Oxygen Consumption-based Assessments of Hemodynamics in Neonates Following Congenital Heart Surgery (Oxy-CAHN Study)
Phase: NA
Conditions: Transposition of the Great Vessels, Hypoplastic Left Heart Syndrome, Oxygen Consumption Based Assessment of Hemodynamics
Sponsor: Boston Children's Hospital

Project Title
Oxygen consumption-based assessments of hemodynamics in neonates following 
congenital heart surgery (Oxy-CAHN Study)
Study Investigators
John Kheir, MD (Principal Investigator)
Mackenzie Ford, MD
Ravi Thiagarajan, MD
James DiNardo, MD
Pedro del Nido, MD
Craig Smallwood, RRT
Nilesh Mehta, MD
Mel Almodovar, MD
Evan Butler, PhD
Dimitar Baranov, PhD
Kimberlee Gauvreau, ScD
Last update, February 1, 2013
NCT 02184169

Project Summary
The purpose of the Oxy-CAHN study is to improve the monitoring capabilities of 
newborn infants recovering from congenital heart surgery.  Currently, we utilize 
important but unsophisticated measures, such as vital signs and lactate measurements, 
to monitor these patients.  Although they are useful in categorizing patients as well or 
unwell, these signs currently lack the power quantify a patient’s risk for cardiac arrest.  
More to the point, they are mostly indirect measures of what we really are assessing, 
which is tissue oxygen delivery.
Our group has signiﬁcant expertise with devices which quantify the amount of oxygen 
that a baby consumes every minute.  These values are more commonly in combination 
with other measures to assess nutritional and metabolism status.  In critically ill patients, 
however, the volume of oxygen consumed by a patient may be limited by the amount of 
oxygen their circulation delivers.  This may represent a critical relationship, which has 
been previously described, but not exploited for the purpose of identifying patients with 
critically low oxygen delivery.  
The aims of this study are therefore (1) to demonstrate that oxygen consumption can be 
safely and precisely measured continuously in newborns undergoing one of two 
common congenital heart surgeries, (2) to determine whether postoperative circulatory 
failure is associated with a precedent change in oxygen consumption, and (3) to 
determine whether the addition of the oxygen-based measurements (including oxygen 
consumption and venous oxygen saturations) to standardly measured parameters will 
add power in predicting which patients will experience postoperative circulatory failure.
If successful, this study may improve our capacity to non-invasively and continuously 
monitor patients following the highest risk congenital heart surgeries, and in the future, 
to create an algorithm which quantiﬁes a patients risk for having a cardiac arrest.  This 
may permit providers to intervene on these patients deﬁnitively, improving the morbidity 
and mortality associated with congenital heart disease.

Abbreviations
Abbreviation
Meaning
ASO
Arterial switch operation
BCH
Boston Children’s Hospital
BTS
Blalock-Taussig shunt
CHD
Congenital heart disease
CICU
Cardiac intensive care unit
CPR
Cardiopulmonary resuscitation
CVP
Cardiovascular Program
DSMB
Data safety and monitoring board
d-TGA/IVS
d-Transposition of the great arteries with an intact 
ventricular septum
ECMO
Extracorporeal membrane oxygenation
EtCO2
End tidal carbon dioxide 
GEE
Generalized estimating equations
HLHS
Hypoplastic left heart sydrome
HP
Hybrid palliation
PAB
Pulmonary artery band
PLOC
Postoperative loss of circulation
Qp/Qs
Ratio of pulmonary blood ﬂow to systemic blood ﬂow
SVC
Superior vena cava
SvO2
Mixed venous oxyhemoglobin saturation
S1P
Stage I palliation
T3
Tracking, Trajectory and Trigger Program (Arcardia 
Solutions)
VCO2
Elimination of carbon dioxide (per minute)
VO2
Oxygen consumption (per minute)

Table of Contents
Introduction
!
The importance of oxygen delivery.................................................................
!
HLHS and the risk of postoperative loss of circulation...................................
!
Currently used markers of oxygen delivery....................................................
!
Preliminary studies.........................................................................................
Study Objectives.......................................................................................................
Study Design.............................................................................................................
Study Population
!
Inclusion criteria..............................................................................................
!
Exclusion criteria.............................................................................................
!
Recruitment methods......................................................................................
Study Treatments
!
Oxygen consumption measurement...............................................................
!
Continuous SVC saturation measurement.....................................................
Endpoints/Outcomes
!
Primary Outcome Measure.............................................................................
!
Secondary Outcome Measures.....................................................................
Data Collection Methods, Assessments and Schedule.............................................
!
Adverse Event Criteria and Reporting Procedures....................................................
Data Management and Statistical Analysis................................................................
Risks and Discomforts...............................................................................................
Potential Beneﬁts
!
Potential Direct Beneﬁts..................................................................................
!
Potential Indirect Beneﬁts...............................................................................
Privacy and Conﬁdentiality Provisions.......................................................................
References................................................................................................................
List of Appendices......................................................................................................
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Background
The Importance of Oxygen Delivery
Cellular function and survival requires a 
continuous supply of oxygen to perform 
aerobic respiration.  Inspired oxygen gas 
traverses pulmonary capillaries and binds to 
hemoglobin, which carries large amounts of 
the molecule to the systemic tissues.  
Systemic oxygen delivery (DO2) is amount of 
oxygen carried by a given volume of blood 
multiplied by its ﬂow rate (cardiac output).  
This represents the amount of oxygen 
available for tissues to consume.  In healthy 
individuals, this supply exceeds demand by a 
substantial margin - some 60-70% of oxygen 
delivered to the tissues returns to the 
systemic veins unused.  The volume of 
oxygen actually consumed by the tissues 
(VO2) of course can never exceed DO2, and is 
generally governed by a patient’s metabolic 
rate.  In critically ill patients, factors which are 
known to increase VO2 include fevers, 
seizures, activity and inotrope administration 
to name a few.  In patients who are very 
critically ill, DO2 may actually decrease below 
a critical threshold known as ‘critical 
DO2‘ (Figure 1).1  Below critical DO2, the 
body’s normal compensatory mechanisms 
(e.g. to increase cardiac output or increase 
the oxygen extraction ratio) are overcome, 
and an insufﬁcient volume of oxygen is 
delivered to tissues, which in turn decreases 
VO2 (since tissues cannot consume oxygen if 
it is not delivered).  
In critically ill patients, e.g. in newborns following open heart surgery, it is common for 
DO2 to be marginal.  This is evidenced by increases in serum markers of anaerobic 
metabolism (namely serum lactate measurements), by evidence of a high oxygen 
extraction ratio (low superior vena cava oxyhemoglobin saturations relative to arterial 
saturations), and by evidence that the cardiovascular system is compensating for 
inadequate cardiac output (e.g. physical signs of increased systemic vascular 
resistance and a fast heart rate).  When the myocardium receives and insufﬁcient 
amount of oxygen, tissue hypoxia ensues and causes myocardial dysfunction.  
Intensive care efforts often focus upon improving tissue perfusion by increasing cardiac 
output, and this requisitely increases myocardial oxygen demands.2  In the most 
Figure 1.  Oxygen delivery is the amount of 
oxygen carried to the tissues, and typically far 
exceeds that which is needed/consumed by the 
tissues.  As oxygen delivery decreases 
progressively (moving right to left across the X 
axis), a critical threshold is reached below which 
oxygen consumption decreases as tissues 
become dysoxic (A).  As tissues become 
progressively hypoxic, an increasing amount of 
oxygen is extracted from hemoglobin, increasing 
the oxygen extraction ratio.  Figure from 
Schumacker, Int Care Med, 1987.

critically ill patients, the myocardium reaches a 
profound state of tissue hypoxia which may 
cause a postoperative loss of circulation (PLOC).
HLHS and the risk of PLOC
Patients with hypoplastic left heart syndrome 
(HLHS) necessarily have so-called ‘single 
ventricle physiology’.  In these patients, the right 
ventricle pumps blood to both the systemic 
circulation (to deliver oxygen) and to the lungs (to 
pick up oxygen, Figure 2).  Normally, these two 
functions occur in series, i.e. the right ventricle 
pumps blood to the lungs and the left ventricleto 
the body.  In two ventricle physiology, each 
ventricle pumps one cardiac output.  In single 
ventricle physiology, however, the right ventricle 
pumps to both circulations in parallel, requiring at 
least 1.6-1.8 cardiac outputs (at times 2-3 cardiac 
outputs),3 which among other things causes a 
disproportionate increase in myocardial VO2.  In 
the postoperative period, the oxygen extraction 
capacity of myocardium may be compromised by 
tissue edema, systemic inﬂammation, and 
mitochondrial dysfunction following the effects of 
cardiopulmonary bypass.  Myocardial oxygen 
delivery can be compromised by anemia (as a 
consequence of postoperative bleeding), and by 
inadequate coronary blood ﬂow (especially 
pronounced in settings of tachycardia - which 
decreases coronary ﬁlling time - and of diastolic 
hypotension due to the presence of a systemic to 
pulmonary shunt).  
In the BCH CICU, approximately 10-15% of 
neonates undergoing a stage I palliation (S1P) 
experience PLOC and receive some resuscitation, 
often times in the form of extracorporeal 
membrane oxygen (EMCO) device support.  These 
patients often experience increased ICU and hospital lengths of stay, higher hospital 
morbidity and mortality, and worse neurologic outcomes.4-6  The purpose of this study is 
to determine whether continuous monitoring of VO2 and SVC saturations will allow 
development of signs to predict which patients are at highest likelihood of experiencing 
a PLOC before the event, permitting time for interventions to take place prior to an 
injurious or potentially lethal event.
Figure 2.  In patients born with an 
inadequate left ventricle, the right 
ventricle is used to pump blood to both 
the body and the lungs simultaneously 
and in parallel by connecting the 
pulmonary artery to the small aorta, and 
creating a shunt from this circulation to 
the lungs.  This circulation leads to 
increased oxygen demand for the heart.  
When this demand is not met, myocardial 
dysfunction and PLOC result.  Figure from 
Ohye, NEJM, 2010.{Ohye:2010kn}

Currently Used Markers of Oxygen Delivery
Assessing the physiologic state of patients is a complex but vitally important task.  At 
the bedside, the clinician combines many pieces of data to assess the adequacy of end 
organ oxygen delivery, each of which has strengths and weakness as a clinical sign.  
Basic hemodynamic parameters (aka vital signs) include a patient’s heart rate, arterial 
and venous blood pressures, oxygen saturations and temperature are central to the 
assessment of a patient’s physiologic state, and are often the most important clues to 
inadequate oxygen delivery.  Further to this includes markers of end organ function, 
such as urine output, coagulation parameter, as well as laboratory indices of hepatic 
and renal function add some degree of conﬁdence that our general assessments are 
correct.  
In patients at higher risk of insufﬁcient DO2, advanced monitoring techniques are 
commonly used.  The three most commonly used techniques in routine use in neonates 
undergoing congenital heart surgery include (1) cerebral near infrared spectroscopy 
(cNIRS), (2) SVC saturation sampling, and (3) serum lactate measurements.  
Cerebral NIRS
cNIRS is a technology which intends to non-invasively quantify (at least as a trend) the 
quantity of oxyhemoglobin versus deoxyhemoglobin within the tissue beds underlying 
the probe.  The probe emits red light to the surface of the forehead, penetrating to the 
cerebral cortex of the brain.  Because oxyhemoglobin absorbs green and blue 
wavelengths, but deoxyhemoglobin does not (hence desaturated patients appear 
cyanotic), the optical properties of the light returning to the sensor depend upon the 
oxyhemoglobin/deoxyhemoglobin ratio within the tissues that the light path crosses.  
The monitor we use most often (Somanetics INVOS Cerebral/Somatic Oximeter) 
senses light at two wavelengths (730 and 810 nm) and converts this number to a 
regional oxyhemoglobin saturation index.  The measurement of NIRS has been 
correlated with jugular venous saturation in humans.7,8  The technology was approved 
for pediatric use in 2005, and has been utilized in several studies of pediatric cardiac 
patients since that time.9,10 
However, there are important limitations in using NIRS to assess mixed venous 
saturation, including the obscuring and competing signal from myoglobin in skeletal 
muscle, interfering with the superimposed spectral signal from red cell hemoglobin.11  
There has been a resultant lack of subsequent evidence validating NIRS with low 
cardiac output in children after cardiac surgery with possible risk of potential harm from 
uncertainty in interpretation of the recorded NIRS values.12  Because of these 
limitations, the ‘gold standard’ for assessing cerebral oxygen delivery is therefore 
quantiﬁcation of SVC oxyhemoglobin saturations.  
SVC oxyhemoglobin saturations
Inadequate DO2  leads to tissue hypoxia, which in turn leads to an increased oxygen 
extraction ratio and central venous desaturation.  Therefore, quantiﬁcation of 
oxyhemoglobin saturation from a pulmonary artery (distal to complete mixing) is 
considered a benchmark measurement when assessing oxygen delivery.  However, 

because this requires placement of a pulmonary artery catheter (which is not commonly 
done in children), blood is more commonly sampled from the SVC for the same 
purpose.  In fact, SVC saturations are at times the most accurate place to sample 
venous blood, as many patients with congenital heart disease (CHD) have left to right 
shunts or even single ventricle physiology, making pulmonary artery saturations difﬁcult 
to interpret.  
Typically, SVC saturations are measured by intermittent sampling of blood from a 
catheter placed into the SVC via the internal jugular vein, or retrograde through the right 
atrium.  The SVC saturation is used to calculate the oxygen extraction ratio, and 
generally values below 40-50% represent a compromised DO2.  The limitations to this 
technique include the following.  (1) Blood must be removed from the body (including 
‘waste’ blood which ﬁlls the catheter) which can lead to anemia.  (2) Even frequent 
sampling of SVC blood is intermittent, and assessing responses of DO2 to interventions 
can be difﬁcult in real time.  (3) Frequent entry into the central line can increase the risk 
of catheter related bloodstream infection.  (4) In patients with profoundly low SVC 
saturations, small amounts of air which enter the blood gas syringe can lead to 
artiﬁcially higher oximetric readings.  
To address these limitations, we will test a recently developed central venous catheter 
which utilizes in vivo reﬂection spectrophotometry on 4 wavelengths (PediaSat catheter; 
Edwards Lifesciences) to accurately quantify oxyhemoglobin saturations in blood 
passing the catheter tip.  This catheter is placed in standard fashion, and is coated with 
both Heparin and antimicrobials in order to diminish the risks of thrombus formation and 
infection, respectively.  Its insertion is similar to standard catheters which are routinely 
placed in the patient populations being studied here.  We have chosen to utilize this 
catheter in this study because it addresses the pitfalls of our current standard of care 
above, and because it will allow a continuous, real-time assessment of cardiac output 
and an estimation of the ratio of pulmonary to systemic blood ﬂow (Qp/Qs).  Of note, the 
catheter was recently used to safely and accurately quantify SvO2 in neonates following 
cardiac surgery.10  
Serum lactate measurement
Serum lactate represents the biproduct of anaerobic respiration within the tissues, and 
is therefore an obvious choice as a marker of inadequate DO2.  It is commonly 
measured in the clinical management of neonates following congenital heart surgery.  
Unfortunately, serum lactate can be falsely low in extreme tissue malperfusion (it is 
thought that lactate does not equilibrate with the plasma in situations of extremely low 
DO2), and can be falsely elevated by the use of inotropes (prototypically, epinephrine) 
and in hepatic dysfunction.  Together, these factors make isolated measurements of 
lactate difﬁcult to interpret.  
It has been previously shown that in adults experiencing a cardiac arrest, a high serum 
lactate (>10 mg/dL) is more common in patients experiencing a recurrent cardiac arrest.
13  It is also known that serum lactate measurements may correlate with chances of 
survival following cardiopulmonary bypass in neonates.14  On a population level, it is 

known that patients who experience a die following a postoperative cardiac arrest have 
higher pre-arrest lactate levels than those who survive.15  However, to date, this 
information has been of limited prospective utility in the prospective management of 
patients, speciﬁcally in guiding therapies to optimize DO2.16,17  
Oxygen consumption
As discussed above, when DO2 decreases below the critical DO2 threshold, VO2 
becomes pathologically supply dependent.  In clinical practice, VO2 is most commonly 
estimated based on normal values, though this has been shown to be an inaccurate 
practice.18  Alternatively, VO2 can be measured in intubated patients by calculating the 
fraction of oxygen that is inspired versus that which is expired during each breath.  That 
information, combined with the volume of each breath, represents the volume of oxygen 
consumed by the patient.  
Several commercially available devices have been shown to exhibit both precision and 
accuracy in quantifying VO2 in newborns, even those following congenital heart surgery.  
For example, Li has described the VO2 of newborns following S1P to be ~80-100 mL/
min/m2 19, using a VO2 monitor which utilizes mass spectroscopic evaluation of inhaled 
versus exhaled gases.  However, none of these studies have attempted to correlate 
VO2 with outcomes, neither short- nor long-term, including PLOC.19-23 
Members of this research team have become familiar with another device used to 
quantify VO2, and have utilized it in several clinical studies to date.24,25  Over the past 
three years, for example, members of our group completed a study in which VO2 and 
VCO2 were quantiﬁed in postoperative Fontan patients using this device in the CICU.24  
The nursing and respiratory care staff are therefore already familiar with the machine 
and its use.  
The device utilizes an in-line adapter which afﬁxes to the end of the endotracheal tube, 
and samples gas concentrations on a breath-to-breath basis (GE Healthcare, E-
CAIOVX module, Waukesha, WI).  The process for gas exchange measurement has 
been described previously.26 In brief, inspiratory and expiratory gas concentrations are 
obtained every breath utilizing a fast differential paramagnetic O2 analyzer and infrared 
CO2 analyzer by side-stream sampling. A ﬁxed oriﬁce, pressure differential 
pneumotachometer (D-lite (+) or Pedi-lite (+), GE Healthcare, Madison, WI) is used to 
measure gas volumes and ﬂows and to calculate VO2.  This device has been well 
validated against mass spectrometry and has been found to be both accurate and 
precise at even low VO2 levels.26
Preliminary Studies
The impetus for this study has stemmed from pre-clinical work performed by the PI.  In 
other work, the PI studied an intravenous treatment for complete asphyxia in which 
oxygen gas is packaged into microparticles to be rendered injectable.27  In this model, 
oxygen consumption was quantiﬁed using the GE device.  We have noticed that 
animals with extreme, untreated asphyxia exhibited a lower VO2 when compared to 
their healthy baseline, and that prior to a subsequent cardiac arrest, many animals 

exhibited a pronounced decrease in 
their measured VO2, a pattern which 
was not present in treated animals 
which did not experience subsequent 
hemodynamic instability (Figure 3).  
Having seen this pattern consistently in 
approximately n=40 animal experiments 
(weight range 2.5-4 kg), we hypothesize 
that in critically ill patients, VO2 may 
decrease below the critical DO2 and 
exhibit measureable, even striking, 
decreases prior to hemodynamic 
decompensation takes place.  If this 
hypothesis is true, quantiﬁcation of VO2 
may represent a new ‘vital sign’ which 
represents end organ oxygen delivery in 
critically ill patients.  Identiﬁcation of 
patients with pathologically supply 
dependent VO2 may permit deﬁnitive 
interventions to take place, e.g. initiation 
of extracorporeal life support, prior to a 
life-threatening PLOC.
Study Objectives
Speciﬁc Aim 1. To demonstrate that 
oxygen consumption (VO2) and superior 
vena cava (SVC) saturations can be 
safely and precisely measured continuously in newborns undergoing surgery for 
hypoplastic left heart syndrome (HLHS) or d-transposition of the great arteries with an 
intact ventricular septum (d-TGA/IVS).
Hypothesis:  Measurement of these oxygen-based parameters will not be associated 
with an increased incidence of equipment-related adverse events (e.g. line 
displacements, inadvertent extubations) and will lead to precise and reproducible 
measurements of these important parameters.
Speciﬁc Aim 2. To determine whether postoperative loss of circulation (PLOC, deﬁned 
as cardiac arrest requiring CPR, ECMO cannulation, or causing death) in these patients 
are associated with a change in oxygen consumption or SVC saturation prior to the 
event.
Hypothesis:  PLOC will be associated with signiﬁcant decreases in both oxygen 
consumption and SVC saturations for at least 10 minutes prior to the onset of cardiac 
arrest.
Speciﬁc Aim 3.  To determine whether the addition of the oxygen-based measurements 
to standardly measured parameters (i.e. vital signs, near-infrared spectroscopy 
Figure 3.  In a proof of concept study, VO2 monitoring of 
rabbits (weight ~3 kg) undergoing a 30 minute period of 
observation, followed by a 15 minute period of asphyxia, 
then a post-asphyxial recovery.  Exemplary VO2 tracings 
shown of animals treated (blue line) and untreated (red 
line) with an intravenous formulation of oxygen which 
prevented severe hypoxemic-ischemic injury.  Animals 
which suffered severe injury exhibited a signiﬁcant 
decrement in VO2 early during the recovery period, a 
pattern which worsened prior to post-asphyxial loss of 
circulation.  Animals who experienced treated asphyxial 
injury had an unchanged VO2 curve.  A central 
hypothesis of this study is therefore whether VO2 may 
represent a sensitive, real-time, prospective, and non-
invasive marker of circulatory failure and inadequate 
DO2 in newborns at risk for this life-threatening 
problem.

measurements, intermittent measurements of lactate and superior vena cava 
saturations) add power in predicting which patients will experience PLOC.
Hypothesis:  Continuous measurements of VO2 and SVC saturations will add 
signiﬁcantly to our ability to predict which patients will undergo PLOC.
Study Design
We will prospectively and continuously measure VO2 and SVC saturations in newborns 
undergoing stage I palliation (S1P) or hybrid palliation (HP) for HLHS (n=20) or arterial 
switch operation (ASO) for d-TGA/IVS (n=20), beginning at the time of ﬁrst preoperative 
intubation and ending at the time of the ﬁrst postoperative extubation.  Newborns will be 
followed for the occurrence of PLOC as the primary endpoint.  A study schematic is 
attached as Appendix 1.
Study Population
Inclusion criteria.  
1. Patient from birth to 6 months of age
2. HLHS AND no prior operations AND planned S1P or HP
OR
d-TGA/IVS AND planned ASO
3. Written parental informed consent
Exclusion criteria.
1. Weight < 2 kg
2. Disease speciﬁc
A. HLHS patients: Infants whose surgical plan includes a neonatal biventricular 
repair will be excluded. 
B. d-TGA/IVS patients:  Newborns with any additional cardiac defect other than 
an atrial septal defect will be excluded.
3. Patients on ECMO preoperatively
4. Clinically signiﬁcant tracheo-esophageal ﬁstula or known preoperative air leak
Recruitment Methods.  The ﬂow of patients and the infrastructure within the CVP at 
BCH is ideally suited for this study.  A list of planned newborn admissions, including 
presumptive anatomical diagnoses) is kept by the Advanced Fetal Care Program 
(AFCP) within the CVP, and is emailed to providers within the Cardiac Intensive Care 
Unit (CICU), which will be screened weekly by the study team.  Additionally, the CICU 
census will be screened each morning by a member of the study team for patients 
meeting inclusion criteria.  As a backup, CICU staff will be formally educated about the 
study and asked to page the PI upon admission of patients meeting inclusion criteria.  
The early newborn period is one which is full of anxiety, stress and an overwhelming 
amount of information.  In the spirit of achieving a more informed consent, we will 
attempt to raise awareness of the study in the following manner.  A one-page brochure 
describing the study will be placed in the employee areas of the AFCP.  Staff members 
who follow expectant mothers whose children have either HLHS or d-TGA/IVS will be 

asked to give the ﬂyer to their patients in order to allow time for parents to consider 
participation prior to the birth of their child.  Study staff will be made available for 
questions by email, phone or in-person for these parents at any time.  The ﬂyer is 
attached as Appendix 2.
When patients are identiﬁed who meeting study criteria, study participation will be 
discussed with the treating team, speciﬁcally including the patient’s cardiac intensivist 
and cardiac surgeon.  Following the verbal assent of the team, parents will be 
approached for written consent.  
Study Treatments
The treatment which newborns with congenital heart disease receive is complex, and is 
directed by a multidisciplinary team which includes a cardiac surgeon, a team of cardiac 
intensivist, a primary cardiologist and an array of cardiac subspecialists (e.g. cardiac 
catheterization staff).  Patients in this protocol will be treated according to the current 
standard of care in the CVP by their treating teams.  As this is a prospective 
observational study, there will be no treatments associated with the study except for the 
application and insertion of the relevant equipment, which is described below.
VO2 monitoring.  Currently, all patients undergoing mechanical ventilation for any reason 
are monitored using a capnograph, a device which features an adapter ﬁtted onto the 
end of the endotracheal tube for the continuous 
monitoring of end-tidal carbon dioxide (EtCO2), and 
other basic spirometric measures (e.g. tidal volume, 
VCO2, lung compliance).  There are several different 
capnograph devices in current use within BCH.  
However, none of these devices measure VO2, which is 
a critical endpoint in our study.  Therefore, patients 
included in the study will be monitored using a device 
with this capability (Datex Ohmeda Critical Care 
Monitor, GE Healthcare, E-CAIOVX module, shown in 
Figure 4).  As discussed above, the study team has 
accumulated signiﬁcant experience with this FDA-
approved device in children, and it has been used in 
other clinical studies in children at BCH.  All cardiac 
intensive care, cardiac anesthesia and cardiac ICU 
nursing staff will be inserviced on the equipment by a 
member of the study team prior to initiation of the study. 
In the opinion of the study team, VO2 has not been validated as a clinically useful piece 
of data in this age group.  Therefore, only the standard parameters of ventilation (i.e. 
end tidal CO2, capnograph waveform, tidal volume and lung compliance measurements) 
will be displayed on the monitor for clinician use for the duration of the study; VO2 will 
be recorded but not displayed on the monitor.
Figure 4.  The E-CAIOVX module of 
the GE monitor to be used in this 
study.  The plastic piece to the left ﬁts 
onto the end of the tracheal tube and 
measures features of inhaled and 
exhaled breath by side-stream 
analysis.  

SVC saturation monitoring.  Currently, all patients undergoing an S1P, HP or ASO 
routinely undergo placement of a temporary central venous catheter placed within the 
internal jugular vein, and terminating within the SVC.  These catheters are standardly 
used for infusion of inotropic medications, constant monitoring of central venous 
pressures and the intermittent withdrawal of blood for SVC saturation measurements.  
These catheters are standardly 4 French in size, are 5 cm in length and contain two 
lumens (Cook Medical).  Following admission to the CICU, these catheters are routinely 
treated with a Heparin infusion at 10 Units/kg/hour through one of the lumens until the 
time of removal.  
In lieu of the standard Cook Medical catheter, the treating team will place a similar FDA-
approved catheter, but which is ﬁtted with a ﬁberoptic sensor which continuously 
records the oxyhemoglobin saturation of the blood to which it is exposed.  The catheter 
is 4.5 French, 5 cm in length, has two lumens, 
and is Heparin bonded (PediaSat catheter, 
Edwards LifeSciences, Model# XT245HK, see 
Figure 5).  The catheter comes will a sterile 
percutaneous insertion kit.  As above, all 
cardiac intensivists, cardiac anesthesiologists 
and CICU nursing staff will receive a formal 
training on the insertion and care of this 
catheter by the company representative (Mr. 
Brad Cangiamila).  Prior to insertion, the 
catheter will be calibrated using an in vitro 
solution which comes with the catheter.  For 
those familiar with the device, this process will 
add 2-3 minutes to the insertion time.  
Following insertion of the catheter, the device 
will be attached to the study monitor (Datex 
Ohmeda Critical Care Monitor, GE Healthcare) 
via a specialized cable.  The catheters will be 
paid for by the PI.
In the opinion of the study team, the SVC saturation is a clinically useful piece of data 
which is routinely used at BCH in the management of patients.  Because the device 
readings have been shown to correlate well with oximetric readings from venous blood, 
the SVC saturation will be continuously displayed on the study monitor for clinicans to 
use at their discretion for the duration of the study.
The study will end following the ﬁrst postoperative extubation or removal of the central 
venous catheter, whichever occurs last.
Figure 5.  The PediaSat catheter to be used 
in this study is functionally the same as 
catheters routinely used in the perioperative 
care of newborns with CHD except that it is 
ﬁtted with a ﬁberoptic probe at its tip which 
continuously reads SVC saturation.  

Endpoints/Outcomes
Primary Outcome.  The primary outcome being measured will be a composite endpoint 
of PLOC, including the need for CPR, the need for ECMO in the setting of CPR, or 
death.
Secondary Outcomes.  Because Aim 3 of this study is to determine whether the 
aforementioned oxygen-based measurements add to the predictive power of the data 
standardly used to assess patients, there will be a substantial amount of data gathered, 
which is outlined below.
•
Oxygen-based parameters unique to this study
•
Oxygen consumption (Q1 second).  The VO2 will be recorded Q1 second as 
part of the ventilatory parameters described below.
•
SVC saturations (Q1 second).  SVC saturations as determined by oximetry 
will be recorded Q1 second.
•
Standard of care monitoring
•
Vital signs.  These data will include heart rate, arterial blood pressures, 
respiratory rate, pulse oximetry, atrial pressures, and central venous pressure. 
As discussed in detail below, these data will be extracted from an existing 
program which records the primary data Q5 second in time stamped fashion 
(T3 Program, Arcardia Solutions).
•
NIRS.  The near-infrared spectroscopy value represents the oxyhemoglobin 
saturation of the deep tissues.  This will be recorded Q1 second in time-
stamped fashion.
•
Ventilatory parameters.  All ventilation parameters will be recorded from the 
spirometry recordings from the capnograph.  These data include end-tidal 
CO2, fraction of inspired CO2, respiratory rate, fraction of inspired O2, fraction 
of expired O2, peak end expiratory pressure, peak inspiratory pressure, 
plateau pressure, mean airway pressure, airway resistance, inpiratory-
expiratory time ratio, inspiratory and expiratory times, inspiratory and 
expiratory tidal volume, compliance of the respiratory system, minute 
ventilation, VCO2, energy expenditure, and respiratory quotient.  These data 
will be recorded Q1 second in time-stamped fashion.
•
Standard labs will be drawn at the treating team’s discretion and gathered from 
the medical record each day.
•
Arterial blood gase and time drawn
•
Serum lactate and time drawn
•
SVC (or other venous) saturations and time drawn
•
Chemistry proﬁle, complete blood count (white blood cell count, hemoglobin, 
hematocrit and platelet count), coagulation proﬁle and times drawn
•
Treatments
•
Inotrope infusions are routinely administered, often in high doses, to these 
patients in the perioperative setting.  It is thought that these infusions affect 
both oxygen delivery to all tissues, as well as increasing myocardial oxygen 
consumption.  
•
Additionally, we will record intermittently administered medications, such as 
epinephrine, calcium gluconate, sodium bicarbonate, hydrocortisone, and 

thyroid replacement therapy, all of which may affect oxygen consumption and 
oxygen delivery as well. 
•
Chest explorations and operative interventions performed at the bedside (e.g. 
clipping of BTS or Sano shunt) will be recorded each day from a review of the 
medical record, discussion with the primary team (including the bedside 
nurse) and the notes within the medical record.
•
Blood loss from chest tubes (in mL/kg each hour) and blood product 
administrations (including the blood products given and the times at which 
they are given) will be recorded from the medical record each day.
•
Sedatives and paralytics are routinely used and also affect oxygen 
consumption.  
•
Diuretic medications are also routinely used, can affect preload.
•
Arrhythmias and 
•
Other clinical parameters
•
Urine output is a crude marker of intravascular volume and end organ oxygen 
delivery.
•
The presence of enteral feedings, the rate of feedings and the caloric 
densities will also be recorded, as these may affect a patient’s systemic 
vascular resistance.  
•
Operative characteristics
•
Full preoperative and postoperative anatomic diagnoses
•
Residual anatomic defects
•
Total pump time, cross-clamp time, circulatory arrest time, regional perfusion 
time, minutes of continuous and modiﬁed ultraﬁltration, blood products 
administered on bypass
Data Collection Methods, Assessments and Schedule
Outcome measurements
The majority of the endpoints presented above are routinely collected within the medical 
record as a part of patient care.  Therefore, the majority of the data will be abstracted 
directly from the medical record and into a spreadsheet for data analysis by a member 
of the study team during each day for the duration of the study.  The PI employs two full-
time technicians within his lab who will assist with this labor intensive process.  
•
The oxygen-based measurements which are central to this study, including VO2, 
SVC saturation, as well as all ventilatory parameters listed above will be saved to 
a computer program (S5 Collect, GE Healthcare) attached to the patient’s 
monitor.  This program saves data in time stamped fashion Q1 second.
•
Time-stamped vital sign data listed above will be exported daily from the 
hospital’s in situ T3 program (Arcadia Solutions).
•
The labs, treatments and other clinical parameters (see previous section) will be 
extracted in time-stamped fashion from the medical record each day by a 
member of the study team.
Patient variables

Upon study enrollment, we will record relevant variables for the purposes of 
comparisons between patients, including gestational age, date and time of birth, gender, 
weight and length, date of admission, known medical problems, current medication list.  
Markers of severity of illness will include the number of organ failures, number and 
dosing of inotropic medications, and any positive cultures.  
Adverse events
Although this is a prospective, observational study which do not anticipate will alter our 
standard practices, we will monitor vigilantly for complications associated with the 
standard therapies used in these patients for differences in study patients.  Namely, we 
will monitor for endotracheal tube complications (e.g. ventilator associated pneumonia, 
accidental extubation) and for central venous line complications (e.g. catheter 
associated bloodstream infections).
Safety end points
Because this is a prospective observational study and is not expected to directly impact 
patient care, we will not have stopping rules for an individual patient per se, except if 
informed consent is withdrawn by a parent or team member. 
Parameters for discontinuation of the research
All components of this study have been tested and validated in the critically ill newborn 
population.  As such, we do not anticipate any technical problems with the observations 
proposed in this study.  However, the research will be discontinued if an interim analysis 
shows a signiﬁcant increase in the adverse events presented above compared with a 
retrospective control.
Adverse Event Criteria and Reporting Procedures
A data safety and monitoring board (DSMB) will be composed of two clinicians 
knowledgeable in the postoperative care of children with congenital heart disease.  The 
DSMB for this study will include John Arnold, MD, Director of Respiratory Care, and staff 
Anesthesiologist and Intensivist at Boston Children’s Hospital, and Kirsten Odegard, 
MD, a staff Cardiac Anesthesiologist at Boston Children’s Hospital.  Meetings will be 
held at the discretion of the DSMB members and study investigators, at least once 
following enrollment of the ﬁrst 5 patients.   The following complications will be 
speciﬁcally monitored for and reported to the DSMB immediately upon occurrence: 
accidental extubation or central venous catheter removal thought to be related to the 
monitoring devices (these are both extremely unlikely given that they are FDA-
approved, widely used devices in children).  
Data Management and Statistical Analysis
Data management methods
Upon entry into the study, each patient will be assigned a unique patient identiﬁer which 
is unique from their medical record number for the purpose of patient tracking.  A 
spreadsheet which links each patient’s UPI and BCH medical record number will be 

kept in a separate binder, locked in the PI’s ofﬁce.  The UPI will be used to identify 
patients on all study-related materials, including the laptop used to collect data from the 
GE monitor (which includes all ventilation parameters and SVC measurements), and on 
the data collection forms.  Data from the T3 system will be extracted from SQL T3 
database, and stored in a deidentiﬁed manner using the same UPI.  
Logistic considerations
At the time of study enrollment, baseline characteristics 
will be collected and recorded on a deidentiﬁed form.  At 
the time of ﬁrst intubation or CVL placement, the pole-
mounted GE monitor will be brought to the room by 
study personnel, and data recording will begin in realtime 
to the S5 Collect program using an attached laptop 
(Figure 6).  The program ﬁle will be saved as the 
patients UPI and will not contain conﬁdential information.  
Care will be taken to synchronize the time stamps within 
each of the devices in order to ensure proper alignment 
of the various data sources.  
Each day, a member of the study team will visit the 
patient’s bedside to abstract the relevant information from 
the medical record, with corroboration from the patient’s 
bedside nurse and treating team.  When needed, the 
patient’s cardiac anesthesiologist or perfusionist will be 
contacted to clarify.  
Using a study laptop, all requisite information will be 
entered into a Microsoft Excel spreadsheet with the desired values listed on the left and 
each hour listed across the right.  Data will be hand-entered into the spreadsheet by a 
member of the research team, and annotated as necessary to clarify discussions with 
relevant parties.  These data will be double checked by a second member of the study 
team within 7 days.
Quality control methods
Quality in the data collected by the oxygen consumption monitor will be ensured by a 
self-test at startup according to the manufacturer’s instructions.  Further, 
anesthesiologist and respiratory care staff will be instructed to monitor for the degree of 
air leak from the respiratory system by calculating the difference between inspiratory 
and expiratory measured tidal volumes.  If the airleak exceeds this value, air may be 
added to the tracheal tube cuff.  We have shown that when this difference is <15%, VO2 
data are accurately measured in newborns.24  Further, an absence of end-tidal CO2 data 
will be used as a signal of an endotracheal tube disconnection and possible suctioning 
event.  VO2 measurements are known to be unstable for several minutes following 
suctioning28, so we will exclude VO2 data for 10 minutes following any ETT disconnect 
from analyses.  
Figure 6.  The oxygen-based 
monitoring and data collection 
systems utilized for this study are 
attached to a rolling pole which can 
be placed anywhere around the 
patient and easily moved for 
convenience and safety.

Data within the SVC monitoring probe will be ensured by an in vitro calibration prior to 
probe insertion.  When ever the treating team sends a venous blood gas from the 
central venous line, the co-oximetry value will be entered into the machine and used to 
recalibrate the probe in real-time.  
Quality in the transfer of data from the medical record to the spreadsheet will be 
ensured by an independent review of the primary data by a second member of the study 
team.  Furthermore, when possible, the ﬁelds for data entry will contain ‘Data 
Validation’ functions (i.e. value will turn red if outside expected limits, and hard stops will 
be inserted for physiologically impossible values).  Additionally, drop down lists will be 
utilized when possible to minimize data entry errors.  
Data Analysis Plan
Patients will be divided into patients who do and do not experience PLOC.  All variables 
will be normalized to hours prior to bypass, bypass time and hours post-bypass time, 
such that  all data for a speciﬁc post-bypass time will be aligned between patients.  All 
weight-dependent variables will be normalized to preoperative body weight.  Using 
GraphPad Prism, each variable will be entered into a different column for analysis.  
Simple analyses (e.g. mean, standard deviation, tests for normality) will be completed 
within GraphPad.   With regards to the primary endpoint, VO2 measurements will be 
analyzed for 120 minutes prior to a PLOC event in cases, and a randomly selected 120 
minute period in controls. Values will be compared between cases and controls
using generalized estimating equations (GEEs) to account for the correlation of multiple 
measurements within the same patient and to compare means between cases and 
controls. A post-hoc broken stick analysis will be used to determine the time prior to the 
event at which the VO2 changed in each patient experiencing an event. Data for HLHS 
and dTGA patients will be pooled together.
More complex analyses will be completed by a collaborating company called Etiometry 
(including Dimitar Baranov, PhD and Evan Butler, PhD, co-investigators on this study), 
with whom the PI and others within the CICU have an established relationship.  
Deidentiﬁed information will be sent to the company, who will complete further analyses.
Power Calculations and Sample Size
The measured oxygen consumption in neonates following S1P has been described as 
86±16 mL/min/m222. A sample size that includes 3 cardiac arrest events would allow us 
to detect a true decrease of 53 mL/min/m2 in oxygen consumption with 90% power and 
a signiﬁcance level of 0.05 (two tailed). Based on the signiﬁcant change in VO2 noted in 
the animal studies preceding cardiac arrest, we do not feel that this number is an 
unreasonable number. In order to collect 3 patients meeting the endpoint, we predict 
that we will require 20 patients undergoing S1P.
Risks and Discomforts
Because this is a prospective, observational study which we do not expect to change 
the standard of care, the risks associated with this study are really those of the standard 

of care.  The VO2 measurements will be taken using an FDA-approved device which 
samples gas from the side of the tracheal tube of each patient.  In reality, the adapter 
used by the study monitor is smaller and lighter than than used in our current 
capnographs, so the risk of accidental endotracheal tube removal should be the same 
or lower.  
The second standard intervention used here which imposes risk is the insertion of an 
internal jugular venous catheter, which again is standard practice in newborns 
undergoing these procedures.  The theoretical risks of this FDA  approved device are no 
different from standard catheters, which include bleeding, infection and thrombosis.  To 
address these, the staff within the CVP at BCH utilize an insertion bundle and antibiotic 
coated catheters, which will be a practice which is unchanged in this study.  As per 
routine in the CICU, the catheters will be infused with a Heparin infusion at 10 Units/kg/
hour through one of the two ports of the line, which will decrease any risk of thrombus 
formation.  The catheters are additionally coated with AMC Thromboshield (a coating 
containing both Heparin and antimicrobials), which will further decrease the risks of both 
infection and thrombus formation.  
Potential Beneﬁts
Potential Direct Beneﬁts
Because this is a prospective observational study, the measurements are not intended 
to change the standard of care by which these patients are treated.  However, there are 
several possible direct beneﬁts to patients:
•
Decrease in venous blood sampling.  It is possible that due to the indwelling 
oximeter that the care team will require fewer blood samples to be tested for SVC 
saturations.  This could potentially decrease the blood loss associated with blood 
sampling and diminish the risk of infection (which is associated with the number 
of times a line is entered).  
•
Improved assessments of Qp/Qs.  As discussed in the background section, the 
ratio of blood ﬂow to the lungs to that of the body is a vitally important number in 
the care of patients with HLHS.  In the CICU, it is common practice to make 
changes in patient management based on this value, although the value itself is 
quite often inaccurately assessed.3  The primary unmeasured variable in the 
calculation of this ratio is the SVC saturation.  The ability to constantly and 
accurately monitor this value, in combination with arterial saturations based on 
pulse oximetry, may vastly improve the quantiﬁcation of the Qp/Qs ratio and 
better inform management decisions at the bedside for critically ill neonates. 
•
Earlier recognition of circulatory failure.  Regardless of a patient’s underlying 
anatomy, the difference in oxyhemoglobin saturation between a patients systemic 
arterial and venous circulations represents the adequacy of end organ oxygen 
delivery (reference Figure 1 above).  It is possible that by continuously monitoring 
both the systemic arterial and venous oxyhemoglobin saturations (the former by 
pulse oximetry), that the treating team will be able to more rapidly identify 
evolving circulatory failure.  There are many interventions which could be utilized 

by the care team prior to PLOC which may improve patient outcomes as a result 
of and in response to this single factor.
Potential Indirect Beneﬁts
This study has the potential to signiﬁcantly improve the way that newborn patients (and 
others) are monitored in the postoperative period.  Currently, the circulation of these 
patients are assessed indirectly, using surrogate measures (using cNIRS, and 
intermittent lactate and SVC saturations measurements) and vital signs.  Because our 
deﬁnitive treatment for refractory circulatory failure is ECMO, and because ECMO itself 
can cause life-threatening complications, it is extremely challenging to determine which 
patients are at a higher risk of death or organ injury from inadequate DO2 compared to 
the risks of these complications from ECMO.  It is possible that if the primary hypothesis 
of the study, that critically ill patients in the CICU exhibit pathologically supply 
dependent oxygen consumption, that VO2 monitoring could add signiﬁcant, continuous, 
noninvasive information to the care of newborns during their highest risk period.  For the 
short term, this could permit treating teams to measure the effects of their interventions 
on oxygen delivery (e.g. addition of inotropes, blood transfusions, clips on shunts) and 
inform these decisions.  For the long-term, it is possible that VO2 and continuous SVC 
saturation monitoring could inform a predictive algorithm for the sensitive and speciﬁc 
prediction of which patients suffer from recalcitrant circulatory insufﬁciency, those which 
may be at risk for PLOC, and who would beneﬁt from ECMO support.  If true, this would 
likely signiﬁcantly improve the survival rate and neurologic outcomes of newborns with 
congenital heart disease. 
Privacy and Conﬁdentiality Provisions
Privacy Provisions
As mentioned above, patients will be identiﬁed by the PI or one of his designees by a 
regular, systematic review of the census and diagnosis list in the Cardiac Intensive Care 
Unit at Boston Children’s Hospital. Therefore, patients will not be approached for 
consent unless they meet full inclusion criteria and their treating team assents. Only 
parents, who will be aware of their child’s diagnosis of congenital heart disease, will be 
approached about the study.  None of the patient’s comorbidities will be discussed with 
the patient or family as part of this study.
Conﬁdentiality Provisions
All data will be tracked using unique patient identiﬁers (UPI). Links between UPI and 
name and medical record number will be kept in a password-protected ﬁle on the PI’s 
computer, and as a printed backup in the PI’s locked ofﬁce. Both of these will be 
destroyed following data analysis. All primary data will be saved on a hard drive 
maintained in the locked ofﬁce of the PI.  All data will be deidentiﬁed using the UPI as 
the only identiﬁer. All data ﬁles will be password protected, and only study investigators 
will have access to this password. All ﬁles sent via email will be sent with encryption.

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List of Appendices
Appendix 1.  Study schematic
Appendix 2.  Parent informational ﬂyer

Enrollment Criteria
Preoperative HLHS (n = 20)
OR
d-TGA/IVS (n=20)
Assent of cardiac surgeon and cardiac intensivist
Parental consent
* Enrollment begins at either first intubation or central venous line insertion (whichever occurs first) and ends at first 
   postoperative extubation or central venous line removal (whichever occurs last).
At first intubation*
-> Calibrate VO2
-> Check ETT leak
-> Begin data collection
-> In vitro calibration
-> Catheter insertion 
-> Confirm position in SVC
At CVL insertion*
Cardiac OR
 
Cardiac ICU
Daily collect:
-> Primary outcome (CPR, ECMO, death)
-> VO2 and SVC saturations
-> Cardiac output and Qp/Qs
-> NIRS, lactate, UOP
-> Inotropes
-> Blood loss and transfusion
-> Sedatives, paralytics
-> Feedings
-> Vital signs
From medical record
and discussion with 
primary team
From T3 database
From S5 Collect™
Oxy-CAHN Study 
Oxygen consumption-based assessments of hemodynamics in neonates following congenital heart surgery