The aim of our study is to evaluate the feasibility of applying transcutaneous CO2 monitoring (tcPCO2) in neonates receiving therapeutic hypothermia and to quantify the agreement between tcPCO2 and PCO2 in this population with or without respiratory support. Although, transcutaneous measurement of CO2 tension is the most commonly used non-invasive CO2 monitoring system in neonatal intensive care, to date tcPCO2 technique has not been evaluated systematically or used routinely in the intensive care of infants with neonatal encephalopathy receiving hypothermia treatment.

Neonatal encephalopathy (NE) affects 3 infants per 1000 live birth every year and can lead to death or permanent neurological deficit. Therapeutic hypothermia (33.5 oC) (TH) 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 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 (6 -89%) 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 NE. 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.

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.

In clinical settings, the tcPCO2 measurement is influenced by many factors and is rather to be used as a trend than an absolute number. Clinical conditions such as hypoperfusion due to shock or acidosis, edema of the subcutaneous tissues, vasoconstriction due to vasoactive agents or lower body temperature may alter the tcPCO2 measurement.

Over and underestimates may occur in the extreme high and low range of tcPCO2 measurements.

The sensor of the device heated up to a constant temperature leading to hyperperfusion of the capillaries and increase of the metabolic rate of the skin by approximately 4-5% per every degree Celsius and consequently the gas solubility and diffusion improves. The sensor calculates the PCO2 electrochemically, by change in pH of an electrolyte solution. After a temperature correction to 37 oC the device provides an estimate of skin surface CO2. Higher temperature of the sensor might be associated with better correlation but also might increase the risk of thermal injury.

In addition, tcPCO2 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.

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 (CrSO2) 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 understand the pathophysiology of autoregulation in this specific patient population.

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

   1. Sentinel event prior to delivery
   2. Apgar score ≤ 5 at 10 min
   3. Requires PPV, Intubation or CPR at 10 min
   4. 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:

   1. Neonatal Encephalopathy Scale Exam Score ≥4
   2. 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

Neonates with Neonatal Encephalopathy receiving therapeutic hypothermia