After birth, babies that have suffered from oxygen deprivation may develop hypoxic-ischemic encephalopathy (HIE). Moderate or severe HIE has been associated with death or disability. Therefore, these infants are treated with therapeutic hypothermia (TH), which should be initiated within the first six hours of life. This study aims to investigate the autonomic nervous system (ANS) function of these infants. Thus far, no systematic evaluation of ANS function has been performed, despite its potential in providing important information. Current methods include clinical assessment of pupils size and reactivity, and measurements of heart/respiratory rates. Thus, ANS function evaluation is rather limited and prone to significant inter-examiner variability. This study propose a more comprehensive analysis of ANS function by investigating heart rate variability (HRV) and whole body skin temperature distribution, skin perfusion, axillary and esophageal temperature complexity. The investigators hypothesize that HRV analysis and a more thorough evaluation of ANS function could provide additional information associated with important clinical outcomes, which could eventually be tested clinically.

1. Problem and Hypothesis:

   Globally, an estimated 1.8 to 7.7 infants per 1000 live term births suffer from perinatal asphyxia or oxygen deprivation. This remains an important cause of HIE. Seven randomized control trials have demonstrated that therapeutic hypothermia (TH) is a safe and effective therapy for infants with moderate and severe HIE if initiated within the first 6 h of life. TH increases the chances of survival without increasing the rates of neurodevelopmental disability.

   Investigations of these infants have focused mainly on daily neurological exams (modified Sarnat Score), electrical activity of the brain (amplitude integrated electroencephalography or aEEG and EEG), and brain imaging. No systematic evaluation of the ANS function has been performed despite its potential in providing important information. Current methods include clinical assessment of pupils size and reactivity, and measurements of heart/respiratory rates and are therefore limited and prone to significant inter-examiner variability. As such, in this study the investigators are planning to performing a more comprehensive analysis of ANS function under the hypothesis that in HIE infants treated with TH; a more thorough analysis of ANS function will provide additional information that can be associated with clinical outcomes.

2. Objectives:

   The objectives of the study are to measure and analyze the following variables of ANS function during TH and compare results between infants with and without poor outcomes:

   • Heart rate variability (primary outcome)
   • Skin temperature distribution and skin perfusion (secondary outcome)
   • Axillary temperature complexity (secondary outcome)
   • Esophageal temperature complexity (secondary outcome)

   A poor outcome will be defined as the composite of death, abnormal neurological exam at the end of the TH period or at discharge or transfer (whichever comes first), and abnormal brain MRI at day of life 10.

3. Methods and Analysis:

   For each newborn diagnosed with moderate or severe HIE and treated with TH, the investigators will collect demographics data using a pre-defined data collection form. Moreover, images of whole body temperature, recordings of axillary and esophageal temperature, and electrocardiogram (ECG), will be performed according to the following steps for days 1, 2 and 3 of TH:

   • Whole body infrared picture: infrared images (IR) of the whole infant will be obtained by using the E60bx camera (FLIR Systems, Inc. USA, Boston, MA). Whole body skin temperature will be analyzed by mapping temperature at the following areas: head, trunk, abdomen, upper and lower limbs, and upper and lower extremities. Mean ± SD and range values will be calculated for each area using the specific IR software. This will allow evaluation of skin temperature distribution for each patient for the specified study periods.
   • Skin perfusion: will be recorded by using the skin blood FlowMeter (ADInstruments, Bella Vista, Australia). A small surface probe will be placed at the abdomen just above the liver area using a self-adhesive ring.
   • Axillary temperature (Ta) and heart rate (HR): Ta will be recorded continuously for 1 h period using a probe placed at the R axilla and connected to the PowerLab data acquisition system®. The complexity of the temperature curve will be quantified using the approximate entropy (ApEn). HR will be measured by applying 3 ECG leads connected to a BioAmp and the PowerLab data acquisition system®. Heart rate variability (HRV) will be calculated using the time domain and frequency domain analysis, from 5 minutes segments of ECG and with the HRV module of the Labchart software®.
   • Esophageal temperature (Tes): will be collected every 5 minutes during the 1 h study period from the Blanketrol system device. Mean ± SD and the coefficient of variation of Tes values will be calculated.

4. Feasibility:

   Systematic evaluations of ANS function using the proposed study design and technologies have never been performed. Therefore, we will use a convenient sample size of 30 patients. In our NICU, approximately 40 infants with moderate and severe HIE are admitted and treated with TH every year. Thus, accounting for a 50-60% of loss to enroll due to refusal to consent, competing studies, unavailability of the research team, and patient instability, we estimate that we'll need a time frame between 24-30 months to achieve the calculated sample size of 30 patients. The same measurements will be performed in 15 patients with mild HIE (not cooled) as a control group.

5. Clinical Significance:

If any measurements of ANS function prove to be robust, they could have important implications for clinical practice. One aspect for future research is whether there is a correlation between ANS function and severity of disability or death.

Inclusion Criteria:

• Patients with Moderate or Severe HIE: 3 or more categories of the modified Sarnat Score in stage 2 or 3 (qualify for therapeutic hypothermia).
• Patients that are initiated on therapeutic hypothermia.
• Patients with Mild HIE, not treated with TH (control)

Exclusion Criteria:

-No encephalopathy, defined normal neurological exam.

Newborns admitted to the Montreal Children's Hospital neonatal intensive care unit (NICU) with mild, moderate or severe hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia (TH).