Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy: Systematic Review

Shah, Prakeshkumar S; Ohlsson, Arne; Perlman, Max

doi:10.1097/01.ogx.0000300470.41760.3b

Cited by 47 publications

(68 citation statements)

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“…All meta-analyses of several main trials and well-described phase I and II randomized studies, which included outcome information, demonstrate consistent relative risk of death or disability of B0.75 and a 95% confidence interval between 0.60 and 0.90. [53][54][55][56] The four trials had similar incidence of primary outcome among control groups, and similar incidence of primary outcome among the intervention groups (40-50%). It is however, important to note that hypothermia results in a reduction in risk of death or disability from 58% to only 47%, suggesting the need for adjunct therapies, such as stem cell regenerative therapy.…”

Section: Limited Endogenous Neurogenesis Following Hypoxic Ischemic Imentioning

confidence: 86%

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Liao

Cotten

Tan

et al. 2012

Bone Marrow Transplant

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Brain injury resulting from perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality in infants and chronic neurologic disability in surviving children. Recent multicenter clinical trials demonstrated the effectiveness of hypothermia initiated within the first 6 postnatal hours to reduce the risk of death or major neurological disabilities among neonates with HIE. However, in these trials, approximately 40% of cooled infants died or survived with significant impairments. Therefore, adjunct therapies are required to improve the outcome in neonates with HIE. Cord blood (CB) is a rich source of stem cells. Administration of human CB cells in animal models of HIE has generally resulted in improved outcomes and multiple mechanisms have been suggested including anti-inflammation, release of neurotrophic factors and stimulation of endogenous neurogenesis. Investigators at Duke are conducting studies of autologous CB infusion in neonates with HIE and in children with cerebral palsy. These pilot studies indicate no added risk from the regimens used, but results of ongoing placebo-controlled trials are needed to assess efficacy. Meanwhile, further investigations are warranted to determine the best strategies, that is, timing, dosing, route of delivery, choice of stem cells and ex vivo modulations, to attain long-term benefits of CB stem cell therapy.

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Section: Limited Endogenous Neurogenesis Following Hypoxic Ischemic Imentioning

confidence: 86%

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Liao

Cotten

Tan

et al. 2012

Bone Marrow Transplant

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“…The only available therapy for neonatal asphyxia is cooling the infant's body to about 33°C (mild hypothermia) for 48-72 h. A series of randomized multicenter trials have established a protective effect of therapeutic hypothermia in reducing long-term sequelae Jacobs et al, 2007;Schulzke et al, 2007;Shah et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection

Chip

Zelmer

Ogunshola

et al. 2011

Neurobiology of Disease

119

110

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Induced hypothermia is the only therapy with proven efficacy to reduce brain damage after perinatal asphyxia. While hypothermia down-regulates global protein synthesis and cell metabolism, low temperature induces a small subset of proteins that includes the RNA-binding protein RBM3 (RNA-binding motif protein 3), which has recently been implicated in cell survival. Here, immunohistochemistry of the developing postnatal murine brain revealed a spatio-temporal neuronal RBM3 expression pattern very similar to that of doublecortin, a marker of neuronal precursor cells. Mild hypothermia (32°C) profoundly promoted RBM3 expression and rescued neuronal cells from forced apoptosis as studied in primary neurons, PC12 cells, and cortical organotypic slice cultures. Blocking RBM3 expression in neuronal cells by specific siRNAs significantly diminished the neuroprotective effect of hypothermia while vector-driven RBM3 over-expression reduced cleavage of PARP, prevented internucleosomal DNA fragmentation, and LDH release also in the absence of hypothermia. Together, neuronal RBM3 up-regulation in response to hypothermia apparently accounts for a substantial proportion of hypothermia-induced neuroprotection. Together, neuronal RBM3 up-regulation in response to hypothermia apparently accounts for a substantial proportion of hypothermia-induced neuroprotection.

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“…[8][9][10] Four negative consequences of hypothermia in TBI patients, based on the specific cerebral pathophysiology characterising these patients, will be presented below, which may explain why hypothermia treatment has not been shown to be effective for outcome -or may even aggravate the outcome in TBI patients. They are (1) the effect of hypothermiainduced stress on the microcirculation of the penumbra zone, (2) side effects of the more frequent use of vasoconstrictors due to a decrease in blood pressure following cooling, (3) the risk of increased contusional bleedings due to hypothermia-induced coagulopathy and (4) the danger associated with an increase in ICP during the rewarming period in patients with an increased ICP.…”

Section: Tentative Explanations For the Lack Of Improved Outcome Aftementioning

confidence: 99%

“…3,9,10 The neuroprotective effects of hypothermia can act on a brain with normal perfusion, where the injuredbut not dead -brain cells have the potential for restitution and regeneration. Under these circumstances, hypothermia, for example, may counteract the negative effects of free radicals released when the perfusion is restored, and reduce the risk of apoptosis.…”

Section: Hypothermia-induced Stress Responsementioning

confidence: 99%

“…2,7 There are rather strong indications from clinical studies that moderate hypothermia (32-35 1C) is beneficial for outcome following a global brain ischaemia, such as after a cardiac arrest 8,9 or following neonatal asphyxia. 7,10 In light of the demonstrated and generally accepted neuroprotective effect of hypothermia in global ischaemia, and also the fact that animal studies have indicated that there may also be beneficial effects in focal ischaemia, such as after a head trauma, 7,11 the expectation that hypothermia would also be a valuable treatment for patients with focal brain ischaemia has been great. Such patients would be those with ischaemic and haemorrhagic stroke, patients with intracerebral haemorrhages and patients who have suffered a severe traumatic brain injury (TBI).…”

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confidence: 99%

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Active cooling in traumatic brain‐injured patients: a questionable therapy?

Grände

Reinstrup

Romner

2009

Acta Anaesthesiol Scand

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Hypothermia is shown to be beneficial for the outcome after a transient global brain ischaemia through its neuroprotective effect. Whether this is also the case after focal ischaemia, such as following a severe traumatic brain injury (TBI), has been investigated in numerous studies, some of which have shown a tendency towards an improved outcome, whereas others have not been able to demonstrate any beneficial effect. A Cochrane report concluded that the majority of the trials that have already been published have been of low quality, with unclear allocation concealment. If only high-quality trials are considered, TBI patients treated with active cooling were more likely to die, a conclusion supported by a recent high-quality Canadian trial on children. Still, there is a belief that a modified protocol with a shorter time from the accident to the start of active cooling, longer cooling and rewarming time and better control of blood pressure and intracranial pressure would be beneficial for TBI patients. This belief has led to the instigation of new trials in adults and in children, including these types of protocol adjustments. The present review provides a short summary of our present knowledge of the use of active cooling in TBI patients, and presents some tentative explanations as to why active cooling has not been shown to be effective for outcome after TBI. We focus particularly on the compromised circulation of the penumbra zone, which may be further reduced by the stress caused by the difference in thermostat and body temperature and by the hypothermia-induced more frequent use of vasoconstrictors, and by the increased risk of contusional bleedings under hypothermia. We suggest that high fever should be reduced pharmacologically.

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Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy: Systematic Review

Cited by 47 publications

References 0 publications

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection

Active cooling in traumatic brain‐injured patients: a questionable therapy?

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