Important questions for future research will focus on ways to improve on initial results with cooling, such as drug plus hypothermia combination therapy and refining duration and depth of cooling or duration of rewarming. Although the latter are important questions for future clinical trials, those who are convinced by the evidence to date should focus on safe implementation of cooling using protocols with established safety and efficacy and should consider ways to increase access to cooling for eligible babies.

Introduction

More than 2 years have passed since the results of three randomised controlled trials (RCTs), which individually and collectively demonstrated the efficacy of hypothermia for the treatment of perinatal hypoxic–ischaemic encephalopathy (HIE) in term or late preterm infants, were published.1, 2, 3, 4 Yet, to date, there is still no general consensus that hypothermia is the standard of care for such infants. Why is this the case? This review aims to address some of the current controversies surrounding hypothermia as a treatment for HIE.

Section snippets

Why is everyone not convinced?

Until recently, the most definite sign that the neonatal community was not universally convinced of the efficacy of hypothermia was that an RCT (the ICE trial), with a non-hypothermic control group, continued to enroll patients in several countries. It would be logical to suppose that investigators who participated in the published or completed trials are most likely to be convinced of the safety and efficacy of cooling, and that this conviction would be demonstrated by their centres now

What are the practical barriers to implementation?

At the time of writing, there is no consensus that hypothermia should be the standard of care for infants with suspected HIE. The advice from authoritative sources that hypothermia should only be undertaken using established protocols with known safety and efficacy is still sound.6, 7 For those convinced by the published evidence, cost and/or limited equipment availability may be barriers to implementation of cooling within an individual centre, while geography may pose an additional barrier to

Who should be cooled? Who should not be cooled?

The results of the Cool Cap trial indicated that the subgroup of infants with the most severe aEEG tracings (severe suppression plus seizures) did not improve with cooling, whereas the majority of infants, who had less severe aEEG abnormalities, showed improved outcome with cooling.² In contrast, a post hoc analysis from the Cool Cap trial,¹² consistent with the results of the NICHD body cooling trial,³ showed that clinical encephalopathy grade (Sarnat II versus III) did not influence the

How might we improve upon our results with cooling?

For those convinced by the current evidence, this is an important question, which will be the focus for future research. Several possible strategies include combinations of potentially neuroprotective drugs with hypothermia; earlier initiation of cooling; increased depth or duration of cooling; and prolonged rewarming. There is some experimental evidence supporting additive or synergistic effects of drugs with hypothermia, including some FDA-approved drugs (topiramate, N-acetylcysteine).14, 15

Neurodevelopmental outcome

As indicated earlier, it is not yet known whether the early promising results with hypothermia based on evaluation at 12–24 months will translate into improved performance at school age. However, given the lack of any other therapies for HIE on the immediate horizon, this limitation is not likely to present a barrier to implementation for many neonatologists, nor is it likely to deter parents from accepting the therapy.

Of more immediate concern, neonatologists and pediatric neurologists should

Conclusion

Until the results of several, now-closed, RCTs are published, the lack of consensus for therapeutic hypothermia as the standard of care for infants with apparent HIE is likely to continue. There is no evidence that one method of cooling is superior. Although devices and protocols to perform hypothermia according to already-published protocols are now available, it is unclear how rapidly this technology will be disseminated while the results of the remaining trials are pending. It is reasonable

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Cited by (30)

Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia
2014, NeuroImage
Citation Excerpt :
Induced hypothermia is currently the only existing treatment to minimize brain injury in these newborns, with decreased death and disability rates at 12–18 months and beyond (Azzopardi et al., 2009; Eicher et al., 2005; Gluckman et al., 2005; Jacobs et al., 2007; Shankaran et al., 2005, 2012). However, some newborns still develop brain injury despite this treatment (Barks, 2008; Higgins and Shankaran, 2009; Higgins et al., 2006). It has been demonstrated that hyperperfusion may be present early on in these newborns, despite treatment with induced hypothermia (Wintermark et al., 2011), and was probably a manifestation of reperfusion injury.
The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic–ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside.
The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia.
In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1–2 MRI scans for each patient, were compared to mixed venous saturation values (SctO₂) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram.
Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO₂ and CBF in asphyxiated newborns with severe HIE (r = 0.88; p value = 0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO₂ and CBF to those with moderate HIE.
NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.
Measurement of brain perfusion in newborns: Pulsed arterial spin labeling (PASL) versus pseudo-continuous arterial spin labeling (pCASL)
2014, NeuroImage: Clinical
Citation Excerpt :
Therapeutic hypothermia is currently the only existing treatment to minimize brain injury in these newborns, with decreased death and disability rates at 12–18 months and beyond (Azzopardi et al., 2009; Eicher et al., 2005a, b; Gluckman et al., 2005; Jacobs et al., 2007; Shankaran et al., 2005; Shankaran et al., 2012). However, some newborns still develop brain injury despite this treatment (Barks, 2008; Higgins et al., 2006; Higgins and Shankaran, 2009). Measuring brain perfusion has been shown to be useful for identifying asphyxiated newborns at risk of developing brain injury, whether or not therapeutic hypothermia was administered (Massaro et al., 2013; Pienaar et al., 2012; Wintermark et al., 2011).
Arterial spin labeling (ASL) perfusion-weighted imaging (PWI) by magnetic resonance imaging (MRI) has been shown to be useful for identifying asphyxiated newborns at risk of developing brain injury, whether or not therapeutic hypothermia was administered. However, this technique has been only rarely used in newborns until now, because of the challenges to obtain sufficient signal-to-noise ratio (SNR) and spatial resolution in newborns.
To compare two methods of ASL-PWI (i.e., single inversion-time pulsed arterial spin labeling [single TI PASL], and pseudo-continuous arterial spin labeling [pCASL]) to assess brain perfusion in asphyxiated newborns treated with therapeutic hypothermia and in healthy newborns.
We conducted a prospective cohort study of term asphyxiated newborns meeting the criteria for therapeutic hypothermia; four additional healthy term newborns were also included as controls. Each of the enrolled newborns was scanned at least once during the first month of life. Each MRI scan included conventional anatomical imaging, as well as PASL and pCASL PWI-MRI. Control and labeled images were registered separately to reduce the effect of motion artifacts. For each scan, the axial slice at the level of the basal ganglia was used for comparisons. Each scan was scored for its image quality. Quantification of whole-slice cerebral blood flow (CBF) was done afterwards using previously described formulas.
A total number of 61 concomitant PASL and pCASL scans were obtained in nineteen asphyxiated newborns treated with therapeutic hypothermia and four healthy newborns. After discarding the scans with very poor image quality, 75% (46/61) remained for comparison between the two ASL methods. pCASL images presented a significantly superior image quality score compared to PASL images (p < 0.0001). Strong correlation was found between the CBF measured by PASL and pCASL (r = 0.61, p < 0.0001).
This study demonstrates that both ASL methods are feasible to assess brain perfusion in healthy and sick newborns. However, pCASL might be a better choice over PASL in newborns, as pCASL perfusion maps had a superior image quality that allowed a more detailed identification of the different brain structures.
The effects of therapeutic hypothermia on term infants with neonatal asphyxial encephalopathy
2011, Journal of Neonatal Nursing
Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain
2011, Brain Research
Citation Excerpt :
Some regions of the brain seem to be more vulnerable to hypoxia–ischemia than others (Rice and Barone, 2000; Towfighi et al., 1997), but apart from the neuronal injury, the white matter damage indicated by loss of myelination has been well documented (Kohlhauser et al., 2000; McQuillen and Ferriero, 2004). Since 1981 and the introduction of the experimental model of unilateral hypoxia–ischemia to the neonatal brain (Rice et al., 1981), a considerable number of intervention strategies have been proposed (Gonzalez and Ferriero, 2008), however apart from hypothermia (Barks, 2008), every therapeutic approach – no matter how promising – was not clinically feasible (Green, 2002). The majority of the studies focus on short-term histological and immunohistochemical evaluation of a series of biological markers and often underestimate the potential long-term side effects and outcome of the treatment.
Hypoxia–ischemia (HI) induced injury of the neonatal brain accounts for behavioral deficits concerning mainly neurological reflexes, sensorimotor functions and learning/memory disabilities that may evolve throughout development. The positive biological effects of resveratrol, a natural compound with anti-oxidant/anti-inflammatory properties found mainly in red wine have been indicated recently. Aim of this study was to investigate the delayed outcome of early administration of resveratrol in an experimental model of hypoxic–ischemic encephalopathy, by means of behavioral analysis and late neuropathological examination. Seven-day-old (P7) rats were separated into 3 groups: Group 1 underwent HI and treated with resveratrol. Group 2 (HI-treated) was subjected to HI and received same volume of saline. Group 3 (sham-operated) was the control group. A battery of behavioral tests was performed from days P8–P66, during which early reflexes (righting reflex, gait, geotaxis), sensorimotor (rope suspension, beam walking, rotarod) and learning/memory function (passive avoidance, Morris water-maze) were examined. Significant difference among the groups was observed in righting reflex, rotarod and water maze tests in which the resveratrol group almost reached the performance of the control animals. The other behavioral tests showed that control and resveratrol groups were better compared to HI, although not significant. Neuropathology study revealed a remarkable reduction of the infarct and preservation of myelination after resveratrol treatment, which was in most cases correlated with the better performance of the resveratrol group. These findings indicate that long-term neuroprotective effect of resveratrol on neonatal HI-induced gray and white matter damage might be associated with the preservation of behavioral functions.
Neonatal Hypothermia: A Method to Provide Neuroprotection After Hypoxic Ischemic Encephalopathy
2011, Newborn and Infant Nursing Reviews
Citation Excerpt :
This intervention affords the nurse the opportunity to examine the skin closely for changes, intervening at the first sign of skin breakdown. The development of sclerema neonatorum has been reported secondary to birth asphyxia before the implementation of therapeutic hypothermia; this ultimately resolves.36 However, sclerema is a disorder of the subcutaneous fat that appears first on the thighs and/or buttocks, then spreads to other body surface areas with the exception of the palms, soles, and genitalia.
The evolving progression of hypoxic ischemic encephalopathy has devastating effects accounting for approximately 23% of the four million annual neonatal deaths globally. Of infants who survive, 25% to 55% will suffer significant neurologic sequelae (Pediatrics 2008;121:648-649; author reply 649-650). Scientific evidence has demonstrated significant improvements in clinical and developmental outcomes through therapeutic hypothermia. Interventions initiated within a predefined “therapeutic window” showed decreased secondary cellular injury and aptotosis. The aim of this article is to provide an account of the hypoxic event at the cellular level describing the progression of injury that leads to ongoing neuronal cell damage and death. Historical accounts of experimental and clinical trials to date are provided, which describe scientific evidence used to develop standardized treatment protocols for hypothermia after hypoxic ischemic encephalopathy. Details of current protocols are also provided. Lastly, a focus on nursing interventions with symptom management is provided, giving supportive rationale to assist the bedside nurse when caring for these complex patients in an effort to potentially improve short- and long-term outcomes.
Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia
2010, American Journal of Obstetrics and Gynecology
We sought to describe placental findings in asphyxiated term newborns meeting therapeutic hypothermia criteria and to assess whether histopathologic correlation exists between these placental lesions and the severity of later brain injury.
We conducted a prospective cohort study of the placentas of asphyxiated newborns, in whom later brain injury was defined by magnetic resonance imaging.
A total of 23 newborns were enrolled. Eighty-seven percent of their placentas had an abnormality on the fetal side of the placenta, including umbilical cord lesions (39%), chorioamnionitis (35%) with fetal vasculitis (22%), chorionic plate meconium (30%), and fetal thrombotic vasculopathy (26%). A total of 48% displayed placental growth restriction. Chorioamnionitis with fetal vasculitis and chorionic plate meconium were significantly associated with brain injury (P = .03). Placental growth restriction appears to significantly offer protection against the development of these injuries (P = .03).
Therapeutic hypothermia may not be effective in asphyxiated newborns whose placentas show evidence of chorioamnionitis with fetal vasculitis and chorionic plate meconium.

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Current controversies in hypothermic neuroprotection

Summary

Introduction

Section snippets

Why is everyone not convinced?

What are the practical barriers to implementation?

Who should be cooled? Who should not be cooled?

How might we improve upon our results with cooling?

Neurodevelopmental outcome

Conclusion

Pediatr Neurol

Lancet

Early Hum Dev

Pediatr Neurol

Pediatr Neurol

Brain Res

J Pediatr

Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy

N Engl J Med

Therapeutic hypothermia following perinatal asphyxia

Arch Dis Child Fetal Neonatal Ed