Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders

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1 Original Paper Received: October 2, 2012 Accepted after revision: February 12, 2013 Published online: April 23, 2013 Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders Floris Groenendaal a Alexandra Casaer b Koen P. Dijkman c Antonio W.D. Gavilanes d Timo R. de Haan e Henk J. ter Horst f Sabine Laroche g Gunnar Naulaers h Monique Rijken i Henrica L.M. van Straaten j Katerina Steiner k Renate M.C. Swarte l Alexandra Zecic m Inge A. Zonnenberg n and the Dutch-Flemish Working Group on Neonatal Neurology a Department of Neonatology, Wilhelmina Children s Hospital/University Medical Center Utrecht, Utrecht, The Netherlands; b Department of Neonatology, AZ St. Jan Bruges-Ostend AV, Bruges, Belgium; c Department of Neonatology, Máxima Medical Centre, Veldhoven, d Department of Neonatology, Maastricht University Medical e Centre, Maastricht, Department of Neonatology, Emma Children s Hospital Academic Medical Center, Amsterdam, and f Department of Neonatology, Beatrix Children s Hospital, University Medical Centre Groningen, Groningen, The Netherlands; g Neonatal Intensive Care, University Hospital, Antwerp, and h Department of Neonatology, University Hospital, Leuven, Belgium; i Department of Neonatology, Leiden University Medical Center, Leiden, j Department of Neonatology, Isala Clinics, Zwolle, k Department of Neonatology, Radboud University Nijmegen Medical Centre, l Nijmegen, and Department of Neonatology, Erasmus Medical Center Sophia, Rotterdam, The Netherlands; m Department of Neonatology, University Hospital, Gent, Belgium; n Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands Key Words Hypothermia Perinatal asphyxia Neurodevelopment Neuroprotection Introduction Abstract Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in Since then, an increasing number of patients has been treated up to 166 in Complications and outcome were registered in an online database. Objectives: The aim of this study was to analyse complications and outcome after implementation. Methods: Data were retrieved from an online database to which all centres had contributed. Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials. Copyright 2013 S. Karger AG, Basel karger@karger.com S. Karger AG, Basel /13/ $38.00/0 Dr. Floris Groenendaal Department of Neonatology Wilhelmina Children s Hospital/ University Medical Center Utrecht Room KE , Lundlaan 6, NL 3584 EA Utrecht (The Netherlands) umcutrecht.nl

2 Introduction Perinatal asphyxia is an important clinical problem in the Netherlands with significant mortality and morbidity [1, 2]. Data of The Netherlands Perinatal Registry demonstrated that at least 200 full-term neonates suffered from severe perinatal asphyxia with an annual birth rate of 180, ,000 [3]. In Flanders the annual birth rate is 65,000 70,000, which would result in 75 cases of severe perinatal asphyxia. In 2007 a report was published by the Cochrane group indicating neuroprotective effects of moderate hypothermia in full-term neonates with perinatal asphyxia [4]. After discussion of this report in the Dutch-Flemish Working Group on Neonatal Neurology in which 14 neonatal intensive care units (NICUs) participate, it was decided to introduce this new therapy in the Dutch language area of Europe. A treatment protocol was discussed and adapted, and a uniform cooling device for total body hypothermia was chosen. Training sessions for nurses and neonatologists were organised in the beginning of 2008 and patients were recorded in a new online database to register outcome as well as potential complications. The present study reports the first clinical and followup results of therapeutic hypothermia in our region. The outcome of hypothermia will be compared to that of the large international randomised controlled trials (RCTs) of therapeutic hypothermia in full-term neonates with perinatal asphyxia. M e t h o d s Treatment Protocol The treatment protocol was adapted from the TOBY trial, which was finishing recruiting at the time of introduction of hypothermia in our region [5]. Inclusion criteria of this trial were available through the internet. In summary, patients were eligible for treatment with hypothermia when the gestational age was at least 36.0 weeks of gestation, and when there was clear presence of perinatal asphyxia (see for online suppl. table 1) followed by neonatal encephalopathy. For the clinical diagnosis of neonatal encephalopathy the Thompson score was used between 1 and 3 h after birth [6]. A Thompson score >7, indicating moderate to severe encephalopathy, was the cutoff value to start therapeutic hypothermia. When available, onechannel or multiple-channel aeeg recordings with a baseline background voltage of 5 μv or less or the presence of seizures were also considered important signs of encephalopathy [7, 8]. Treatment with hypothermia was restricted to neonates admitted within 6 h after birth, and was applied exclusively in one of the level III NICUs. It was decided to apply total body hypothermia. Duration of therapy was 72 h and depth of hypothermia was set at a core temperature of C, using a rectal temperature probe. All units used the same device, CritiCool (The Surgical Company, Amersfoort, The Netherlands). In the protocol it was strongly advised to use morphine to alleviate stress [9]. Clinical and/or aeeg-detected seizures were treated according to the Dutch neonatal seizure protocol which includes a step-up of phenobarbital, midazolam and lidocaine [10]. Follow-up was planned at a postnatal age of 24 months in the routine follow-up program of the NICUs or by local paediatricians. Followup protocols were not uniform; Griffith s developmental quotients or Bayley scales of Infant and Toddler Development-III were used in most cases. Death, cerebral palsy or developmental delay of more than 3 months was considered an adverse outcome. Patient outcome as well as serious or unexpected complications were recorded anonymously in the web-based hypothermia database and discussed during regular meetings of the Dutch-Flemish Working Group on Neonatal Neurology. For this observational study a waiver of informed consent was obtained. S u b j e c t s 332 patients were treated between 31 January 2008 and 1 January In 2010, when all NICUs offered hypothermia, 166 patients received treatment ( fig. 1 ). Hypothermia was also offered to 24 patients with congenital malformations, such as Down syndrome, congenital pulmonary or cardiac malformations, metabolic disorders, and unspecified syndromes. Some of these abnormalities were not yet diagnosed at the start of hypothermia. Treatment with hypothermia was offered, since it was considered beneficial also in these neonates. Patient data are presented in table 1, comparing surviving patients and those who died. Student s t tests, χ 2 tests or non-parametric tests were used where appropriate. A p value of 0.05 was considered significant. R e s u l t s In the first 3 years, 332 patients were treated, including the 24 neonates with congenital malformations. The number of patients treated per level III NICU ranged from 3 to 71, and increased rapidly after implementation ( fig. 1 ). The remaining part of this paper will describe the 308 patients without congenital malformations or metabolic disorders. The range of gestational age was weeks, birth weight ranged from 1,900 to 5,200 g, and age at start of hypothermia ranged from 45 min to 8 h. In 16 neonates, hypothermia was started later than 6 h after birth. Initially, (passive) hypothermia was not offered during transportation. Recently some units have started to provide hypothermia during transfer by ambulance of the patient from level II to level III units. Effects of Hypothermia Mortality in the patients without congenital malformations was similar in the Netherlands and Flanders with an average of 31.8%. Gestational age, birth weight, and age 16 Groenendaal et al.

3 50 45 Fig. 1. Number of patients treated with hypothermia per 3-month period. Treated with hypothermia Period Table 1. Gestational age, birth weight and start of hypothermia in neonates without congenital malformations Survived Died Significance p value Netherlands 177 (69.1) 79 (30.9) <0.419 Flanders 33 (63.5) 19 (36.5) Sex, male/female 107/103 57/41 <0.24 Gestational age, weeks 39.6± ±1.7 <0.57 Birth weight, g 3,417±627 3,367±580 <0.51 Lowest ph a 6.94± ±0.23 <0.008 Apgar score 5 min b, median (IQR) 3.5 (3) 2 (3.25) <0.001 Thompson score c, median (IQR) 10 (3) 14 (4) <0.001 Start hypothermia, h d 4:13±1:31 4:01±1:24 <0.31 Inborn/outborn 38/172 18/80 <0.95 Seizures during NICU admission 128 (61.0) 78 (79.6) <0.001 Normal (% total) 146 (47.4) Cerebral palsy 21 (6.8) Developmental delay 19 (6.2) Hearing loss 2 (0.6) Unknown follow-up 22 (7.1) Data are expressed as mean ± SD, as percentages in parentheses. a Umbilical cord blood gas, or postnatal blood gas from artery or vein. Not reported in 125 (37 died, 88 survived). b Not reported in 14 (8 died, 6 survived). c Highest values before hypothermia. Not reported in 130 (43 died, 87 survived). d Not reported in 44 (14 died, 30 survived). at which hypothermia was started was similar in the neonates who died and in those who survived. The mortality in pati ents without congenital malformations (31.8%, 95% confidence interval ) is not significantly different from the mortality reported in the RCTs (26.7%, table 2 ). Of the 308 patients without congenital malformations, 42 (13.6%) had a serious adverse outcome reported: cerebral palsy in 21, delayed development of more than 3 months in 19 patients, and severe hearing loss in 2. Milder abnormalities were hemianopia in 1 patient, and Erb s paresis in 3 patients. Introduction of Hypothermia 17

4 Table 2. Outcome of hypothermia in the Netherlands and Flanders compared to data of large randomized trials of therapeutic hypothermia in asphyxiated full-term neonates Reference (first author) Year Hypothermia Adverse outcome in survivors n (% of total; % of survivors) Mortality n (%) Combined adverse outcome n (%) 95% CI Shankaran [12] (20.6; 26.9) 24 (23.5) 45 (44.1) Gluckman [11] (21.3; 31.9) 36 (33.3) 59 (54.6) Azzopardi [5] (19.6; 26.4) 42 (25.8) 74 (45.4) Zhou [13] (11.0; 13.8) 20 (20.0) 31 (31.0) Simbruner [24] (13.2; 21.2) 20 (37.7) 27 (50.9) Jacobs [14] (26.2; 35.0) 27 (25.2) 55 (51.4) Total (19.3; 26.3) 169 (26.7) 291 (46.0) Netherlands/Flanders Excluding (13.6; 20.0) 98 (31.8) 140 (45.5) Congenital malformations (n = 24) Unknown follow-up 22 Follow-up was unknown in 22 patients. Clinical variables in these 22 were comparable to the other surviving patients (data not shown). The total adverse outcome (death or cerebral palsy, moderate or severe developmental delay, or hearing loss) percentage of the patients without congenital mal formations is 45.5% (95% confidence interval %), which is comparable to that of the RCTs in table 2 (46.0%). In 1 out of the 3 patients with a gestational age <36 weeks, outcome was good (1 unknown), and in 5 out of 15 patients with a gestational age >35.9 weeks and a birth weight <2,500 g, outcome was good (2 unknown). Apgar scores at 5 min and ph values were significantly lower and Thompson scores significantly higher in the non-surviving neonates. However, many ph values and Thompson scores were not recorded (see Discussion). C ompli c at ion s Complications in our patients which may be attributed to hypothermia were subcutaneous fat necrosis (n = 2), overcooling (temperature <33.0 C; n = 5), and thrombosis of a subclavian vein (n = 1). Severe hypotension and persistent pulmonary hypertension were reported but were mostly considered part of the medical history including group B streptococcal septicaemia or meconium aspiration syndrome. Neonates with Congenital Abnormalities Of 24 newborns with abnormalities who were cooled, follow-up data are known of 22. Nine died, 2 had cerebral palsy, and 6 delayed development (including those with trisomy-21). Discussion Moderate therapeutic hypothermia has been implemented in the Netherlands and Flanders rapidly and successfully since the publication of two large trials [11, 12]. In a relatively short period of time, more than 330 patients have been treated, including neonates with congenital malformations who have been excluded from the trials. Mortality in the neonates without congenital malformations was still high with 31.8%, and not different between the Netherlands and Flanders. Mortality was slightly, although not significantly, higher than the mortality reported in some of the large international multicentre trials with exclusively moderate to severe encephalopathy cases [5, 12]. Since the majority of deaths resulted from redirection of care, the relatively high mortality in the Netherlands and Flanders might reflect policies of care that may be different from those units that contributed to the randomised clinical trials. Redirection of care was always based on the combination of severe clinical, aeeg and abnormalities on brain imaging. In addition, in the two trials with the lowest mortality [13, 14], patients with hypoxic-ischaemic encephalopathy grade 1 according to Sarnat were included. These neonates were not treated with hypothermia in the Netherlands and Flanders according to the current protocol. The adverse outcome combining death and severe impairments is comparable to that of the RCTs reported in table 2. This is very reassuring since it was feared in our countries that due to the new therapy more seriously impaired neonates would survive. 18 Groenendaal et al.

5 Time to start hypothermia was an important item of the database. Even in two small countries with rather short travelling distances to the nearest NICU, time to start hypothermia was approximately 4 h. We cannot exclude that the outcome may be improved by earlier commencing hypothermia. In addition, during the first year, hypothermia was not provided during transportation of the patient to the NICU, since neonatologists were concerned that persistent pulmonary hypertension of the neonate might by aggravated by hypothermia. At present, most centres provide passive cooling with temperature monitoring during transportation. Excessive cooling during transportation was reported in 1 patient. This emphasises the need for careful temperature monitoring during transportation [15, 16]. Complications of hypothermia were rare and similar to those reported by others, such as subcutaneous fat necrosis [17 20]. Careful observation of the skin of patients during total body hypothermia may prevent this rare but important complication. Overcooling was seen infrequently, possibly through the use of a similar servo-controlled cooling device in all units. Hypothermia was offered to neonates who were not involved in clinical trials, such as neonates with Down syndrome or congenital malformations. Although neonates with these congenital problems were not included in clinical trials for obvious reasons, clinicians in the NICUs decided that there was no reason to withhold hypothermia from these patients. Specific problems of hypothermia in these patients were not reported, and use of hypothermia appears not to be different in these patients. Further studies, however, are needed to demonstrate whether hypothermia is useful in neonates with a gestational age <36 weeks or a birth weight <1,800 g. Also, starting hypothermia at a later time point than 6 h after birth has not been proven to be effective yet. Trials are commenced addressing these questions ( In daily practise and in contrast with guidelines, hypothermia has been offered to neonates with a gestational age <36 weeks (n = 3) and later than 6 h after birth (n = 16). In experiments, delayed hypothermia might be harmful [21, 22]. There are several limitations of the present study. In the present population it was impossible to present uniform criteria of perinatal asphyxia, e.g. umbilical cord blood gases are not performed routinely in the Netherlands. In addition, in most level II hospitals only capillary blood gases were obtained postnatally, therefore many blood gas values were missing. Definitions of perinatal asphyxia included a low Apgar score at 5 min, and not at 10 min as in the TOBY trial. Although more neonates might be labelled asphyxiated than in the TOBY trial, the presence of moderate to severe encephalopathy was required to qualify for treatment with hypothermia making the results comparable to those of the RCTs. Neonatal encephalopathy was based on either clinical signs of encephalopathy, including a depressed level of consciousness or seizures, a Sarnat II or III score [23], a high Thompson score [6], or on aeeg criteria [5], which is different from another large randomised trial where only one criterion (clinical encephalopathy [12] ) was used. Although the Thompson score used in the neo. neuro.network-trial [24] was an inclusion criterion for treatment with hypothermia, many units started hypothermia without actual recording of Thompson scores. Nevertheless, moderate or severe encephalopathy needed to be present clinically before the start of hypothermia. To the best of our knowledge, clinical examination and aeeg have not been compared for assessing the severity of encephalopathy and selecting neonates for treatment with hypothermia. A second limitation is that follow-up has not been performed uniformly which may result in less precise outcome data compared to the trials. Still, whichever method was chosen for follow-up assessments, a 3-month delay at 24 months indicates a developmental delay of at least 1 standard deviation (SD) whichever method of follow-up was used. Thirdly, whereas mortality has been documented during the last two decades in The Netherlands Perinatal Registry, there are no historical data of long-term neurodevelopmental outcome of full-term neonates with perinatal asphyxia in the Netherlands. The effects of the use of therapeutic hypothermia on long-term neurodevelopmental outcome can therefore not be compared to neurodevelopmental outcome in the previous years. The effects on mortality do not appear to be very different from the years before hypothermia. In most cases, mortality is a result of redirection of care because of serious, irreversible brain injury. Results of neurodevelopmental outcome after hypothermia, however, are completely comparable to those of the international trials. Another limitation is that the information in the database is not extensive. No detailed information about patients such as aeeg findings can be presented. Hopefully future linkage to The Netherlands Perinatal Registry will enable us to provide detailed information on patients treated with therapeutic hypothermia. Brain imaging, such as MRI, was not performed routinely in all units in Introduction of Hypothermia 19

6 these patients. No financial resources are available for structured follow-up of these patients. Insurance companies need to be asked to finance future follow-up to provide more detailed information on the effects of this treatment. This is relevant, since more subtle deviations may become apparent at later ages, especially in neonates with less severe perinatal asphyxia [25]. Conclusion The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful. To these patients a new treatment could be offered that alleviated the effects of perinatal asphyxia on the brain and resulted in an overall good outcome in those patients who survived perinatal asphyxia. Results are comparable to those of the large international trials. Acknowledgement The authors thank all intensive care nurses for the active involvement in introducing hypothermia in our two countries. Members of the Dutch-Flemish Working Group on Neonatal Neurology T.R. de Haan, B.T. Poll-The, L. Toledo, J.M. Niermeijer, Academic Medical Center, Amsterdam, The Netherlands; R.J. Vermeulen, I.A. Zonnenberg, F. van den Dungen, VU University Medical Center, Amsterdam, The Netherlands; S. Laroche, University Hospital, Antwerp, Belgium; A. Casaer, AZ St. Jan Bruges- Ostend AV, Bruges, Belgium; E. Peters, P. van Zwieten, Juliana Children s Hospital, The Hague, The Netherlands; K. de Coen, A. Zecic, University Hospital, Gent, Belgium; A. Bos, O.F. Brouwer, H.J. ter Horst, R. Lunsing, D. Sival, University Medical Centre Groningen, Groningen, The Netherlands; L. Laan, C.M. Peeters- Scholte, W.C.G. Plandsoen, M. Rijken, S.J. Steggerda, Leiden University Medical Center, Leiden, The Netherlands; G. Naulaers, E. Ortibus, University Hospital, Leuven, Belgium; J.S.H. Vles, A.W.D. Gavilanes, Maastricht University Medical Centre, Maastricht, The Netherlands, K.D. Liem, L. Sie, K. 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