Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns

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1 Paediatrics & Child Health, 2017, doi: /pch/pxx062 Original Article Advance Access publication 23 May 2017 Original Article Initiation of passive cooling at referring centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns Brigitte Lemyre MD 1, Linh Ly MD 2, Vann Chau MD 3,4, Anil Chacko MD 2, Nicholas Barrowman PhD 5, Hilary Whyte MD 2,4, Steven P. Miller MD 3,4 1 Department of Pediatrics, Children s Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario; 2 Department of Pediatrics (Neonatology), The Hospital for Sick Children and University of Toronto, Toronto, Ontario; 3 Department of Pediatrics (Neurology), The Hospital for Sick Children and University of Toronto, Toronto, Ontario; 4 Neurosciences & Mental Health Research Institute, Toronto, Ontario; 5 Children s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario Correspondence: Brigitte Lemyre, Division of Neonatology, Department of Pediatrics, Children s Hospital of Eastern Ontario, Ottawa, Ontario, K1H 8L1. Telephone , fax , blemyre@toh.on.ca This research originated at the Children s Hospital of Eastern Ontario and at The Hospital for Sick Children. The Research Ethics Boards of both institutions approved the study. Abstract Objective: To identify factors associated with early initiation and achievement of therapeutic hypothermia (TH) in newborns with hypoxic ischemic encephalopathy (HIE). Methods: Retrospective cohort study of newborns who received TH according to National Institute of Child Health and Human Development (NICHD) criteria in two academic level 3 Neonatal Intensive Care Units (NICU) between 2009 and All infants were transported by a neonatal transport team (NNTT). Multivariate linear regression including who initiated cooling and degree of resuscitation in the model was performed. Results: Two hundred and seven infants were included. Waiting for advice from a tertiary care NICU was independently associated with a 50 minute delay in the median time of initiation of TH. The need for extensive resuscitation (cardiopulmonary resuscitation [CPR] or epinephrine) was independently associated with a reduction of 43 minutes in the median time to reach target core temperature. Log-transformed time to initiation of TH was associated with time to reach target core temperature (P<0.001). A doubling of time to initiation of TH corresponds to a 24% (95% CI 18% to 30%) increase in median time to reach target core temperature. Conclusions: Initiating passive cooling at the referring centre, before transfer, is critical to faster achievement of target core temperature in asphyxiated infants. Greater outreach education and development of clinical care pathways are needed to improve optimal delivery of TH to enhance outcome. Keywords: Asphyxia; Hypothermia; Newborn. BACKGROUND Systematic reviews of therapeutic hypothermia (TH) to a core temperature of 33 to 34 C for infants with hypoxic ischemic encephalopathy (HIE) report a reduction in the risk of death or disability at 18 to 24 months, whether the encephalopathy is moderate or severe (1,2). Data from experimental models of HIE show that the sooner cooling is initiated, the more likely it is to be beneficial. Initiation of TH 90 minutes after reperfusion in a sheep model was associated with less white matter injury compared to initiation at 5.5 hours whereas TH initiated after seizures, at 8.5 h did not prevent brain injury (3,4). Similarly, in a large clinical trial, a trend toward improved outcomes was found in infants cooled prior to 4 hours of life (5). Therapeutic hypothermia is a standard of care in Canada, for infants who meet eligibility criteria. The Canadian Paediatric Society s Fetus and Newborn Committee has recommended that TH be offered only in level 3 Neonatal Intensive Care Units (NICUs) who have resources and expertise to treat multiorgan failure commonly associated with perinatal asphyxia and HIE and possible complications of TH (6). As tertiary care NICUs across Canada serve as the referral centre for often vast geographical areas, initiation and achievement The Author Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please journals.permissions@oup.com 264

2 Paediatrics & Child Health, 2017, Vol. 22, No of target core temperature in a timely fashion can be challenging. The clinical presentation of the patient, level of expertise of the physician on site at the regional/community centre, distance to travel and availability of a transport team are some of the factors that may influence the recommendation to and timing of initiation of cooling. The objective of this study was to identify factors associated with early initiation (time to initiation of TH, or when the warmer was turned off or passive cooling started) and achievement of TH (when core temperature was within range of 33 to 34 degrees) in two Canadian tertiary NICUs serving exclusively outborn neonatal populations. Study design We retrospectively reviewed two cohorts of asphyxiated newborns who received TH. Newborn infants admitted for TH either at The Hospital for Sick Children (SickKids), Toronto, Canada ( January 2009 to December 2013) or the Children s Hospital of Eastern Ontario (CHEO), Ottawa, Canada (October 2009 to December 2013), both academic tertiary (level 3) NICUs, were included. The study protocol was approved by the local Research Ethics Committees of both institutions. Population Infants 35 weeks gestation by best obstetric estimate and <6 hours of age were eligible if they met criteria A or B: A) cord ph 7.0 or base deficit 16 or B) cord ph 7.01 to 7.15 or base deficit 10 to 15.9 and a history of an acute perinatal event (cord prolapse, placental abruption ) and either an Apgar score 5 at 10 minutes or at least 10 minutes of positive pressure ventilation. Infants who met criteria A) or B) and also had signs of moderate to severe encephalopathy (seizures or at least three findings on clinical exam, as described in the National Institute of Child Health and Human Development (NICHD) study (7,8), were eligible to receive TH. Infants with severe intrauterine growth restriction (weight <1800 g), evidence of head trauma or intracranial hemorrhage, clinically significant coagulopathy despite treatment and moribund infants or infants with major congenital or genetic abnormalities, in whom no further aggressive treatment was planned were excluded as they did not meet criteria to receive TH. Intervention Both academic centres serve large geographical areas, with dedicated neonatal transport teams (NNTT) and established protocols for TH and the management of neonates suspected to have hypoxic ischemic encephalopathy. The process to transfer an infant with perinatal asphyxia and HIE first involves physicians in regional centres (level 1 or level 2 neonatal units) to call their tertiary care NICU to seek advice and activate the NNTT. The call is answered by a neonatology fellow and/or a transport nurse/coordinator with further consultation with a neonatologist. Advice regarding initiation of passive cooling or to await further evaluation by the NNTT, once on site, is provided, based on the clinical scenario, findings on clinical exam, availability of the NNTT, distance to travel and likelihood of the baby arriving at the tertiary care NICU before 6 hours of life. Alternatively, some physicians in regional centres begin passive cooling prior to initiating the phone call to their tertiary NICU. If not already initiated by the referring centre, the NNTT initiates TH passively by turning off the overbed warmer. Core temperature (rectal) is measured every 15 minutes. If passive cooling alone fails to lower core temperature, the NNTT begins active cooling, as described by Kendall et al. (9). Active cooling is performed by applying cold pack(s) across the chest and/or under the head and shoulders, as described by Jacobs et al. (10). Once admitted to the NICU, TH is continued by placing the infant on a cooling blanket (Blanketroll 3) with constant monitoring of rectal temperature, with the goal to maintain core temperature between 33.0 and 34.0 C. Data collected Data was obtained by reviewing patients health records and included gestational age, gender, birth weight, Apgar scores, cord ph, perinatal complications, details regarding resuscitation, mode of delivery, degree of encephalopathy, timing of initiation of passive cooling (defined as time when the over bed warmer was turned off) and who initiated passive cooling (physician in birth centre prior to calling NICU, physician in birth centre after advice from neonatology fellow/neonatologist, NNTT or after admission to the NICU). Outcomes This study had two primary outcomes: the age, in hours, when passive cooling was initiated, and the age when the target core temperature of 33.0 to 34.0 C was achieved. Statistical analysis Descriptive statistics were used to summarize the study sample. For discrete variables, frequencies and percentages were computed. For continuous variables, the mean, standard deviation, median, interquartile range and range were computed. Since the distributions of time to initiate TH and age when target core temperature was reached were skewed, these variables were log transformed prior to analysis, resulting in approximately normal distributions. Backtransformed model coefficients can therefore be interpreted as medians. The model for log-transformed time to initiation of TH included the following as predictors: type of resuscitation, who initiated TH, site, birth weight and gestational age. The model for log-transformed age when target core temperature was reached included the following as predictors: log-transformed time to initiation of TH, type of resuscitation, who initiated TH, site (SickKids or CHEO), birth weight, gestational age and severity of encephalopathy on admission. RESULTS Two hundred and sixty-eight infants were included in the study. Twenty-five per cent of the patients had a definitive time to onset of brain injury (e.g., placental abruption, cord prolapse, uterine rupture). Table 1 provides baseline characteristics and intervention information on each cohort and the combined cohort. Apgar scores at 10 minutes were lower at CHEO at baseline. There was also a difference between the cohorts regarding who initiated TH: At SickKids, it was most often initiated immediately postadvice from the tertiary care NICU, whereas at CHEO, it was most often initiated by the NNTT. TH was initiated at a median of 1.9 hours of life (2.1 hours at CHEO and 1.8 hours at SickKids) and core temperature was reached at a median of 4.8 hours of life (5.6 hours at CHEO and 4.8 hours at SickKids). One hundred and eighty-nine infants were cooled in 6 hours. For 79 infants (29%), we achieved hypothermia (core temperature 33 to 34 C) beyond 6 hours of life. There is no difference (post hoc analysis) in the 10 minutes Apgar score, cord ph, resuscitation score or SNAPPE score of infants who achieved hypothermia before or after 6 hours. There is no clinically meaningful difference between the severity of encephalopathy on admission between these infants either. Forty-six babies (17.2%) in the cohort died; 12 (19.7%) at CHEO and 34 (16.4%) at SickKids. In a multiple regression model for log-transformed time of initiation of TH, the need for extensive resuscitation (cardiopulmonary resuscitation [CPR] or epinephrine) was independently associated with initiating TH earlier, by a median of 1.5 hours. Waiting for advice from a tertiary care NICU was independently associated with a delay of 50 minutes (median) in the time of initiation of TH, while waiting for the NNTT was independently associated with a median delay of 177 minutes (Figure 1). Site, birth weight, Apgar scores at 5 and 10 minutes, cord ph and gestational age were not statistically significant. In a multiple regression model for log-transformed age when target core temperature was reached, need for extensive resuscitation (CPR or epinephrine)

3 266 Paediatrics & Child Health, 2017, Vol. 22, No. 5 Table 1. Baseline characteristics and interventions Baseline characteristics CHEO N=61 SickKids N=207 Overall N=268 P value Gestational age (weeks); mean (SD) 39.0 (1.6) 38.8 (1.7) 38.8 (1.7) 0.31 Birthweight (kg); mean (SD) 3.3 (0.6) 3.4 (0.7) 3.3 (0.6) 0.58 Apgar score at 10 min; median (interquartile range) a 4 (3 5) 5 (3 6) 4.5 (3 6) 0.03 Arterial cord gas ph; mean (SD) b 6.92 (0.16) 6.93 (0.17) 6.92 (0.17) 0.84 Base excess; mean (SD) 16.3 (6.0) 17.5 (7.6) 17.2 (7.2) 0.28 Degree of encephalopathy on admission Mild (Stage 1) 16 (26%) 49 (23.7%) 65 (24.2%) 0.44 Moderate (Stage 2) 30 (49.2%) 128 (61.8%) 158 (59%) Severe (Stage 3) 11 (18%) 30 (14.5%) 41 (15.3%) Interventions Resuscitation; n (%) Cardiopulmonary resuscitation or epinephrine 18 (29.5%) 78 (37.7%) 96 (35.8%) Endotracheal tube 22 (36.1%) 97 (46.9%) 119 (44.4%) Less invasive 21 (34.4%) 32 (15.5%) 53 (19.8%) Who initiated cooling; n (%) c Centre before advice 23 (37.7%) 45 (22.1%) 68 (25.7%) Centre after advice 13 (21.3%) 122 (59.8%) 135 (50.9%) Neonatal transport 23 (37.7%) 25 (12.3%) 48 (18.1%) NICU 2 (3.3%) 12 (5.9%) 14 (5.3%) NICU Neonatal Intensive Care Unit; SD Standard deviation. a Apgar score was missing for 16 subjects in the SickKids site for a total of 16 missing values overall. b Arterial cord gas ph was missing for 2 subjects in the CHEO site and 29 subjects in the SickKids site for a total of 31 missing values overall. c Information on who initiated cooling was missing for 3 subjects in the SickKids site Figure 1. Time of initiation of therapeutic hypothermia according to who initiated it. Note the logarithmic scaling of the vertical axis. was independently associated with a reduction of 43 minutes in the median time to reach target core temperature. Degree of encephalopathy was also associated with time to reach target, with severe encephalopathy reaching core temperature 80 minutes (P=0.004) sooner and moderate encephalopathy 45 minutes sooner (P=0.05) than mild encephalopathy cases. Log-transformed time to initiation of TH was associated with time to reach target core temperature (P<0.001). A doubling of time to initiation of TH corresponds to a 24% (95% CI 18% to 30%) increase in median time to reach target core temperature (Figure 2). Each additional kilogram of birth weight was independently associated with a 12% increase in median time to reach target core temperature (95% CI 3% to 22%). Waiting for advice from our tertiary care centres (P=0.37), site (P=0.07) and gestational age (P=0.57) were not independently associated with time to reach target core temperature. In our cohorts, six infants have recorded temperatures between 30.0 and 32.0 C and 1 reached 29.7 C prior to NICU admission. No infant had associated complications, such as hypotension, hypoxemia or hemorrhage. DISCUSSION The optimal time window to initiate TH is thought to be within the first 5.5 to 6 hours after birth (11). It is unclear whether later onset of TH is useful and there is animal data suggesting harm after 12 hours (12). Recent evidence suggests that the sooner cooling is commenced, the more likely it is to be beneficial (13). In a recent cohort study of 80 infants, Thoresen et al. report psychomotor development index (PDI) scores at 18 to 20 months 11 points higher in infants cooled 3 hours of life as opposed to those cooled over 3 hours of life (14). We

4 Paediatrics & Child Health, 2017, Vol. 22, No Figure 2. Correlation between time of initiation of therapeutic hypothermia and age when target temperature was achieved. Note the logarithmic scaling of the horizontal and vertical axis. achieved target core temperature at 4.8 hours, which compared to the NICHD study (5.5 hours) and Australian ICE trial (6 hours) (7,10). In a large combined cohort of infants who received TH for HIE, we observed that the most important modifiable factor associated with earlier achievement of target core temperature is earlier initiation of passive cooling. Awaiting advice from a tertiary care centre or the arrival of the NNTT significantly delayed the initiation of TH. The delay in advice seemed related to the need to contact the neonatologist after initial discussions with the community physician, especially for less clear-cut or milder cases of encephalopathy. It can be difficult to determine the degree of encephalopathy during a phone call; one must weigh the risks of instituting TH in a patient that does not need it against the risks of noninstituting it in a patient who might benefit. A recent cohort study points out that 40% of infants not cooled due to mild encephalopathy had brain lesions on MRI (15). Both centres have changed their process to answer transport calls since 2014, with a neonatologist now on the bridge line from the beginning. The impact of such change will be measured in the future. More extensive resuscitation, a nonmodifiable factor and a marker of illness severity, likely triggers clinicians to think about initiating passive cooling earlier. An earlier study observed that sicker infants with possibly more brain injury also cool down easier, as a natural protective mechanism (16). We also observed that severity of encephalopathy was associated with the time to reach target core temperature. Birth weight, another nonmodifiable factor, was negatively associated with time to target core temperature. Although not reported previously, this makes physiological sense, as the more body weight and surface, the more time it is likely to take to lower body temperature, especially when passive cooling is initially used. In the NICHD trial, it was reported that smaller babies were more likely to have a recorded temperature under 32 C during cooling (17). Concerns have been raised regarding initiation of TH outside of tertiary care centres or during transport, due to the possibility of over-cooling infants, which has been reported in up to one third of infants in some cohorts (18 20). Tertiary care NICUs in Ontario cover large geographical areas. Waiting for cooling to be initiated by the NICU would preclude many infants from receiving TH within the acceptable time window. In a trial using servo-controlled cooling devices adapted for transport, more infants stayed within target temperatures (21). However they are expensive and can be cumbersome to carry. One such device has only been approved by Health Canada earlier this year. Despite the fact that both units have similar policies regarding eligibility criteria for TH, variations in practice were identified, specifically in the process to initiate passive cooling. The decision to advise a community physician to initiate passive cooling is a delicate one, taking into account the clinical picture, experience of the physician, resources in the community hospital, availability of the NNTT and estimated time to arrive in community hospital. Given that passive cooling was the only approach recommended for community hospitals and that it inconsistently achieves a core temperature < 34.0 C, variations in distance to travel may account for the difference observed in time to achieve target temperature between the two sites (9,22). One limitation of the study is its retrospective nature. The cohorts were also of very uneven size, by nature of the size of the institutions. As such, we did not have enough power to detect an effect due to site in our regression model. The distance to travel varies between the two geographical areas served by SickKids and CHEO. This distance, which may account for differences in time to reaching target core temperature, was not captured in our data collection. While not a limitation, it must be acknowledged that the population reflects a heterogeneous condition, in keeping with the Vermont-Oxford Network observation (23).The strengths of the study include the size of the cohort in real-world clinical practice, where all infants received TH and the inclusion of two institutions, which increases generalizability of the findings. CONCLUSION Initiating passive cooling at the referring centre, before transfer, is critical to earlier initiation and faster achievement of target core temperature in asphyxiated infants. Having consultant neonatologists to answer the initial call for advice/ transfer may enhance the speed with which a decision to provide TH is reached. Greater outreach, education and development of clinical care pathways, with emphasis on regular temperature monitoring, are needed to improve optimal delivery of TH in a safe fashion and, ultimately, to improve outcomes. 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