Leveraging Telemedicine to Reduce Disparities in Time to Initiation of Therapeutic Hypothermia in Rural Settings; a Pilot Feasibility Study
Phase: NA
Conditions: Neonatal Encephalopathy
Sponsor: MaineHealth

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Title:  Telemedicine to Improve Use of Therapeutic Hypothermia in Rural Settings 
    
Clinicaltrials.gov #: NCT03706417
Background: Neonatal Encephalopathy (NE) is a clinical syndrome affecting between 2-5 per 
1000 live births1. Abnormalities in the newborn neurological exam are the hallmark of NE which 
occurs due to the combined effects of lack of oxygen and blood flow to the brain around the 
time of birth. As many as 15-20% of infants with NE do not survive their brain injury and 25% of 
survivors experience substantial neuro-developmental deficits including intellectual disability, 
cerebral palsy, epilepsy and hearing or vision loss2. Until recently, infants suspected of having 
NE were treated with supportive care alone as there were no known therapeutic interventions. 
Approximately ten years ago, however, treatment options dramatically changed with the 
introduction of therapeutic hypothermia (TH), a novel neuroprotective therapy which involves 
deliberately decreasing the infant’s body temperature to 33.5°C for 72 hours. The early safety 
studies of TH3, 4 were published in the late 1990’s and the positive results of the first efficacy 
trials in 20055, 6 moved this promising therapy into mainstream clinical practice. In a meta-
analysis of 8 published clinical trials, TH was associated with a 25% decrease in the aggregated 
outcome of all-cause mortality and severe neurological abnormality and, as such, has become 
the standard of care for these critically ill infants7. 
Maine Medical Center (MMC), a tertiary care center with the only Neonatal Intensive 
Care unit (NICU) in the southern part of the state, employed TH for the first time in 2008. 
Eastern Maine Medical Center (EMMC) 
is the only tertiary care center in the 
northern part of the state and began 
using TH in 2009. In 2012, a Neonatal 
Neurology Program was started at MMC 
and this program was extended to 
EMMC through a unique and 
unprecedented collaboration in 2013. At 
both institutions, the number of infants 
treated with TH gradually increased with 
improved recognition of the mild to 
moderate forms of NE (Figure 1). While educational outreach efforts have successfully 
increased awareness of the symptoms of NE at both tertiary care centers in the state, infants 
who may benefit from TH are still not always recognized in a timely fashion. Missed 

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opportunities for TH can occur when an infant’s clinical presentation is less severe compared to 
those included in the original randomized controlled trials. 
While TH must be initiated within the first 6 hours of life, there is solid evidence for 
improved outcomes in those for whom TH is initiated earlier. As a result of exceptional 
preclinical animal models of NE in the fetal lamb and piglet, there is a robust biochemical 
understanding of the temporal evolution of brain injury in neonates. TH must be initiated prior to 
6 hours of life to intercede upon the second stage of injury with its features of excitotoxicity and 
associated cascade of inflammatory mediators that cause seizures and ultimately cell death10. 
Animal models have demonstrated lack of neuronal rescue if TH is initiated late (8.5 hours after 
ischemic insult)11 and have also demonstrated improved neuronal rescue with earlier initiation of 
TH at less than 3 hours12.  In a prospective cohort study, infants treated with TH prior to three 
hours of life were found to have improved motor function compared to those whose treatment 
was initiated after 3 hours13.  In one of the first clinical trials of TH, the relative risk of death or 
severe abnormal neurological outcome was decreased in those for whom TH was started before 
4 hours of life14. This combination of animal and human data suggests that mechanisms to 
improve the rapid initiation of TH, such as through a teleconsult, may lead to improved 
outcomes for infants with NE. In the proposed study, we hypothesize that use of telemedicine 
consults between a tertiary care center and a community hospital can improve the assessment, 
management, and short-term outcomes of infants with NE by decreasing delay in the initiation of 
TH through rapid and accurate assessment of NE.  
 
 
Overview of the Study Design:  
We propose to conduct a pilot intervention trial assessing the feasibility of decreasing the time 
to initiate TH for infants born in community hospitals who receive a Maine Neonatal 
Encephalopathy Teleconsult (Maine NET) compared 1:2 to with matched historical controls from 
the MMC database. We will also qualitatively assess provider experience of Maine NET 
(Appendix C) via zoom interviews and the parent perception of the process of having a 
telemedicine consult and participating in research in the setting of a critically ill newborn 
(Appendix D).  
 
Study Goals: 
The goals of this study are to: 
1. Utilize telehealth for Neonatal Encephalopathy consults in community hospitals to 
determine if telemedicine can reduce time to initiation of TH treatment 

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2. Capture parent experience of telemedicine consult and remote consent process 
3. Capture delivery hospital clinicians’ (from community hospitals and tertiary care centers) 
experience of utilizing telemedicine for neonatal neurological exams to assist in decision 
making for therapeutic hypothermia 
4. Identify themes from parent and clinician experiences to identify areas of improvement 
for future consultations 
5. Publish research findings 
6. Utilize data to improve future telehealth consultations 
 
Human Subjects:  
Recruitment sites: Multiple community hospitals in Maine have been offered the opportunity to 
participate in this feasibility study and all centers have provided letters indicating a strong desire 
for participation. See site list for recruiting community hospitals.  
Inclusion criteria:  Infants in need of Maine NET will be identified by the “Time is Brain” poster 
(see Appendix A) that was created and distributed across the state to all newborn nurseries at 
community hospitals in 2016. This poster is in routine clinical use and is intended to assist in the 
identification of infants with symptoms of NE. Rather than having inexperienced providers at 
community sites examine inclusion criteria for TH and make a determination of eligibility, this 
poster uses a color scheme in which the green designation denotes characteristics of low-risk 
infants who are not in need of consultation, the yellow designation denotes characteristics of 
moderate risk infants who should have consultation and who may need transfer, and the red 
designation denotes characteristics of high risk infants who are critically ill and will benefit from 
immediate consultation and transfer to a tertiary care center. Infants included in this study will 
be born at a community hospital, will be in either the yellow or red category on the “Time is 
Brain” poster, will be younger than 6 hours of age at the time of the consultation. Infants in the 
historical control group will be selected from the MMC database and matched according to 
gender, gestational age, severity of presenting encephalopathy (mild, moderate or severe) and 
community site at which the infant was born. Matching will occur after the 35 Maine NET 
subjects have been treated with TH. Infants assessed by Maine NET who are not treated with 
TH will not be compared to the control group. The control subjects will be chosen by an 
investigator blinded to the time to initiate TH and outcome of the infants from the database. 
Infants used for historical controls must have a time of TH initiation recorded in the MMC 
Therapeutic Hypothermia database. Any parent of any neonate, whether treated with 
hypothermia or not, will be eligible to participate in an interview about their telemedicine and 
research experience.  

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Exclusion criteria: Infants older than 6 hours at the time Maine NET is requested and infants for 
whom TH is not an appropriate therapy (e.g. due to premature birth or moribund status) will be 
excluded.  
Number of subjects: We intend to recruit a total of 125 infants from the participating centers. 
Each center has referred between 0 and 6 infants for TH annually for the past 4 years and, by 
involving this number centers, it is likely that the targeted goal of 125 study subjects is 
achievable (Table 1). We have increased the number from 10 to 20 and then to 40 and then to 
100 due to the fact that not all recruited infants will be treated with TH and to have an adequate 
sample size to make statistical comparisons with historical controls. We anticipate that by 
recruiting 125 infants we will be able to analyze data in the best way possible. We will recruit no 
more than 30 parents for the interviews. 
Power calculation: With new funding from the COBRE grant, this study has expanded to recruit 
125 subjects of whom we expect 30 to have been treated with hypothermia. 30 subjects in each 
group would yield 95% power to detect a 1hour difference in time to initiate TH. 
Informed consent: Prior to the onset of any research related activities, informed consent for the 
main study will be obtained from one of the infant’s parents through the telehealth interface.  A 
paper copy of the informed consent document (ICF) will be provided to the parent and will be 
described in full detail by Dr. Craig who will answer all the parent’s questions thoroughly.  The 
parent will then sign and date and time the ICF document if they wish to have their infant 
participate.  Parents will be asked to initial the informed consent document if they wish to be 
contacted about participation in the parent interview portion of the project. The physician at the 
participating hospital will witness the parent signature and also sign, date and time the ICF on 
the witness line. Dr. Craig will then sign a separate copy of the ICF and date and time it as well.  
The consent form that the parent signed will be transported with the baby to MMC or faxed to 
MMC by providers from the community hospital and will be conjoined with the copy signed by 
Dr. Craig and then uploaded into the infant’s electronic medical record.  
 
If a parent chooses not to participate, Dr. Craig will thank the family for considering and the 
standard of care consult will occur without employing telemedicine. The current standard of care 
for infants born in community hospitals is to have the provider attending the delivery 
(pediatrician or family medicine doctor) call the NICU at MMC to describe the cord gas 
parameters, the Apgar scores and the level of NE in the infant as well as any other clinically 
relevant data. The Neonatologist at MMC may suggest that the community provider “passively 
cool” the newborn per our standard guideline (see Appendix B) until the transport team arrives 
to make the actual determination of whether the infant will require TH treatment. 

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Compensation: Subjects will not be compensated for participation. 
 
Follow-up plan: All subjects treated with TH will be offered routine neurological follow up at ages 
3, 6 and 12 months per usual clinical routine after treatment with TH. These follow up visits are 
to insure maximization of early intervention services if they are needed. These follow up 
appointments are part of standard clinical care.  
 
Primary Outcome: Hour of life in which TH is started. The “zero hour” for TH is recorded in the 
infant’s electronic medical record and refers to the time at which the infant starts the TH 
protocol.   
 
Secondary Outcomes: Time at which passive cooling is initiated, temperatures recorded by 
the community hospital during passive cooling, in–hospital mortality, presence of seizures on 
electroencephalogram (EEG) and brain injury on MRI. The EEG is a routine part of the clinical 
care of an infant treated with TH and is applied for the 72 hours during TH. The PI is the person 
primarily responsible for interpreting the results of the EEG. The MRI is also part of the routine 
clinical care of infants treated with TH and is interpreted by a neuroradiologist who is unaware of 
the status of the infant regarding whether Maine NET was utilized.  
 
Analysis: Baseline differences in selected characteristics between infants assessed by Maine 
NET versus historical controls will be compared using Fisher’s exact tests for categorical 
variables and t-tests, or their non-parametric equivalents for continuous variables. The primary 
analysis will compare differences in the time to achieve TH between infants assessed by Maine 
NET versus historical controls using a t-test. For secondary outcomes of mortality, seizures on 
EEG, and brain injury on MRI, chi-square or Fisher’s exact test will be used for analysis of the 
frequency of these adverse outcomes.  
 
Potential limitations and contingencies: Maine NET has been successfully locally 
implemented at MMC with 11 successful teleconsults already performed. There are IT and other 
challenges involved in implementing Maine NET at outside hospitals, but, as should be evident 
from the enthusiastic letters of support, these institutions are more than eager to have this level 
of assistance and will work collaboratively to resolve challenges. If for some reason the Maine 

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NET cannot happen, providers will always default to the standard of care which is a phone call 
for assistance with decision making.   
 
Potential Risks and Benefits: When working with PHI identifiers, there is always a risk of loss 
of confidentiality. This risk will be minimized in this study through use of a HIPAA compliant 
RedCap system, limited password-protected access, and use of a Master List, which will 
remove all PHI identifiers from the data that is used for analysis. Interview recordings will be 
stored on encrypted flash drives and within the MaineHealth Protected file share folder, which 
only the study team has access to. All identifiers will be removed from interview transcription for 
analysis. 
Potential benefits for this study include determining if telemedicine can reduce time to initiation 
of TH treatment in community hospitals as well as documenting parent and provider experience 
in participation in telehealth consults for neonatal encephalopathy. 
 

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