UK cooling TOBY. register. UK TOBY Cooling Register Protocol

Transcription

1 UK cooling TOBY register UK TOBY Cooling Register Protocol Version 3, 11th June 2007

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3 1 Contents 1. Background Perinatal asphyxial encephalopathy Pathogenesis of perinatal asphyxial encephalopathy Mild induced hypothermia The need for a Cooling Register Aims of Register Methods of treatment with hypothermia Subject Group Selection criteria for treatment with cooling Timing of cooling treatment Duration of treatment with cooling Potential harmful effects of treatment with cooling Training 6 2. Early identification of infants at risk of perinatal asphyxial encephalopathy Clinical features Neuroimaging Amplitude integrated EEG (aeeg) 6 3. Data collection 7 4. Administration Management Group Advisory Group Use of data Dissemination of information 9 References 10

4 2 1. Background 1.1 Perinatal asphyxial encephalopathy A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy: 1 up to 30% will develop seizures, approximately 25% of infants who suffer moderate asphyxial encephalopathy will develop cerebral palsy, whilst almost all infants with severe encephalopathy die or survive with multiple handicaps 2. Perinatal asphyxia causing moderate or severe encephalopathy occurs in approximately 2/1000 births 3 and may account for up to 30% of cases of cerebral palsy; it is consequently a very significant health care and financial burden to the NHS. Current management of perinatal hypoxic-ischaemic injury consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants. No specific treatments are presently available. 1.2 Pathogenesis of perinatal asphyxial encephalopathy Experimental studies 4,5 have shown that a severe perinatal hypoxic-ischaemic insult results in an evolving process of adverse biochemical events that include increased levels of neurotransmitters, excessive production of free radicals, increased intracellular calcium, and stimulation of inflammatory mediators and messengers that initiate apoptotic cell death. Alterations in cerebral energy metabolism can be observed during and following hypoxic-ischaemic insult. During hypoxic-ischaemic insult cerebral metabolism is impaired and cerebral high-energy phosphate levels fall precipitously. Following termination of the insult, cerebral energy metabolism initially recovers but may then deteriorate 6-24 hours later. This secondary energy failure is not contingent on impaired substrate supply and its severity is related to survival, head growth and neurodevelopmental outcome at 1 and 4 years 6-8. Although the secondary phase of impaired cerebral energy metabolism resolves after about 72 hours, a persistent disturbance may be detected for several months 9, Mild induced hypothermia Experimental studies show that following hypoxic ischaemic injury, mild induced hypothermia a reduction of body temperature by about 3 C - preserves cerebral energy metabolism, reduces cerebral tissue injury and improves neurological function 11,12. Randomised trials in full term and near full term newborns suggest that treatment with mild hypothermia is safe and may improve survival without disabilities up to 18 months of age 13-15, but long term efficacy and safety are yet to be established. Although the optimal time of initiation, the depth and duration and the method of cooling are uncertain, in the absence of specific treatments many clinicians will wish to consider treating asphyxiated infants with hypothermia.

5 3 As an experimental treatment, mild induced hypothermia has only been used in the context of clinical trials; one such trial was the TOBY study in the UK. In the TOBY study, hypothermia was administered by experienced clinicians, following the study protocol, and infants were closely monitored and procedures were in place to identify and report adverse events. 1.4 The need for a Cooling Register In anticipation of the active recruitment phase of the TOBY study ending in November 2006 it was recognised that there would be continued interest in providing cooling; however, the facility to abide by guidelines, collect data, and report adverse events would no longer be in place. The UK TOBY Cooling Register was established to address these problems and facilitate appropriate use of cooling for the treatment of infants with encephalopathy. The register serves the whole of the UK, while promoting collaboration with overseas centres where cooling is undertaken and encouraging the establishment of similar registers in other countries. The register collects anonymised data only, and as a service evaluation of current practice does not require review or approval by a Research Ethics Committee. 1.5 Aims of Register The aims of the Register are to: Determine the likely demand in the UK for treatment of newborns infants with cooling. This would be important information for the NHS to consider when evaluating whether cooling should become standard treatment following perinatal asphyxial encephalopathy. The Department of Health Patient Research Safety Programme recently commissioned a review of neonatal encephalopathy 16, which proposed that national surveillance of neonatal encephalopathy should be considered. Identify adverse events associated with treatment with cooling. Although no clinically significant adverse events related to cooling have been reported in the clinical trials so far, relatively few infants have received cooling in these studies (approximately 250 infants) so that uncommon events may have been missed. Adverse events may be more likely to occur when cooling is undertaken outside the context of a clinical trial. Ensure uniform clinical management to a high standard in this high risk group of infants. Until now no specific treatment for infants with asphyxial encephalopathy was available. The Register will ensure that this high risk group of infants are treated to a specified protocol which would minimise the risk of inappropriate or inadequate treatment, and maximise the benefit of treatment with cooling. Facilitate further clinical trials of neuroprotection following asphyxia. The promising results of clinical trials of cooling and the successful enrolment of infants into the TOBY Study confirm that it is feasible to carry out clinical trials of emergency interventions very soon after birth, and that clinically significant improvement in outcome is possible. The TOBY study group is poised to carry out further trials of promising new treatments in combination with cooling. A Register co-ordinated by the TOBY office would widen participation, and facilitate

6 timely research, which would lead to earlier integration of research findings into clinical practice. 1.6 Methods of treatment with hypothermia The aim of intervention with hypothermia is to maintain a cerebral temperature of approximately C for about 72 hours, commencing as soon as possible after resuscitation. Two approaches have been used: head cooling combined with minimal to mild whole body cooling or surface whole body cooling to the target cerebral temperature. The aim of selective head cooling is to achieve adequate cerebral cooling with only small reduction in core body temperature, thus minimising potential harmful effects of cooling. This is achieved by surface cooling the head whilst actively warming the rest of the body. Although, experimentally, a significant cerebral/core temperature gradient can be obtained in this way, the actual brain temperature achieved in clinical practice is uncertain, and this is a drawback of this method of treatment. Nevertheless, approved equipment to provide selective head cooling is now available (Olympic Medical Seattle USA). In contrast, whole body surface cooling relies on the assumption that brain temperature is close to core body temperature. Typically whole body cooling is achieved by simple measures such as a fan or the application of cold packs around the baby or, probably more reliably, by means of a cooling mattress or blanket. However, the equipment currently available was not originally intended for use in neonates. 1.7 Subject Group The UK TOBY Cooling Register is a database designed to document the use of cooling (whether selective head cooling or whole body cooling) for term infants who have experienced perinatal asphyxia. The decision to treat infants with cooling remains the responsibility of the attending senior clinician. Infants who meet the following criteria may be considered for treatment with cooling: 36 weeks completed gestation require resuscitation at birth develop seizures or moderate or severe encephalopathy after resuscitation Contraindications: conditions requiring immediate or imminent surgery other abnormalities indicative of a poor long term outcome These are relative contraindications that should be assessed by the attending senior clinician. Cooling is not appropriate in moribund infants.

7 1.8 Selection criteria for treatment with cooling The above criteria identify those infants most likely to benefit from treatment with cooling. Abnormal amplitude integrated EEG recordings during the first few hours after birth help to confirm suitability, but initiation of cooling may be commenced prior to cerebral function monitoring. Conversely, if an infant has commenced cooling and is shortly afterwards found to have a normal aeeg recording, it may then be appropriate to consider discontinuation of cooling. 1.9 Timing of cooling treatment The interval between the insult and initiation of hypothermia, the severity of the insult and the duration and depth of hypothermia may critically affect the therapeutic response to hypothermia. Most studies indicate that the maximum benefit occurs when treatment is started within six hours of the insult 17-24, although limited neuroprotection has been observed when hypothermia is started as late as 12 hours. Therefore, hypothermic treatment following perinatal asphyxia will need to be started as soon as practically possible. Limited benefit only might be expected if treatment is delayed beyond six hours after birth Duration of treatment with cooling The duration of treatment with hypothermia has varied greatly in experimental studies. Consistently beneficial effects have been observed when moderate hypothermia was maintained for hours. It has been suggested that treatment up to 72 hours may be required if the interval before inducing hypothermia is prolonged or milder degrees of hypothermia are employed 25. A rebound rise in epileptiform activity in fetal lambs 25 and in intracranial pressure in adults with stroke 26 have been reported when hypothermia was discontinued before 72 hours. It is recommended that cooling should continue for 72 hours, after which gradual rewarming at no more than 0.5 C per hour to normothermia should be applied Potential harmful effects of treatment with cooling Mild cooling is associated with physiological changes in cardiovascular parameters: blood pressure rises and heart rate falls linearly with cooling. With deeper cooling, several potentially harmful abnormalities may occur: the q-t interval increases linearly with the depth of cooling and ventricular tachy-arrhythmias may be induced, and neutropenia, thrombocytopenia and hypokalemia may also occur. These abnormalities are more severe and more common when the core temperature is less than about 32 C 27, and may cause severe complications and even death. An increased risk of infection, primarily pneumonia, has also been reported in studies of cooling in adults. Despite these potentially harmful effects of cooling, no clinically significant complications related to treatment with cooling in asphyxiated infants have been reported so far. However, in these reported studies cooling has been carried out in specialist centres according to research protocols with specified selection criteria and patient monitoring procedures, and the adherence to the protocols is strictly

8 monitored. If cooling is used more widely and without proper guidance, there is a danger that cooling will be applied inappropriately to infants and without adequate monitoring so that inadvertent excessive hypothermia or inadequate cooling may occur. Because of the apparent safety of cooling in the clinical studies reported so far, clinical staff may underestimate or be unaware of the potential complications of inadvertent excessive cooling, or rebound hyperthermia Training It is important that cooling is provided by staff who are aware of possible complications, and are able to deliver treatment to the required standards, as detailed in the Clinician s Handbook. Training in the use of the cooling equipment must be undertaken, as well as in cerebral function monitoring and interpretation of traces. 2. Early identification of infants at risk of perinatal asphyxial encephalopathy 2.1 Clinical features Early identification by clinical features of infants at risk of developing encephalopathy is difficult. Fetal heart rate patterns are not very helpful 28,29 and neither the Apgar scores recorded immediately after birth 30,31 nor umbilical cord blood gas analysis 32,33 are good predictors of the likelihood or severity of post asphyxial encephalopathy. However, a continuing need for resuscitation and acidemia with a cord blood ph <7.0, are considered essential features of perinatal asphyxia. 2.2 Neuroimaging Abnormal appearances can be observed on cranial ultrasonography, computerized tomography 34 and magnetic resonance imaging (MRI) 35. However, these abnormalities may not be apparent during the first hours after birth. Therefore, these techniques may be of use as prognostic indicators but not for early selection of infants for neuroprotective therapies. MRI is the imaging modality of choice for assessing the distribution of injury, and likely prognosis and to support a diagnosis of hypoxic ischaemic encephalopathy. The optimum time for performing MRI examination is between 5 and 14 days of age. 2.3 Amplitude integrated EEG (aeeg) Standard electroencephalography and measurement of evoked potentials provide objective evidence for abnormal cerebral function following perinatal asphyxia 36,37. However, these techniques are difficult to apply very soon after birth. Continuous amplitude integrated electroencephalography (aeeg) with a cerebral function monitor during the first six hours after birth provides a more simple objective measure for the presence of encephalopath y37,38. The aeeg records a single channel EEG from 2 biparietal electrodes. The filtered signal, containing the main EEG frequencies, is rectified, smoothed and amplitude integrated before it is written out, at

9 7 the bedside on slow-speed paper (6 cm/hour). It is easier to interpret the aeeg than the conventional EEG, although it gives less information on the underlying type of activity. Cerebral function monitoring should be performed on infants treated with cooling, starting before the induction of cooling if possible, or as soon as possible during their treatment. 3. Data collection Uniquely numbered data forms will be supplied to neonatal units likely to undertake treatment with hypothermia. When an infant is treated, and a completed form is returned to the register office, an entry on the register is created using the number on the form. This number will be used to identify that infant for all further correspondence with the treatment centre and future data collection by the Register. Hospitals submitting data to the register will be required to have systems established that make it possible for future correspondence and data collection to take place. Data collection will start when hypothermia is induced and will continue for 96 hours, including the period during and immediately after rewarming. Basic clinical background information about the pregnancy and delivery will be collected, hourly rectal temperature recordings, conditions requiring treatment including seizures, hypotension, coagulopathy will be monitored, and a daily score of encephalopathy will be completed. Short term outcome information will be collected. If an infant is transferred to another hospital after cooling has been completed, before discharge home or death, the treatment hospital where cooling was administered will be asked to acquire information on the eventual outcome for this infant and then to submit this anonymised information to the register. An MRI should be done in all infants within about 2 weeks of birth. Information from the MRI report will be requested by the register. Follow up data should be collected at approximately 2 years by the treatment hospital, and a reminder will be issued from the register to this effect. A data collection form will be provided on which to record data on neurodevelopmental impairment, growth and neurological status.

10 4. Administration The Register will be based at and administered by the National Perinatal Epidemiology Unit, University of Oxford. This is a multidisciplinary epidemiology unit, funded by the Department of Health. Its staff include epidemiologists, statisticians, health economists, clinicians and trial managers. The unit is currently running or planning several perinatal trials and 2 disease registers (4Child, CAROBB) as well as UKOSS, an obstetric surveillance system Management Group The register is run by a multidisciplinary team, and is led by a neonatologist and an epidemiologist. A co-ordinator administers the day-to-day running of the register, supported by a computer scientist, statistician and data entry clerk. The management group meets regularly, at least monthly. 4.2 Advisory Group Dr Denis Azzopardi Professor Peter Brocklehurst Dr Andrew Currie Professor David Edwards Professor Henry Halliday Professor Malcolm Levene Dr Elia Maalouf Professor Neil Marlow Mr Ed Juszczak Professor Marianne Thoresen Professor Michael Weindling Professor Andrew Whitelaw Scientific and clinical advice is provided by a team of specialists in neonatology, hypothermia and neuroprotection. The advisory group meets annually. 4.3 Use of data Data collected by the register will be used to complement the information gathered in clinical trials. It will provide descriptive data on the frequency of use of cooling in neonatal care, the characteristics of infants undergoing cooling and the clinical outcomes in such infants. It will also provide an overview of how cooling is used in the UK and help to determine policy. It will facilitate planning for the provision of resources to support the use of cooling, in respect of staff training and funding for equipment, for example. Any data providing evidence of adverse events, or strengths and weaknesses of the treatment may be used to amend clinical guidelines on the use of hypothermia.

11 4.4 Dissemination of information This will be an important role of the register. Initially neonatal units across the UK will need to be aware of the existence of the register and its purpose. As data collection progresses and more information becomes available, the benefits gained from this increasing knowledge will be shared with practitioners. Materials such as information leaflets, and posters, presentations will be developed as appropriate to encourage cooling to be delivered when it is most likely to confer benefit on the patient and to the highest possible standards based on the evidence from the research available.

12 10 References Shankaran S, Woldt E, Koepke T, Bedard MP, Nandyal R. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991; 25(2): Yudkin PL, Johnson A, Clover LM, Murphy KW. Assessing the contribution of birth asphyxia to cerebral palsy in term singletons. Paediatr.Perinat.Epidemiol. 1995;9: Levene MI. Management and outcome of Birth Asphyxia. In Levene MI, Lilford RJ, Bennett MJ, Punt J, eds. Fetal and Neonatal Neurology and Neurosurgery., pp London: Churchill Livingstone, Thoresen M, Satas S, Puka-Sundvall M et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 1997; 8(15): Edwards AD, Yue X, Squier MV et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995; 217(3): Roth SC, Baudin J, McCormick DC et al. Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years. Dev Med Child Neurol 1993; 35(9): Roth SC, Baudin J, Cady E et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol 1997; 39(11): Hanrahan JDCIJAD, Cowan FMSJ, Bell JD, Bryant DJ, Edwards AD. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol 1999; 41(2): Robertson NJ, Cox IJ, Cowan FM, Counsell SJ, Azzopardi D, Edwards AD. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr Res 1999; 46(3): Hanrahan JD, Cox IJ, Edwards AD et al. Persistent increases in cerebral lactate concentration after birth asphyxia. Pediatr Res 1998; 44(3): Amess PN, Penrice J, Cady EB, Lorek A, Wylezinska M, Cooper CE et al. Mild hypothermia after severe transient hypoxia-ischemia reduces the delayed rise in cerebral lactate in the newborn piglet. Pediatr.Res. 1997;41: Bona E, Hagberg H, Loberg EM, Bagenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr.Res. 1998;43: Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:

13 Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N.Engl.J Med. 2005;353: Higgins RD, Raju TN, Perlman J, Azzopardi DV, Blackmon LR, Clark RH et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 2006;148: Kurinczuk JJ, Barralet JH, Redshaw M, Brocklehurst P. Report to the Patient Safety Research Programme (Policy Research Programme of the Department of Health). Monitoring the incidence of neonatal encephalopathy - what next? Oxford:NPEU, Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995; 15(11): Bona E, Hagberg H, Loberg EM, Bagenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998; 43(6): Wagner BP, Nedelcu J, Martin E. Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats. Pediatr Res 2002; 51(3): Thoresen M, Penrice J, Lorek A et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995; 37(5): Globus MY, Busto R, Lin B, Schnippering H, Ginsberg MD. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem 1995; 65(3): Kumar K, Evans AT. Effect of hypothermia on microglial reaction in ischemic brain. Neuroreport 1997; 8(4): Si QS, Nakamura Y, Kataoka K. Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide. Neuroscience 1997; 81(1): Taylor DL, Mehmet H, Cady EB, Edwards AD. Improved neuroprotection with hypothermia delayed by 6 hours following cerebral hypoxia-ischemia in the 14- day-old rat. Pediatr Res 2002; 51(1): Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997; 99(2): Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998; 29(12):

14 Clifton GL, Allen S, Berry J, Koch SM. Systemic hypothermia in treatment of brain injury. J Neurotrauma. 1992; S Nelson KB, Dambrosia JM, Ting TY, Grether JK. Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N Engl J Med 1996; 334(10): Spencer JA, Badawi N, Burton P, Keogh J, Pemberton P, Stanley F. The intrapartum CTG prior to neonatal encephalopathy at term: a case-control study. Br J Obstet Gynaecol 1997; 104(1): Nelson K B, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics 1981; 68(1): Levene MI, Sands C, Grindulis H, Moore JR. Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet 1986; 1(8472): Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics 1996; 97(4): Ekert P, Perlman M, Steinlin M, Hao Y. Predicting the outcome of postasphyxial hypoxic-ischemic encephalopathy within 4 hours of birth. J Pediatr 1997; 131(4): Barkovich AJ. The encephalopathic neonate: choosing the proper imaging technique. AJNR Am J Neuroradiol 1997; 18(10): Rutherford MA, Pennock J, Counsell Seal. Abnormal magnetic resonance signal in the internal capsule predicts poor outcome in infants with hypoxic-ischaemic encephalopathy by continuous EEG in asphyxiated full-term infants. Pediatrics 1998; 102: Guarino Y, Brayshaw C, Edwards A, Acolet D, Azzopardi D. Prediction of hypoxicischaemic encephalopathy by continuous EED in asphyxiated full-term infants. Pediatrics Research 1996; Eken P, Toet MC, Groenendaal F, de Vries LS. Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 1995; 73(2):F Hellstrom Westas L, Rosen I, Svenningsen NW. Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. Arch Dis Child Fetal Neonatal Ed 1995; 72(1):F National Perinatal Epidemiology Unit: ox.ac.uk/carobb;

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16 UK cooling TOBY register Clinical Co-ordinating Centre: Department of Paediatrics Faculty of Medicine Imperial College London Hammersmith Campus Du Cane Road London Tel: W12 0NN Fax: Data Co-ordinating Centre: TOBY Office National Perinatal Epidemiology Unit University of Oxford Old Road Campus Headington Oxford Tel: OX3 7LF Fax: Web: