Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units

doi:10.1016/j.resuscitation.2008.04.027

Resuscitation

Volume 78, Issue 1, July 2008, Pages 7-12

https://doi.org/10.1016/j.resuscitation.2008.04.027 Get rights and content

Summary

Recent evidence suggests that the current ILCOR guidelines regarding hypothermia for the treatment of neonatal encephalopathy need urgent revision. In 2005 when the current ILCOR guidelines were finalised one large (CoolCap trial, n = 235) and one small RCT (n = 67), in addition to pilot trials, had been published, and demonstrated that therapeutic hypothermia after perinatal asphyxia was safe. The CoolCap trial showed a borderline overall effect on death and disability at 18 months of age, but significant improvement in a large subset of infants with less severe electroencephalographic changes. Based on this and other available evidence, the 2005 ILCOR guidelines supported post-resuscitation hypothermia in paediatric patients after cardiac arrest, but not after neonatal resuscitation. Subsequently, a whole body cooling trial supported by the NICHD reported a significant overall improvement in death or disability. Further large neonatal trials of hypothermia have stopped recruitment and their final results are likely to be published 2009–2011.

Many important questions around the optimal therapeutic use of hypothermia remain to be answered. Nevertheless, independent meta-analyses of the published trials now indicate a consistent, robust beneficial effect of therapeutic hypothermia for moderate to severe neonatal encephalopathy, with a mean NNT between 6 and 8. Given that there is currently no other clinically proven treatment for infants with neonatal encephalopathy we propose that an interim advisory statement should be issued to support and guide the introduction of therapeutic hypothermia into routine clinical practice.

Introduction

Post-resuscitation moderate to severe acute neonatal encephalopathy in infants born at term is associated with a high rate of death or devastating long-term disabilities. There has been no significant improvement in the risk of this tragic event over recent decades and only supportive care is routinely available at present. The possibility that mild cooling might be beneficial has tantalised clinicians for over 300 years.¹ In the present review we critically review the available clinical evidence for therapeutic hypothermia in relation to the relevant 2005 recommendations of the International Liaison Committee on Resuscitation (ILCOR). These recommendations are updated every five years, as evidence changes.²

Section snippets

Consensus on science

A reduction of body temperature by 2–3 °C (modest hypothermia) following cerebral hypoxia-ischaemia reduces cerebral metabolic and biochemical abnormalities and cerebral injury and improves function in experimental neonatal models (LOE 6).3, 4, 5 In adults, induced hypothermia (temperature of 32–34 °C) for 12–24 h improves neurological outcome after cardiac arrest due to ventricular arrhythmias but not after trauma or stroke (LOE 7).⁶ In a multicentre trial involving newborns with suspected

New data and information following the 2005 ILCOR statement

In October 2005 a second large randomised controlled trial (RCT) was published,¹⁰ in which 208 infants were treated with whole body cooling at a rectal temperature of 33.5 ± 0.5 °C or normothermia for 72 h. Entry criteria were similar to those of the CoolCap trial,⁷ except that only clinical and not aEEG criteria were used (see Table 1). This study found a significant improvement in the composite outcome of death or moderate to severe disability at 18 months of age in the treatment group (Table 2).

Suggestions for practical implementation

We propose that intensive care nurseries should now consider adopting one of the validated protocols for the selection of term infants with HIE (see Table 1), be appropriately equipped and train staff to offer hypothermia according to the protocol of the currently published large hypothermia trials.7, 10 Given the practical limitations on any future formal trials, it is vital that strict protocols, including universal follow up should be adopted. Because HIE is a relatively uncommon condition,

Conflict of interest statement

There are no conflicts of interest or financial interests to reveal.

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Perinatal management: Lessons learned from the neonatal research network
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Recent contributions of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) regarding obstetrical perinatal interventions and neonatal delivery room practices include the following: the impact of multiple antepartum factors including maternal diabetes, hypertension, obesity and mode of delivery on outcomes of extremely preterm newborns, effects of delayed delivery interval for extremely preterm multiples, effects of antenatal steroids on preterm newborn outcomes and the impact of antenatal magnesium sulfate therapy on neurodevelopmental outcomes for extremely preterm infants. NRN studies also contribute important evidence for neonatal delivery room resuscitation guidelines including umbilical cord management and maintenance of euthermia immediately after birth. The updated NRN outcome calculator helps better counsel families regarding possible outcomes for the most immature newborns if resuscitation is attempted at birth. Thus, the NRN provides substantial information regarding effects of perinatal management on newborn infants.
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Both therapies place the patient at risk for severe hypothermia.23 Since severely encephalopathic newborns may have temperature dysregulation, they are at risk for this condition and the subsequent complications including bleeding, thrombosis, sepsis and dysrhythmias.26,27 The inclusion by some transport teams of an active cooling device on transport will allow this controlled therapy to be initiated at the referring hospital.28
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The majority of brain injuries that lead to cerebral palsy, developmental disability, and mental health disorders have their onset in utero. These lifelong conditions come with great economic and emotional burden as they impact function in nearly all domains of affected individuals’ lives. Unfortunately, current therapeutic options are limited. There remains a focus on rescue, rehabilitation, and regeneration after the injury has occurred, rather than aiming to prevent the initial injury. Prevention would imply treating the mother during pregnancy to alter the fetal environment and in turn, treat the fetus. Fear of harming the developing fetus remains as a result of errors of the past such as the release of thalidomide. In this review, we outline evidence from animal studies and clinical trials that have explored maternal dietary supplementation with natural health products (including nutraceuticals and functional foods) for perinatal brain injury prevention. Namely, we discuss magnesium sulphate, creatine, choline, melatonin, resveratrol and broccoli sprouts/sulforaphane. Although clinical trials have only been completed in this realm for magnesium sulphate, results in animal models have been promising, suggesting that this is a productive avenue for further research. Natural health products may provide safe, effective, affordable, and easily accessible prevention of fetal brain injury and resulting lifelong disabilities.
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Peri-mortem caesarean section (PMCS) is a very rare procedure performed to improve the chances of survival for both mother and fetus following cardiorespiratory arrest. Non-obstetricians including Emergency Physicians (EPs) are often called upon to perform this procedure under challenging and suboptimal circumstances. We reported a case of PMCS performed timely after traumatic cardiorespiratory arrest that resulted in fetal survival.
A 25-year-old primigravida female and six-month pregnant presented to the Emergency Department (ED) of an adult tertiary hospital. She experienced traumatic cardiorespiratory arrest for nearly 27 min following a high-speed motor vehicle crash. Upon ED arrival, she was in pulseless electrical activity. She was immediately intubated with continuation of cardiopulmonary resuscitation. She received bilateral tube thoracostomies as well as intravenous (IV) transfusion of blood products, adrenaline and tranexamic acid. Her fundal height was two centimeters above the umbilicus on palpation. The EP performed a PMCS via a midline laparotomy 3–4 min upon ED arrival. The baby was bradycardic and cyanosed with no spontaneous respiration at birth and was resuscitated by a second EP. She was intubated and the EP gained IV access using a cannula introduced into the umbilical vein. Neonatal hypothermia was avoided using cling wrap. The baby was transported to a nearby neonatal intensive unit. She survived and is currently one year old.
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We reviewed the limited literature regarding this potentially life-saving emergency procedure and highlighted the challenges facing our resuscitation team.
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Careful positioning and skin care are important for these infants, who are frequently hypoactive, obtunded, or even comatose, to prevent skin breakdown and fat necrosis.34 Monitoring and documenting changes in neurologic status, especially clinical seizures, are of utmost importance for the corroboration of continuous EEG and/or aEEG data.17,23,24 After 72 hours of therapeutic cooling is completed, rewarming is initiated.
Hypoxic-ischemic encephalopathy (HIE) is a potentially devastating complication related to events in the prenatal and/or intrapartum period that lead to a depressed infant, or worse, a stillbirth. Prompt recognition of risk factors for HIE is required, followed by rapid delivery of the infant to ensure an optimal outcome. Clinical indicators can be applied to determine which infants are at risk of compromised long-term developmental outcomes and are helpful in guiding bedside care. Cooling is the standard of care when complications from HIE are expected, but it has not eliminated the sequelae in all cases. Novel adjuncts to cooling are being developed, with a common theme of neuroprotection. This article will focus on key aspects of clinical care that are important for the bedside nurse to recognize and understand, and will present information on the current standard of care, as well as provide insight into future directions that are currently under investigation.

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^☆: A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.04.027.

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ReviewTherapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units☆

Summary

Introduction

Section snippets

Consensus on science

New data and information following the 2005 ILCOR statement

Suggestions for practical implementation

Conflict of interest statement

Lancet

Pediatr Neurol

Pediatr Neurol

NeuroRx

J Pediatr

Early Hum Dev

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs

J Clin Invest

Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia

Pediatr Res

Posthypoxic cooling of neonatal rats provides protection against brain injury

Arch Dis Child Fetal Neonatal Ed

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

N Engl J Med

Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy

Pediatrics

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy

N Engl J Med

Review
Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units☆