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Clinicians worldwide are encouraged by the results of the large randomized controlled trials (RCTs) and systematic reviews that demonstrated the efficacy of hypothermia in improving neurologic and developmental outcomes in term and late preterm infants with hypoxic–ischaemic encephalopathy (HIE) [1–5]. These studies have brought an increased interest in the aetiology, recognition, management and outcome of encephalopathic infants. Based on these studies, many clinicians have started or are considering offering therapeutic hypothermia for the treatment of HIE. As more infants are receiving treatment, registries have been and are being developed that use observational study methods to gain insight and information regarding neonatal encephalopathy (NE) and therapeutic hypothermia outside of RCTs. This chapter will focus on how these registries shed light on how effective this emerging therapy will be in the real world setting and how the registry method may track adverse events that occur in frequencies too rare to be discovered in the trials that proved efficacy. One can anticipate that centres will be using this therapy for infants outside of the inclusion parameters and methods designated by the initial trials; registries will track this “therapeutic drift”. The registries also document the evaluations and treatments that a typical infant receives and are ideally suited to track the dissemination of adjunctive therapies as they arise. Registries are able to obtain information on the larger cohort of infants with neonatal encephalopathy in addition to smaller subsets of those cooled. Last, this chapter will focus solely on infants receiving therapy and report on the characteristics and initial results of the two registries currently in use: the United Kingdom TOBY Cooling Register (TOBY Register) and the Vermont Oxford Network Neonatal Encephalopathy Registry (VON NER).
Efficacy versus effectiveness
Despite the efficacy and relative safety demonstrated by the recent trials, many questions exist with regards to the safety, refinement and optimization of the procedure. Future randomized controlled trials of hypothermia versus normothermia will be difficult to perform as randomization to a normothermic control group could be construed as unethical . To further study encephalopathic infants and monitor the practice of therapeutic hypothermia, research methods beyond RCTs are indicated. Although RCTs are considered the foundation by which we determine whether a given intervention is efficacious, they are ill suited to address issues such as safety monitoring and establishing effectiveness in a real world setting.
Moderate cooling by 3–4°C is the first successful neural rescue therapy for neonatal encephalopathy. Induced moderate cooling has also been shown to protect the brain in adults following cardiac arrest and has shown promise in other forms of cerebral injury. Although there are several historical reports of induced cooling, the implementation of moderate cooling for neural rescue in newborns with hypoxic–ischaemic brain injury is the culmination of a series of research spanning decades that: proved the potential for neural rescue following perinatal asphyxia ; consistently showed benefit in appropriate experimental models [2,3]; examined safety and feasibility in preliminary clinical studies [4,5]; confirmed efficacy by synthesis of the results of several well-conducted randomized clinical trials in newborns ; and was followed by rapid implementation into clinical practice and ongoing surveillance . This chapter will examine the findings of the clinical trials of neural rescue therapy with moderate cooling in newborns. The results of these studies led to recommendations by expert groups, specialist advisory committees and regulatory authorities for the rapid implementation into clinical practice of treatment with cooling for neonatal encephalopathy [8–10].
It is interesting to consider why this intervention has succeeded when so many other apparently promising therapies failed to show benefit in clinical trials. The lack of success of neuroprotective interventions in adult stroke led to a series of special meetings of stakeholders, namely neurologists, industry representatives, patient groups and regulatory authorities – the STAIR meetings. These meetings generated recommendations for preclinical evaluation, clinical study design, enhancing trial implementation and completion and, more recently, novel approaches to measuring outcomes, data analysis and use of new technologies such as telemedicine and electronic databases [11,12]. In many aspects, the development of neural rescue with moderate cooling followed several of the recommendations now being made to facilitate the discovery and evaluation of new neural rescue therapies.
Trials of mild hypothermia have recently proved in principle that neuroprotective therapy after delivery is possible but the protection is only partial and additional therapies are needed [1–3]. There are several candidate treatments suitable for trial (see Chapter 18) and the challenge is how to test several therapies efficiently so that only those with a high chance of success progress to pragmatic phase 3 trials. The major costs of large randomized trials mean that it is essential that only treatments with a high chance of success are studied; indeed while the financial costs are often obvious, the opportunity cost is equally if not more important. Every patient enrolled in a trial of a useless therapy is excluded from a trial of one that might work, so ill-advised major trials are a significant drag on progress in the field. It is notable that 11 years elapsed between the first demonstration that post-asphyxial hypothermia modified perinatal hypoxic-ischaemic encephalopathy in animals and the first evidence of a clinical benefit in newborn infants.
This is a familiar problem in drug development which is usually solved by testing an agent in small and rapid phase 2 studies which employ biological markers or surrogate outcomes to define a biological effect and provide evidence to support and plan pragmatic studies. However, these intermediary endpoints have to be used with circumspection as they are not substitutes for proof of clinical benefit, merely an experimental tool for efficient study of new treatments .
Worldwide more than one million babies die annually from perinatal asphyxia and its associated complications such as neonatal encephalopathy – one of the major causes of cerebral palsy and cognitive deficiencies in children aside from prematurity. Cooling the head – or the entire body – minimizes neuronal death, enabling the neonatal brain to be 'rescued' thus greatly improving developmental outcomes. Hypothermic neural rescue therapy has revolutionized the treatment of this condition and is a major recent achievement in neonatal medicine. This landmark book provides a brief scientific underpinning of hypothermic neural rescue therapy and lays out the evidence base for good practice. Internationally recognized authorities give practical advice, drawn from personal experience, on how to deliver hypothermia in the neonatal intensive care unit. A valuable addition to any neonatal unit, this is essential reading for neonatologists, neonatal nurses and paediatric neurologists.
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