Transcutaneous Carbon Dioxide Monitoring in Neonates Receiving Therapeutic Hypothermia for Neonatal Encephalopathy
Conditions: Neonatal Encephalopathy
Sponsor: Brigham and Women's Hospital

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Mohamed El-Dib  
PROTOCOL TITLE 
Transcutaneous carbon dioxide monitoring in neonates receiving therapeutic hypothermia for 
neonatal encephalopathy  
 
FUNDING 
Not funded  
 
 
VERSION DATE 
9/8/2020  
 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
Optimization of intensive care of neonates with Neonatal Encephalopathy (NE) has the potential 
to prevent injury progression and further improve neurodevelopmental outcomes. Several studies 
have shown the association between hypocarbia and the increased risk of adverse 
neurodevelopmental outcome in infants with NE. The consistent findings of an association 
between hypocarbia and adverse outcomes suggest that the close monitoring of carbon dioxide 
exchange and the avoidance of hypocarbia is highly important in this vulnerable patient 
population. Arterial blood gas analysis, the gold standard for monitoring the respiratory 
components of acid-base homeostasis, has obvious limitations that preclude its continuous use to 
follow the dynamically changing level of PCO2. Alternative, non-invasive monitoring techniques 
have been developed to measure PCO2 trends continuously. Transcutaneous measurement of CO2 
tension (tcPCO2) has never been tested in infants undergoing therapeutic hypothermia (TH). 
The first aim of the present study is to evaluate the feasibility of application of transcutaneous 
CO2 monitoring in neonates receiving therapeutic hypothermia for Neonatal Encephalopathy and 
to evaluate the agreement between tcPCO2 and PCO2 in this population. The second aim of the 
study is to assess the association between cerebral oxygen saturation (CrSO2) as a marker of 
cerebral perfusion and tcPCO2 trends as a marker of PCO2 in blood. The monitoring of cerebral 

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Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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oxygenation by using Near Infrared Spectroscopy (NIRS) together with tcPCO2 measurements 
can be beneficial for infants with NE and can help to understand the pathophysiology of 
autoregulation in this specific patient population. 
1) To evaluate the feasibility of applying transcutaneous CO2 monitoring in neonates 
receiving therapeutic hypothermia and to quantify the agreement between tcPCO2 and 
PCO2 in this population with or without respiratory support.  
 
We hypothesize that tcPCO2 will be feasible and its trend will correlate with trends of PCO2 
measurements  
Although continuous CO2 monitoring would be desirable in this patient population, to date tcPCO2 
technique has not been evaluated systematically or used routinely in the intensive care of infants 
with neonatal encephalopathy receiving TH. Continuous monitoring may allow to avoid the 
extreme levels and the fluctuation of PCO2 and may improve the intensive care and the long-term 
outcomes of infants with NE 
 
2) To assess the correlation between cerebral oxygen saturation as a marker for cerebral 
perfusion and tcPCO2, as a marker of PCO2 in neonates receiving therapeutic hypothermia. 
 
We hypothesize that an acute decrease in tcPCO2 will reduce cerebral oxygenation as a marker of 
decreased cerebral perfusion.  
Decreased cerebral perfusion could be deleterious to the previously injured brain if oxygen 
transport and extraction are diminished, and the removal of potentially toxic metabolites is 
reduced. 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Neonatal encephalopathy affects 3 infants per 1000 live birth every year and can lead to 
death or permanent neurological deficit.  Therapeutic hypothermia (33.5 oC) has been clearly 
proven to reduce mortality and adverse neurodevelopmental outcome in patients with moderate to 
severe NE.  However, even with hypothermia, nearly half of the infants with NE are at risk of 

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Version Date:  October 15, 2014 
 
  
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death or severe disability. Optimization of intensive care of these neonates might have the potential 
to prevent injury progression and further improve neurodevelopmental outcomes.  
Multiple analyses noted a high rate of incidence of hypocarbia during the first hours of 
postnatal life possibly due to the strong respiratory effort secondary to metabolic acidosis and the 
hypothermia treatment which causes a 20-30% reduction in metabolic rate. Furthermore, several 
studies have shown the association between hypocarbia and the increased risk of adverse 
neurodevelopmental outcome in infants with NE. Hypocarbia has the potential to exacerbate brain 
injury via multiple mechanisms. Hypocarbia was associated with nuclear DNA fragmentation in 
the cerebral cortex, membrane lipid peroxidation and increased neuronal excitability in animal 
models.  
 It is well established, that carbon dioxide is one of the most potent regulator of cerebral 
blood flow (CBF), with hypercarbia causing cerebral vasodilation and increased cerebral blood 
flow by 1 to 2 ml/100g/minute per 1 mmHg in PaCO2, whereas hypocarbia causes cerebral 
vasoconstriction. Reducing PaCO2 to 20 to 25 mmHg decreases CBF by 40 to 50%. Hypocarbia 
may decrease oxygen supply further due to the cerebral vasoconstriction and the leftward shift of 
oxyhemoglobin curve.  
It has been well known for decades that hypocarbia is associated with periventricular 
leukomalacia and, or, cerebral palsy in preterm neonates. In term, asphyxiated neonates the 
secondary analysis of the landmark CoolCap and NICHD hypothermia trials established that 
hypocarbia has a dose-dependent effect on long term neurodevelopmental outcomes. Both 
minimum and cumulative exposure to PCO2 less than 35 mmHg within the first 12 hours of life 
increased the risk of death and adverse neurodevelopmental outcome in the secondary analysis of 
NICHD trial. Consistent with this, the post-hoc analysis of CoolCap study showed that the 
probability of unfavorable outcome was raised dose-dependently with decreasing PCO2 in infants 
with moderate and severe HIE. Moreover, a recent retrospective study also reported an association 
between hypocarbia over the first 4 days of life and brain injury on MRI. The consistent findings 
of an association between hypocarbia and adverse outcomes suggest that the close monitoring of 
carbon dioxide exchange and the avoidance of hypocarbia is highly important in this vulnerable 
patient population.  
Arterial blood gas analysis, the gold standard for monitoring the respiratory components 
of acid-base homeostasis, has obvious limitations that preclude its continuous use to follow the 
dynamically changing level of PCO2. Moreover, repeated arterial samplings can lead to significant 
blood loss and an increased risk of bacteremia.  

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Alternative, non-invasive monitoring techniques have been developed to measure PCO2 
trends continuously. Transcutaneous measurement of CO2 tension is the most commonly used 
non-invasive CO2 monitoring system in neonatal intensive care and several studies demonstrated 
a good agreement between the PCO2 in blood samples and tcPCO2 in premature infants. 
Transcutaneous CO2 monitoring is recommended when there is a limited arterial blood gas access 
and/or the patient is on invasive mechanical ventilation. In the present study our aim is to measure 
PCO2 continuously in infants undergoing TH regardless of the respiratory support in order to 
evaluate its feasibility in cooled infants.  
As detailed above, changes in pCO2 affect cerebral perfusion. Therefore, it is important to 
analyze the cerebral oxygenation and metabolism with the association of PCO2 trends. Continuous 
cerebral regional oxygen saturation monitoring has been already used routinely in the intensive 
care of the infants with NE by using Near Infrared Spectroscopy (NIRS). NIRS is a non-invasive 
tool that can be used to measure changes in oxygenated, deoxygenated, and total hemoglobin of 
brain tissue from which cerebral regional oxygen saturation can be derived as a surrogate of 
cerebral oxygen consumption. A significant positive correlation was found between 
transcutaneous PCO2 levels and tissue oxygenation index in preterm infants. In line with this, an 
acute increase in end tidal CO2 (etCO2) was associated with an increase in cerebral oxygenation, 
whereas an acute decrease was associated with reduced cerebral oxygenation. The tcPCO2 and 
etCO2 were used as a surrogate marker of PCO2.  
Although continuous CO2 monitoring would be desirable in this patient population, to date 
tcPCO2 technique has not been evaluated systematically or used routinely in the intensive care of 
infants with neonatal encephalopathy receiving TH. Continuous monitoring may allow to avoid 
the extreme levels and the fluctuation of PCO2 and may improve the intensive care and the long-
term outcomes of infants with NE  The monitoring of cerebral oxygenation by using NIRS together 
with tcPCO2 measurements can be beneficial for  infants with NE and can help to clarify the 
pathophysiology of autoregulation in this specific patient population. 
 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 

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This will be a single center prospective study conducted in the Brigham and Women’s Hospital, 
Department of Pediatric Newborn Medicine. All infants greater than or equal to 34 weeks gestation 
and eligible for therapeutic hypothermia will be enrolled regardless of their respiratory support.   
Inclusion criteria 
Any neonates with neonatal encephalopathy admitted to receive therapeutic hypothermia will be 
a candidate for this study. 
Current criteria for therapeutic hypothermia at BWH include the following: 
1. ≥34 weeks’ gestation  
2. Any one of the followings  
a. Sentinel event prior to delivery  
b. Apgar score ≤ 5 at 10 min  
c. Requires PPV, Intubation or CPR at 10 min  
d. pH ≤ 7.1 (from cord or blood gas within 60 min of birth)  
e. Abnormal Base Excess ≤ - 10 mEq/L (from cord or blood gas within 60 min of 
birth) 
3. Any one of the followings:   
a. Neonatal Encephalopathy Scale Exam Score ≥4  
b. Seizure or clinical concern for seizure  
Exclusion criteria  
1. 
Infants with major birth defect, genetic or metabolic syndrome 
2. 
Neonates in extremis with possibility of redirection to palliative care   
 
We will enroll up to 100 patients. 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
Once an infant is identified as being eligible for TH treatment and hypothermia was 
initiated according to the department clinical practice guidelines, and written informed consent 
was obtained from one of the parents, tcPCO2 monitoring can be started. Transcutaneous CO2 will 
be measured by SenTec Digital Monitor (software version SW-V07.00; MPB SW-V05.00.12) with 

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Version Date:  October 15, 2014 
 
  
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V-Sign™ Sensor (SenTec AG, Thervil, Switzerland). This study will follow the BWH Newborn 
respiratory care guideline titled “Transcutaneous CO2 Monitoring”. This guideline will be 
followed point by point to precisely calibrate and applicate the sensor to the skin. After accurate 
calibration a trained health care professional will be applied the attachment ring and electrode to 
the skin of abdomen, and/or inner or outer thighs (see respiratory protocol for details). Electrode 
temperature of 41 oC was chosen following the instructions of the manufacturer. Ten minutes are 
allowed to achieve stable measuring conditions. Special attention must be given to skin injuries.  
Changing sensor site and recalibrating the device as often as every 8 hours is necessary in order to 
avoid skin injury and improve correlation. Calibration should be done prior to with each site 
change.  
Neonates on ventilatory support, will be already receiving tcPCO2 monitoring as well as 
repeated blood gases for clinical purpose. In these cases, we will just collect clinical data in the 
research record. For patients who have fewer than 4 clinical blood gases ordered during the 
monitoring period, we may use a small blood sample (0.2 ml) from the routine daily clinical blood 
draw to measure blood gas for research purposes. There will be up to four blood gases including 
the ones that are clinically ordered. 
For those on no respiratory support, we will also obtain up to four blood gases from the 
routine daily clinical blood draws, in addition to applying tcPCO2 monitoring.  
Although the results of the research blood gas will not be blinded to the clinicians, this 
blood gas will not be charged to the patient billing and will not be included in medical record. 
Further blood sample collections will be based on the decisions of attending physicians.  
Moreover, the attending clinicians will be not blinded to the tcPCO2 values. The tcPCO2 
values will be documented in the patient records as per the Department protocol.  
 
Continuous cerebral regional oxygen saturation monitoring has been already used routinely 
in the intensive care of the infants with NE by using Near Infrared Spectroscopy. The clinical 
practice guideline of NIRS (INVOS™ 5100C Cerebral/Somatic Oximeter), titled “Clinical NIRS 
(Near Infra-Red Spectroscopy) in the NICU” will be followed in the present study.  
 
As part of the study we will collect data from clinical monitors (amplitude integrated 
electroencephalography, NIRS, cardiovascular monitor) connected to the neonates for clinical 
reasons. In addition, we will collect data from the medical record including demographic, clinical, 
laboratory and imaging data.  Demographic, clinical, monitoring and imaging data will be 

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extracted from medical charts and electronic hospital medical records accessed through the 
participating hospital’s network, then entered into our encrypted, password-protected redcap 
database accessible only to the PI and study staff members. 
A Moberg CNS Monitor will be used to consolidate the recording process for NIRS and 
clinical monitor data. If the Moberg Monitor is unavailable, then an external auxiliary box will be 
used to record and co-register clinical parameters from the patient’s bedside monitor up to 16 
channels. Most data from the patient’s bedside monitors will be extracted and stored in our 
computer with the tcPCO2 data. Specifically, outputs of the cardiovascular and other bedside 
monitors will be either attached directly to our device for data collection. When not possible the 
data will be recovered from Epic. The extracted data will be time locked with the tcPCO2 data for 
synchronization.  
If the external auxiliary box is used instead of the Moberg CNS Monitor, then an additional 
research pulse oximeter (Masimo Radical 7) will be used. The current bedside pulse oximeter 
monitors data in the BWH NICU currently cannot be recorded or saved at sufficient temporal 
resolution. In Epic data are saved once per minute, which is too slow for our purposes. Hence, 
using an extra research pulse oximeter, when Moberg Monitor will be unavailable, will allow us 
to acquire digital output with sufficient temporal resolution. The FDA- approved device will be 
used in the same way as the clinical pulse oximeter during the study period.  
 
Study period will end when rewarming is completed.  
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
This research protocol will not interfere with standard of care. Standard of care at BWH 
includes assessment for therapeutic hypothermia based upon a clinical practice guideline.  
Transcutaneous CO2 monitoring is recommended to all patients undergoing therapeutic 
hypothermia if the patient receives respiratory support. In the present study our aim is to measure 
PCO2 continuously in infants undergoing TH with or without respiratory support in order to 
evaluate its feasibility in cooled infants. Neonates on ventilatory support, will be already receiving 
tcPCO2 monitoring as well as repeated blood gases for clinical purpose. In these cases, we will 
just collect these clinical data in the research record. For patients who have fewer than 4 clinical 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
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blood gases ordered during the monitoring period, we may use a small blood sample (0.2 ml) from 
the routine daily clinical blood draw to measure blood gas for research purposes. There will be up 
to four blood gases including the ones that are clinically ordered. 
 
For those on no respiratory support, we will also obtain up to four blood gases from the 
routine daily clinical blood draws, in addition to applying tcPCO2 monitoring. Although the results 
of the blood gas will not be blinded to the clinicians, this blood gas will not be charged to the 
patient billing and will not be included in medical record. Further blood sample collections will be 
based on the decisions of attending physicians. Moreover, the attending clinicians will be not 
blinded to the tcPCO2 values. The tcPCO2 values will be documented in the patient records as per 
the Department protocol.  
If the external auxiliary box is used instead of the Moberg CNS Monitor, then an additional 
research pulse oximeter (Masimo Radical 7) will be used. The current bedside pulse oximeter 
monitors data in the BWH NICU currently cannot be recorded or saved at sufficient temporal 
resolution. In Epic data are saved once per minute, which is too slow for our purposes. Hence, 
using an extra research pulse oximeter, when Moberg Monitor will be unavailable, will allow us 
to acquire digital output with sufficient temporal resolution. The FDA- approved device will be 
used in the same way as the clinical pulse oximeter during the study period.  
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
Transcutaneous measurement of CO2 tension is the most commonly used non-invasive CO2 
monitoring system in neonatal intensive care. At our Department tcPCO2 monitoring is strongly 
recommended during TH while infants receiving invasive mechanical ventilation and/or there is a 
limited arterial blood gas access. This study will follow the BWH Newborn respiratory care 
guideline titled “Transcutaneous CO2 Monitoring”. This guideline will be followed point by point 
to precisely calibrate and applicate the sensor to the skin. 
 
To estimate the CO2 level in the skin surface, the sensor of the device heated up to 41 oC to improve 
carbon-dioxide solubility in capillary vessels.  We will change the sensor site as often as every 8 
hours at the time of the routine nursing care in order to minimize the risk for skin irritation. 
 

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We consider that, there are no specific risks or discomforts related to the additional blood gases 
(up to four) for research purposes as we are obtaining 0.2ml from the routine clinical blood draws. 
Additionally, we consider that there are no specific risks or discomforts for the potential 
application of an additional pulse oximetry probe.  
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
In general, any safety concerns will be addressed immediately with PI Dr. Mohamed El-Dib. The 
PI will attend monthly meetings with the study team where any safety issues are further discussed 
and then presented to the Partners IRB if required. Severe or urgent safety concerns will be 
communicated immediately to the PI by cell phone. The PI will report immediately to the Partners 
IRB.  
 
Physical Safety during tcPCO2 monitoring 
Sensor of the tcPCO2 monitor is operated at a constant sensor temperature of typically 41 °C in 
neonatal patients. Special attention will be given to skin integrity at the sensor site. Changing the 
sensor site will be mandatory every 8 hours.  The measurement will be stopped immediately if 
skin injury is noted or if the parents request it for any reason.   
 
Safeguarding Patient Privacy 
To ensure subject confidentiality and limit unauthorized access, all data will be transferred and 
stored using anonymized subject identifiers, identifiable only by randomly assigned alphanumeric 
identifiers. All protected health information (PHI) will be maintained in the strictest confidence.  
PHI data will be held in secure format in a password-protected redcap database behind Partner’s 
Firewall.  PHI records can be identified only by study number.  A log of study number and 
identifying data and hard copy will be kept in a locked file cabinet. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.

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Sensor is operated at a constant sensor temperature of typically 41 °C in neonates. Because 
of the increased local skin temperature thermal injury may occur. Special attention must be given 
to patients under hypothermia because of the poor skin tissue perfusion due to vasoconstriction, 
that may increase the risk of skin damage. However, tcPCO2 monitoring was tested before on very 
preterm infants with more fragile skin and skin complications were reported in the minority of the 
cases. The skin integrity under the sensor will be assessed at a minimum of every 8 hours 
throughout the monitoring period to change site and recalibrate the device per manufacturer 
recommendation. If there is any concern for development of skin complications the electrode will 
be removed from this site immediately. This monitoring technique is considered to present 
minimal risk–that is, no more risk than the subject would encounter in everyday life.  
 
Risks Related to Privacy and Confidentiality 
Demographic, clinical, monitoring and neuroimaging data will be extracted from medical 
charts and electronic hospital medical records accessed through the participating hospital’s 
network, then entered into our encrypted, password-protected redcap database accessible only to 
the PI and study staff members. Information will be extracted from medical charts and electronic 
hospital medical records accessed through the participating hospital’s network. Confidentiality 
will be ensured by alphanumeric identifiers to each subject. The original consent forms will be 
stored in a secure locked cabinet at BWH. Medical Records Numbers will be stored electronically, 
separate from patients' data that will be stored in a password protected database. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
While there is no direct benefit to the infants enrolled in this study, the results from this 
observational study could improve the supportive care of infants with NE and may have an impact 
on long term outcome.   The continuous non-invasive monitoring of CO2 levels may help to avoid 
the extreme levels in PCO2 and prevent further brain damage.  Results of these monitor will be 

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displayed on the bedside. Any severe alteration would alert the clinician to correlate with clinical 
condition of the baby. 
 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
Our inclusion/exclusion criteria are based on clinical information that are proven diagnostic 
measures for encephalopathy, and have not been shown to systematically vary between individuals 
of differing sociodemographic qualities.  
 
 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
We will not exclude non- English speaking participants.  
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Non-English-Speaking-Subjects.pdf 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
 
Recruitment of study infants will be undertaken in accordance with our departmental standard 
operating procedure (see SOP and letter of introduction for parents attached) for participant 
recruitment in the NICU.  

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In this study, it is important to enroll patients in the first hours after birth. This is the time where 
babies get most of the blood gases routinely done for clinical care. In addition, this the most critical 
time to monitor these babies since hypocarbia in the first hours of life was associated with 
abnormal outcome. According to the SOP, and since enrollment is time sensitive, PI or IRB 
approved study designate will approach families after having permission from the attending 
overseeing the care of the potential subject. 
Study aims, and procedure will be reviewed with all interested parents. Ample opportunity for 
questions and consideration of discomforts will be provided. Subjects will be provided with a copy 
of the consent form (and if applicable, the short form) they signed. The original signed consent 
form will be kept in a secured storage file 
 
 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
 
Non applicable  
 
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Recruitment-Of-Research-Subjects.pdf
 
          Guidelines for Advertisements for Recruiting Subjects
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Guidelines-for-Advertisements.pdf 
 
          Remuneration for Research Subjects
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-Research/Remuneration-for-
Research-Subjects.pdf 
 
 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.

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Research investigators will be the only persons obtaining consent from each study infant’s 
parent/s. These persons will be responsible for ensuring that informed consent is given freely, 
without coercion, and based on a clear understanding of what participation involves. Mothers and 
fathers/partners will be approached in the Neonatal Intensive Care Unit. Study aims and procedure 
will be reviewed with all interested parents. We also have a simply written brochure specifically 
designed for parents that explains what would be involved for their infant and their rights as a 
research participant. Ample opportunity for questions and consideration of discomforts will be 
provided. Subjects will always be made aware that they may speak with the PI or any of the other 
co-investigators if they so wish. Subjects will be provided with a copy of the consent form (and if 
applicable, the short form) they signed. The original signed consent form will be kept in a secured 
storage file. 
 
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
      https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb 
 
For guidance, refer to the following Partners policy: 
     Informed Consent of Research Subjects:
     https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Informed-Consent-of-Research-Subjects.pdf
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
 
(1) The safety and/or efficacy data that will be reviewed include: 

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- Study accrual rate (how many subjects are consented to participate) 
- Compliance with eligibility criteria 
- Adherence to study methods 
- Adverse events and other problems or trends that may indicate safety concern for participants 
 
(2) Planned frequency of review: 
- The team will be continuously updated on recruitment and study staff will meet regularly to 
review progress and safety with Dr. El-Dib, as well as to discuss challenges in recruitment, 
implementation, and data analysis. 
- These regular meetings will help to ensure that additional risks to subjects are identified in a 
timely manner, and that research data are validly capturing all appropriate information that can be 
used to answer the study questions. 
 
(3) Quality control input will also be provided by the study staff. 
- Principal Investigator, Mohamed El-Dib will be responsible for reviewing both study 
implementation and data collected to ensure the safety and efficacy of this study. 
 
 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
If a study subject experiences an adverse event, it will be reported by the researcher who identified 
the event to the PI, then subsequently to the Partners IRB. The AE will be reported within 24 hours 
of occurrence via fax or e-mail. A full report will be submitted to the IRB within seven days of 
initial receipt for life-threatening severe adverse events, and within 15 days for non-life-
threatening adverse events. The PI will submit any and all reports regarding the event to the IRB 
once available. 
 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
15 
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
All co-investigators, collaborators, and research staff are certified to conduct their assigned 
responsibilities in this study. The PI, Mohamed El-Dib, will be responsible for monitoring the 
implementation of the research and analysis of study data. All investigators and study staff will be 
responsible for maintaining the integrity of this project and for monitoring the components of the 
study in which they have expertise. Study staff will meet regularly to review adherence to the IRB-
approved protocol, report on conduct of assigned responsibilities, and discuss monitoring the 
integrity of the data. 
 
 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
         https://www.partners.org/Assets/Documents/Medical-Research/Clinical-Research/DSMP-in-
Human-Subjects-Research.pdf 
 
          Reporting Unanticipated Problems (including Adverse Events)
          https://www.partners.org/Assets/Documents/Medical-Research/Clinical-
Research/Reporting-Unanticipated-Problems-including-Adverse-Events.pdf
 
 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
16 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
 
Patient information is always confidential and only accessed by approved study personnel. 
Documents are stored in locked filing cabinets and on password-protected servers. Subjects will 
be assigned a unique study ID number and no names, medical record numbers, or characteristic 
data that could identify patients will appear in publications or presentations of the data collected. 
 
Research team members will undergo all confidentially and HIPAA training before being granted 
access. 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
No specimens or data will be sent to research collaborators outside Partners. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 
There will be no specimens or data stored at collaborating sites outside Partners. 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
There will be no specimens or data collected by research collaborators outside Partners. 
 
 
 

Partners Human Subjects Research Application Form 
  
Filename: Protocol Summary 
Version Date:  October 15, 2014 
 
  
17 
References  
1. 
Kurinczuk, J.J., M. White-Koning, and N. Badawi, Epidemiology of neonatal 
encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev, 2010. 86(6): p. 329-38. 
2. 
Edwards, A.D., et al., Neurological outcomes at 18 months of age after moderate 
hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial 
data. BMJ, 2010. 340: p. c363. 
3. 
Jacobs, S.E., et al., Cooling for newborns with hypoxic ischaemic encephalopathy. 
Cochrane Database Syst Rev, 2013(1): p. CD003311. 
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Nadeem, M., et al., Blood carbon dioxide levels and adverse outcome in neonatal hypoxic-
ischemic encephalopathy. Am J Perinatol, 2010. 27(5): p. 361-5. 
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Pappas, A., et al., Hypocarbia and adverse outcome in neonatal hypoxic-ischemic 
encephalopathy. J Pediatr, 2011. 158(5): p. 752-758 e1. 
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Yenari, M.A. and H.S. Han, Neuroprotective mechanisms of hypothermia in brain 
ischaemia. Nat Rev Neurosci, 2012. 13(4): p. 267-78. 
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G Klinger, J.B., P Shah, M Perlman, Do hyperoxaemia and hypocapnia add to the risk of 
brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed, 2005: p. 49-52. 
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Lingappan, K., et al., Relationship between PCO2 and unfavorable outcome in infants with 
moderate-to-severe hypoxic ischemic encephalopathy. Pediatr Res, 2016. 80(2): p. 204-8. 
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Lopez Laporte, M.A., et al., Association between hypocapnia and ventilation during the 
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Pirot, A.L., et al., Effects of severe hypocapnia on expression of Bax and Bcl-2 proteins, 
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newborn piglets. Neonatology, 2007. 91(1): p. 20-27. 
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Curley, G., J.G. Laffey, and B.P. Kavanagh, Bench-to-bedside review: carbon dioxide. Crit 
Care, 2010. 14(2): p. 220. 
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Greisen, G., Autoregulation of cerebral blood flow in newborn babies. Early Hum Dev, 
2005. 81(5): p. 423-8. 
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Greisen, G., H. Munck, and H. Lou, Severe hypocarbia in preterm infants and 
neurodevelopmental deficit. Acta Paediatr Scand, 1987. 76(3): p. 401-4. 

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Tingay, D.G., M.J. Stewart, and C.J. Morley, Monitoring of end tidal carbon dioxide and 
transcutaneous carbon dioxide during neonatal transport. Arch Dis Child Fetal Neonatal Ed, 
2005. 90(6): p. F523-6. 
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Sandberg, K.L., H. Brynjarsson, and O. Hjalmarson, Transcutaneous blood gas monitoring 
during neonatal intensive care. Acta Paediatr, 2011. 100(5): p. 676-9. 
17. 
Hejlesen, O.K., et al., Clinical implications of a quality assessment of transcutaneous CO2 
monitoring in preterm infants in neonatal intensive care. Stud Health Technol Inform, 2009. 150: 
p. 490-4. 
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Aly, S., et al., Transcutaneous Carbon Dioxide Monitoring with Reduced-Temperature 
Probes in Very Low Birth Weight Infants. Am J Perinatol, 2017. 34(5): p. 480-485. 
19. 
Mukhopadhyay, S., R. Maurer, and K.M. Puopolo, Neonatal Transcutaneous Carbon 
Dioxide Monitoring--Effect on Clinical Management and Outcomes. Respir Care, 2016. 61(1): p. 
90-7. 
20. 
Restrepo, R.D., et al., AARC clinical practice guideline: transcutaneous monitoring of 
carbon dioxide and oxygen: 2012. Respir Care, 2012. 57(11): p. 1955-62. 
21. 
Sorensen, L.C., L. Brage-Andersen, and G. Greisen, Effects of the transcutaneous electrode 
temperature on the accuracy of transcutaneous carbon dioxide tension. Scand J Clin Lab Invest, 
2011. 71(7): p. 548-52. 
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Chalak, L.F., T. Tarumi, and R. Zhang, The "neurovascular unit approach" to evaluate 
mechanisms of dysfunctional autoregulation in asphyxiated newborns in the era of hypothermia 
therapy. Early Hum Dev, 2014. 90(10): p. 687-94. 
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Vanderhaegen, J., et al., The effect of changes in tPCO2 on the fractional tissue oxygen 
extraction--as measured by near-infrared spectroscopy--in neonates during the first days of life. 
Eur J Paediatr Neurol, 2009. 13(2): p. 128-34. 
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Dix, L.M.L., et al., Carbon Dioxide Fluctuations Are Associated with Changes in Cerebral 
Oxygenation and Electrical Activity in Infants Born Preterm. J Pediatr, 2017. 187: p. 66-72 e1.