Bedside Resources to Gauge Intravascular Volume Status in Hypovolemic Infants in the Operating Room
Phase: NA
Conditions: Hypovolemia, Craniosynostoses
Sponsor: University of Colorado, Denver

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 18-2513 
Project Title: Bedside Resources to Gauge Intravascular Volume Status in Hypovolemic Infants in 
the Operating Room 
Principal Investigator: Sarkis C Derderian  
Version Date: 07/01/2019 
 
1. Lay Language: 
 
Predicting fluid responsiveness in the operating room is essential to guide balanced resuscitation.  
Aggressive resuscitation may lead to significant morbidities, such as intra-abdominal hypertension, 
pulmonary edema, difficulty with ventilator liberalization, and consequently increased mortality 
[1].  Alternatively, under resuscitation may lead to mal-perfusion and end-organ dysfunction. 
 
A plethora of indices and tools have been studied and marketed to assess intravascular volume 
status with only a few proven reliable with reproducible results.  Based on pre-fluid challenge 
values, several of these tools have been used to predict who may benefit from additional fluid (fluid 
responders).  Alternatively, some of these tools have been used to distinguish fluid responders from 
non-responders based on changes in pre- and post-fluid challenge values.  Among these tools, the 
pulmonary artery catheter provides measurements of both left and right heart pressures which can 
be applied to calculate the cardiac output (CO) and stroke volume (SV).  Changes in these values 
(e.g. an increase in the stroke volume by 10%) between pre- and post-fluid challenge have been 
used to define fluid responders.  This devise, however, is invasive with several significant risks, and 
therefore is rarely used in children.  Echocardiography, on the other hand, is a non-invasive bedside 
study also used to assess CO and SV but is expensive and requires trained echosonagraphers for 
application.  Further, because a transthoracic probe is required to obtain the images, application in 
the operating room is difficult as the chest is often in the operating field limiting access to the 
echosonagrapher. Lastly, the esophageal aortic blood flow device (CardioQ-EDM, Deltex Medical, 
Chichester, UK) has been found in multiple adult and pediatric studies to reliably distinguish fluid 
responders from non-responders intensive care unit (ICU) and operating room [2-6].  Much like an 
orogastric tube, this device is simply placed by a provider in the patient’s esophagus and uses 
Doppler waveforms to measure aortic blood flow velocities (Figure 1).  Variations in the amplitude 
of peak velocities has been shown to corelate with intravascular volume status[2-6].  Specifically, a 
change in the peak velocity by greater than 10% between pre- and post-fluid challenge values has 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
been shown to accurately distinguishes those who are fluid responsive from those who are not with 
similar accuracy to echocardiography and pulmonary artery catheter readings[7].   
 
Figure 1 
 
A 
 
 
 
 
 
B               
                
 
Legend:  A) Illustration of CardioQ-EDM position. In children age 15 years and younger, the device is introduced through the oral cavity.  
B) Correct placement confirmed by descending aortic waveform.  
 
 
In recent years with continued technological advancements, there has been enthusiasm about less 
invasive, and in some cases, non-invasive, tools to gauge volume status.  Among these, bedside 
ultrasonography (performed by providers rather than sonographers) is a common tool used to 
evaluate the inferior vena cava (IVC) collapsibility index (CI) has been shown to be a reliable tool in 
adults [8].  Another non-invasive device uses a photoplethysmoraphic probe (CipherOx-CRI) placed 
on a digit to calculate the compensatory reserve index (CRI), a marker of proximity to 
hemodynamic collapse [9]. Both IVC CI and CRI have been shown in multiple adult studies to 
predictive the need for volume expansion, but their utility in the pediatric population is unknown.   
 
The goal if this proposed study is to employ the CardioQ-EDM probe to define fluid responders from 
non-responders among infants undergoing cranial vault reconstruction for craniosynostosis.  After 
defining these two groups in this single arm prospective trial, we will compare the predictive utility 
of non-invasive devices such as the CipherOx-CRI and IVC CI to currently employed indices (heart 
rate, systolic blood pressure, urine output and pulse pressure variability) to gauge the need for 
additional fluid and ongoing resuscitation.  If the CipherOx-CRI or IVC CI proved to be as predictive 
or better at predicting fluid responders, we hope to replace invasive arterial lines with non-invasive 
tools to guide resuscitation.   
 
We chose this population for several reasons.  First, CHCO performs approximately 50-70 of these 
cases a year making them a relatively accessible group. Second, these children are generally healthy 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
which will minimize physiologic confounders.  Additionally, they are paralyzed, have normal 
respiratory compliance, and providers maintain normothermia all of which will minimizing 
confounders.  Another unique benefit to this population is that these infants have been nil per os for 
several hours prior to surgery, putting them at risk for hypovolemia, and after induction, 
independent of the provider’s assessment of intravascular volume status, they all receive a bolus of 
crystalloid (10mL/kg).  This baseline data should provide sufficient data for analysis; but because 
these procedures are associated with significant blood loss and hypovolemia requiring aggressive 
resuscitation in the form of fluid or blood boluses[10], we plan to continue to collect pre- and post- 
bolus data with the hope to further validate the benefit of non-invasive tools such as the CipherOx-
CRI and IVC CI in the setting of ongoing blood loss.   
 
Aggregated data collected from the past five cases suggests that these infants lose approximately 
100 mL of blood (17.2 mL/kg), receive 200 mL (37 mL/kg) of crystalloid and 75 mL (12.9 mL/kg) 
of blood (Table 1).   
 
Table 1: Previous Five Cranial Vault Reconstruction Procedures 
Case 
Number 
Age 
(months) 
Weight 
(kg) 
Blood Loss 
Infusion 
 
(ml) 
(ml/kg) 
Crystalloid 
Colloid 
(mL) 
Blood 
(mL) 
(ml/kg) 
(mL) 
(ml/kg) 
1 
5 
5.8 
100 
17.2 
200 
34.5 
0 
75 
12.9 
2 
4 
5.4 
75 
13.9 
200 
37.0 
0 
55 
10.2 
3 
8 
7.0 
80 
11.4 
180 
25.7 
0 
0 
0 
4 
7 
7.1 
125 
17.6 
500 
70.4 
0 
119 
16.8 
5 
3 
6.6 
200 
30.3 
300 
45.5 
0 
255 
38.6 
Mean 
5.4 
6.38 
116 
18.1 
276 
42.6 
0 
100.8 
15.7 
Median 
5 
6.6 
100 
17.2 
200 
37.0 
0 
75 
12.9 
 
As intravascular volume status is often difficult to assess clinically, we aim to determine the 
predictability of non-invasive devices to guide resuscitation.  In this prospective observational 
study, we hope to identify: 
1. The proportion of children within the cohort who are fluid responsive based on 
CardioQ-EDM aortic blood flow velocity changes pre- and post-bolus,   
2. The PPV, NPV, sensitivity, specificity, and optimal threshold for CRI, IVC CI, pulse 
pressure variability, stroke volume variability, heart rate, systolic blood 
pressure, and mean arterial pressures in predicting fluid responders as 
determined by CardioQ-EDM, and  
3. Assess confounding variables that may influence the predictive utility of such 
devices 
 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
2. Background 
 
Objective measures to guide resuscitation became mainstream with the introduction of the 
pulmonary artery catheter in 1970 [11].  Over the ensuing decades, several randomized control 
trials demonstrated that the use of pulmonary artery catheters did not incur a survival advantage.  
In fact, the complexity inherent in placing, operating, and interpreting data from this tool is not 
without risk. Thus, in large part, these invasive devises have fallen out of favor [12-14]. There has 
since been a focus on developing minimally invasive and non-invasive tools to gauge intravascular 
volume status in order to accurately direct resuscitation.   
 
Several of these techniques rely on cardiopulmonary interactions with the cyclic variations of intra-
thoracic pressure produced by ventilation.  In a mechanically ventilated patient, changes in intra-
thoracic pressures are transmitted to the right ventricle with increased pressure during inspiration 
and decreased pressure during exhalation.  In patients who are intravascularly deplete, these 
pressure shifts lead to larger variations in measured parameters such as pulse pressure, IVC 
collapsibility, and plethysmography throughout the respiratory cycle.  Figure 2 describes the 
variation in pulse pressure which is represented by ΔPs.  Plethysmography variation and CI are 
derived in a similar fashion using corresponding waveforms with the notion that more variation 
correlates with less intravascular volume.   
 
 
Figure 2 
 
Ppmin, minimal arterial pulse pressure; Ppmax, maximal arterial pulse pressure; Psmin, minimal arterial systolic pressure; Psmax, maximal 
arterial systolic pressure; ΔPs, pulse pressure variability.  From Vasodilation increases pulse pressure variation, mimicking hypovolemic 
status in rabbits. Westphal GA, Goncalves AR, Bedin A et al., 2018, Clinics[15].  
 
 
Tools and indices available to measure intravascular volume status are numerous with the most 
frequent utilized ones described in Table 2. These indices range from simply measuring the systolic 
blood pressure to using computer generated algorithms in order to calculate a CRI.  This 
armamentarium has vast applicability, but the predictive utility is variable, influenced by several 
confounders, and must be applied in the appropriate clinical setting.  
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
Table 2:  Intravascular Volume Status Measurements 
 
INVASIVE DEVICES 
 
SWAN-GANZ CATHETER       
CO, SVR, SV, LVEDAI, GEDVI, CVP, PCWP 
CENTRAL VENOUS CATHETERS 
CVP, SvO2, DpCO2 
ARTERIAL LINES 
PPV, SVV, SPV 
ESOPHAGEAL DOPPLER 
DVpeak, SV, CO, ABF 
CAPNOMETER 
DETCO2  
 
 
NON-INVASIVE 
 
VITAL SIGNS 
HR, SBP 
PLETHYSMOGRAPHY 
Plethysmography variation index 
ULTRASONOGRAPHY 
IVC CI 
ECHOCARDIOGRAM 
CO, SV 
COMPENSATORY RESERVE INDEX 
CRI 
CO – cardiac output, SVR – systemic vascular resistance, SV – stroke volume, LV – left ventricular end-diastolic area index, GEDVI – global 
end-diastolic volume increase, CVP – central venous pressure, PCWP – pulmonary capillary wedge pressure, SvO2 – mixed venous oxygen 
saturation, DpCO2 – delta partial pressure of carbon dioxide, PPV – pulse pressure variation, SVV – stroke volume variation, SPV – 
systolic pressure variation, DVpeak – delta aortic blood flow peak velocity, ABF -  aortic blood flow, DETCO2 – delta end-tidal carbon 
dioxide level, HR – heart rate, SBP – systolic blood pressure, IVC – inferior vena cava, CI – collapsibility index, CO – cardiac, CRI – 
compensatory reserve index   
 
 
 
While large series have evaluated the predictive utility of various devices in adults, reports 
appraising tools used to assess fluid responsiveness in children are limited with heterogeneous 
findings [16].  A systematic review by Gan et al. published in 2013 reviewed 12 pediatric studies 
that, in total, evaluated 24 markers of fluid responsiveness in 439 children.  The only variable that 
was repeatedly found predictive of fluid responsiveness and distinguish fluid responders from non-
responders was variation in aortic blood flow peak velocity (ΔVPeak) obtained from the CardioQ-
EDM. Not only has this tool been shown to predict those who will benefit from additional fluid, but, 
based on changes in pre- and post- fluid ΔVPeak, in it has been shown to accurately distinguish fluid 
responders from non-responders [7]. 
 
In adults, the esophageal CardioQ-EDM has been used both in the operating room and ICU.  Among 
adult trauma patients admitted to the ICU, CardioQ-EDM has been used to guide resuscitation and 
shown to decrease infection complications as well as reduce ICU and hospital length of stay [17].  In 
children, increased enthusiasm in recent years has led to a number of small clinical trials most of 
which have been performed in Europe.  In a metanalysis published in 2016 included six studies and 
163 ventilated children, comparing CardioQ-EDM to echocardiography the authors concluded that 
the area under the summary receiver operating characteristic curve to distinguish responders from 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
non-responders for ΔVPeak was 0.94 [18].  While the optimal ΔVPeak varied from 7-20% among 
studies, one of the larger series using a ΔVPeak of 10% as a threshold found the sensitivity and 
specificity to be 100% in distinguishing fluid responders based on aortic velocity–time integrals 
identified by transthoracic echocardiogram [7].  Based on these results, we plan to define fluid 
responders as those who have >10% ΔVPeak between pre- and post-fluid challenge. 
 
Bedside evaluation of the IVC to calculate the CI is a commonly used tool in adults [19, 20].  It serves 
as a surrogate to measure preload variation induced by mechanical ventilation.  The technique 
requires limited ultrasonographic experience often at the critical care or anesthesia fellow level.  In 
pediatrics, the predictive utility of IVC CI has only been evaluated in small series with conflicting 
results [21].   
 
The CRI is another non-invasive devise using a photoplethysmoraphic probe (CipherOx-CRI) placed 
on the index finger. Based on data gathered from the probe, a computer-generated algorithm is then 
used to calculate a number between zero and one, referred to the CRI (Figure 3)  [22].  The CRI 
correlates to one’s intravascular volume status and proximity to hemodynamic collapse [23].   
 
Figure 3 
 
Legend: CRI, compensatory reserve index. CRI=1 is normovolemia and CRI=0 is the point at which the patient is at highest risk for 
hemodynamic decompensation.   
 
 
Confounders that can influence dynamic measurements must also be considered.  For instance, 
cardiac arrhythmias, small tidal volumes, spontaneous respiration, and high positive end-
expiratory pressure have been found to decrease the predictive utility of pulse pressure variability 
and IVC CI [24-26].  Thus, it is paramount to use and apply these measurements in the appropriate 
clinical setting.  Presumably, the influence confounding variables have on the predictive utility of 
these indices in children is similar to that of adults, however, comparative analyses have not been 
performed.  Thus, when interpreted in the appropriate clinical context, these minimally and non-
invasive devices are tools available to guide a balanced fluid resuscitation; however, while small 
series exist in various pediatric populations, validation is necessary in order to apply these tools in 
hypovolemic children with significant blood loss. 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
 
While numerous tools are available to guide resuscitation, one potential benefit of this project is to 
validate the use of CipherOx-CRI in this cohort.  If CRI proves to be a valuable predictor of 
intravascular volume status and the need for volume expansion, this could negate the need for 
arterial line placement which is time consuming, invasive, and associated with complications such 
as arterial thrombosis.  Furthermore, after validation in this cohort, additional studies could be 
performed in other groups of children at risk for hemorrhagic shock in the hopes to guide ongoing 
resuscitation accurately without the need for invasive devices.   
 
 
3. Specific Aims and Hypotheses: 
 
Aim I: Among infants undergoing cranial vault reconstruction for craniosynostosis, we aim to 
determine the proportion who respond to clinically administered fluid or blood products defined 
by pre- and post-fluid challenge EDM ΔVPeak >10%. 
 
Hypothesis Ia:  We hypothesize that approximately half of the cohort will be fluid 
responsive defined by ΔVPeak by > 10% after a 10 mL/kg fluid bolus is administered 
immediately following induction.  Although this is a prediction, it is based on previous 
published reports suggesting a relatively even distribution among patients who clinicians 
believe need volume expansion.   Additionally, because these children have a mean weight 
of 6.4 kg and will have been nil per os for several hours prior to surgery, they are at risk for 
intravascular volume depletion even prior to blood loss.   
 
Hypothesis Ib:  Because clinicians use pulse pressure variability, heart rate, systolic blood 
pressure, urine output, and blood loss to gauge need for ongoing resuscitation (either 
crystalloid, colloid, or blood), we suspect that more than half of subsequent fluid challenges 
will be given to infants who are fluid responsive (defined by a pre- and post-bolus ΔVPeak 
of > 10%). 
 
 
Aim II: To determine the PPV, NPV, sensitivity, specificity, and optimal threshold for CRI, 
collapsibility index, pulse pressure variability, stroke volume variability, heart rate, systolic blood 
pressure, and mean arterial pressure as tools to predict fluid responsiveness using pre- and post-
fluid challenge EDM ΔVPeak >10% to define fluid responders. 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
Hypothesis II:  CRI and collapsibility index will reliably predict fluid responsive patients 
with an approximate area under the receiver operating characteristic curve (AUROC) of 0.9 
while other indices will have a lower predictive accuracy.   
 
 
Aim III: Evaluate confounding variables that may influence predictive measures outlined in Aim II. 
 
Hypothesis III:  Confounding variables that may decrease the predictive accuracy of indices 
described in Aim II include spontaneous breathing over the ventilator, minimal blood loss, 
and hypothermia 
 
 
4. Materials and Methods: 
 
4.1 Pre-trial Training 
 
1) Prior to patient enrollment, the principle investigator (PI) and two co-investigators 
will be trained by a certified ultrasonographer regarding how to measure the IVC CI.  
After participating in a one-hour skills lab, the PI and co-investigators will be 
evaluated for competency and reproducibility.  If deemed incompetent, remediation 
will be required prior to the start of the trial.  Additionally, we will confirm inter-
observer reliability between co-investigators to assure measurement reliability.   
 
2) The PI and Co-investigators (Drs. Shahi or Phillips) will be trained in the 
appropriate placement and operation of the CardioQ-EDM probe and monitor by a 
manufacturer representative.  Given the PI’s extensive experience with both nasal 
and oroesophogeal device placement (see below), after the manufacturer 
representative confirms competency with appropriate probe positioning, he will be 
responsible for all probes placed.  Prior to enrolling patients in the study, a 
manufacturer representative will provide a live demonstration in a child undergoing 
cranial vault reconstruction after informed consent.    
 
 
4.2 Materials Necessary 
 
1. Esophageal aortic Doppler (CardioQ-EDM) probe = 30 provided by Deltex Medical  

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
2. CardioQ-EDM monitor = 2 provided by Deltex Medical 
3. Bedside Ultrasound = 2 machines are available in the operating room at all times 
4. CipherOx CRI – Provided by Division of Pediatric Surgery 
 
 
4.3 Patient recruitment 
 
Patients will be identified by the PI based on communication with the craniosynostosis clinic team.  
Parents/guardians of eligible candidates will be approached by a study team member at their pre-
operative appointment or on the day of surgery for voluntary participation.  If recruitment is 
insufficient (<70%), a $20 gift card will be used as incentive for study participation.  Funding will be 
provided by the division of pediatric surgery if this is necessary.   
 
4.3.1 Population: Children older than 3 months and younger than 2 years of age who 
undergo cranial vault reconstruction in the supine position will be included.   Children with 
associated syndromes will be included as long as they do not have known underlying 
cardiac abnormalities.  Consent will be translated into Spanish as well for those in whom it 
is indicated.   
 
4.3.2 Exclusion Criteria: Children with known underlying cardiac anomalies or cardiac 
arrhythmias, infants younger 3 months of age or greater than 2 years of age.  In addition, 
children weighing less than 3 kg will be excluded at the recommendation of the 
manufacturer.  While vasopressor (epinephrine, norepinephrine, and/or vasopressin) 
support is not a contraindication, fluid boluses administered during dosage adjustments 
will be excluded from analysis.  Patients who are placed in the prone position for surgery 
will also be excluded given the difficulty with obtaining a window to measure the IVC CI and 
possible effect on reported measurements.  Additionally, if abnormal anatomy is discovered 
while assessing the IVC, these children will also be excluded from analysis. 
 
 
 
4.4 Definitions 
 
• Bolus – 10 - 20 ml/kg fluid (isotonic crystalloid, colloid, or blood product) up to 1 L 
and given within a 10 minutes period 
• Fluid responders – Children who have a pre- and post-fluid challenge ΔVPeak > 10% 
calculated using the equation (ΔVPeakpre = (VPeakmaxpre – VPeakminpre)/ 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
[(Vpeakmeanpre]) -  (ΔVPeakpost = (VPeakmaxpost – VPeakminpost)/ [(Vpeakmeanpost]) 
x 100 
• Multiple fluid challenges – If more than one fluid bolus is administered at least 30 
minutes apart, they will be reported as individual events  
• Pre-bolus measurements – Hemodynamic measurements will be calculated or 
recorded three times thirty seconds apart and averaged just before a bolus is 
administered.  Cine loops from IVC measurements will be recorded three times, 
thirty seconds apart for post-hoc CI calculation. Peak aortic velocity and CRI will be 
recorded on the EDM monitor and averaged over 90 seconds.   
• Post-bolus measurements - Hemodynamic measurements will be calculated or 
recorded three times and averaged five minutes after a bolus is completed. These 
measurements will be time and repeated in an identical fashion to pre-bolus 
measurements.     
 
 
4.5 Decision for volume expansion 
 
All children receive a 10 ml/kg crystalloid bolus immediately after induction.  The need/decision 
for a fluid bolus will be determined by the anesthesiologist based on clinical judgement. Currently, 
the anesthesiologist places an arterial line at the beginning of the case and using pulse pressure 
variability, HR, SBP, MAP, urine output, and blood loss determines whether or not a fluid or blood 
bolus is appropriate.  Data collected from the CardioQ-EDM, CipherOx-CRI, and bedside ultrasound 
will not be provided to the care team.   
 
 
4.6 Data Acquisition  
 
If consent is obtained, a CardioQ-EDM probe will be placed on the day of surgery after induction of 
general anesthesia.  One of the investigators will be present in the operating room for the duration 
of surgery to perform study procedures (PI or Co-investigators (Drs. Shahi or Phillips) to place all 
CardioQ-EDM probes) and gather study data. The anesthesiologist will inform the investigator of 
plans to provide a fluid or blood bolus per clinical judgement in addition to the protocolized 10 
ml/kg bolus provided after induction.  While the anesthesiologist is preparing to administer volume 
expansion, a co-investigator will collect pre-fluid bolus data.  Administration of fluid will not be 
delayed for any reason, including performance of study measurements.  Measurements will be 
recorded for data analysis at the completion of the trial (see below).  Additionally, a CipherOx-CRI 
probe will be placed on the patient’s index finger (again, recorded data will be interpreted post hoc) 
and a bedside ultrasound will be performed by either the PI or one of two co-investigators to 
measure the IVC CI.  The IVC CI will be visualized through a sub-xyphoid window.  The ultrasound 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
indicator will be aimed at the child’s left flank. Once the right atrium is identified, the ultrasound 
probe will be turned 90 degrees counterclockwise so the indicator is directed at the head. The best 
way to evaluate the IVC diameter through the respiratory cycle is to use M mode. After positioning 
the probe appropriately in order to visualize the IVC 2 cm inferior to the cavo-atrial junction, the M 
mode will be activated to measure variation in the IVC diameter with respiration.  Ultrasound cine-
loops will be recorded, and CI will be calculated post-hoc.  Data will be recorded on the Data 
Collection Form for each fluid bolus administered. The PI and co-investigators will manage all 
aspects of investigational devices.  
 
Day of Surgery Step-by-step Description: 
1. While the anesthesiologist intubates and places an arterial-line, the CardioQ-EDM monitor, 
CipherOx-CRI device, and U/S will be set up 
2. After positioning the patient for surgery, the CardioQ-EDM device will be placed through the 
mouth into the esophagus by the PI or Co-investigators (Drs. Shahi or Phillips) and the 
aortic Doppler waveform will be confirmed.  Additionally, the CipherOx-CRI finger probe 
will be placed, and a baseline IVC CI will be measured and recorded. 
3. Baseline values and measurements (included in Table 3) will be recorded.  Additionally, the 
baseline ΔVPeak and CRI will be recorded.  
4. A protocolized 10 mg/kg crystalloid fluid bolus will be administered  
5. Two minutes after the bolus has completed, repeat EDM and CRI values will be recordings 
and a repeat abdominal ultrasound to measure the IVC CI will be obtained.   
6. If an additional fluid bolus or blood transfusion is administered during the remainder of the 
procedure, steps 3 and 5 will be repeated.   
 
 
 
4.6.1 Demographic Data: Age, weight, height, body mass index (BMI), gender, and ethnicity will be 
collected from medical records. 
 
4.6.2 Ventilator Data:  pressure or volume control, tidal volume (ml/kg) and peak end-expiratory 
pressure (PEEP), peak inspiratory pressure (PIP), and spontaneously breathing.  
 
4.6.3 CardioQ-EDM Data: Based on a validated internal nomogram derived from the child’s age, 
height, and weight[27], peak velocities will be obtained from the Cardio-EDM monitor. 
 
4.6.4 Fluid Data/Vasopressor Administration: Number, time, type, and volume of fluid/blood 
administered will be recorded in real time. Vasopressor agent, dose, and time administered will 
also be reported. 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
 
4.6.5 Waveform/Vital Data: As it is currently not possible to extract waveform data from the 
operating room monitors, we will record data in real time.  Values listed below will be reported on 
an excel spreadsheet.    
 
Parameters to measure: 
All parameters will be measured x 3 with 30 seconds between each measurement and 
averaged  
• Systolic blood pressure (measured by arterial line) 
• Mean arterial pressure (calculated from arterial line) 
• Heart rate 
• Pulse pressure variability (measured by arterial line) = acquired from arterial 
line 
• Stroke volume variability – acquired from arterial line 
• DVpeak = (VPeakmax – VPeakmin)/ [(Vpeakmean] x 100 
• Compensatory reserve index – algorithmically generated  
• Inferior vena cava collapsibility index = Maximum diameter (expiration) – 
minimum diameter (inspiration)/maximum diameter (expiration) in M mode 
 
4.7 Data Blinding:   
 
Reporting bias will be minimized by limiting interactions between the study team and OR team.  
Furthermore, as all children receive a bolus prior to incision, independent of available indices used 
to assess intravascular volume status, bias should be minimized for this fluid bolus.  As these 
devices are experimental in this patient population, anesthesiologists will be blinded to 
hemodynamic data generated by the CardioQ-EDM, bedside ultrasound, and CipherOx CRI. If data is 
needed in an emergent setting, the subject will be excluded from analysis. Although recorded 
measurements from the Cardio-Q EDM monitor will be visible to the study team, IVC measurements 
will be stored and calculated post-hoc by a co-investigator blinded to whether or not the subject is 
or is not fluid responsive.  Additionally, a trained statistician not involved in data collection will be 
paid for analysis.  It should also be noted at Dr. Steven Moulton is a paid officer of CipherOx but will 
not be involved in the data collection and analysis. 
 
 
4.8 Data Analysis 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
Univariate comparisons between various measures will be compared between the fluid responder 
and non-responder groups using t-tests or Fisher’s exact test for continuous and categorical 
measures, respectively. Area under the curve will be calculated for CI and CRI using both simple 
logistic regression models including no confounders and multiple logistic regression models 
including confounders. Confounders will be identified for inclusion in the multiple logistic 
regression models by calculating the univariate association with the gold standard (using a p<0.10 
threshold). These adjusted models will be used to verify thresholds for classification using CI and 
CRI which will then be applied to calculate classification summary measures (e.g., PPV, NPV, 
sensitivity, and specificity). Data analysis will be performed by a biostatistician funded by the 
Division of Pediatric Surgery using R and SAS statistical software programs. 
 
 
4.9 Risk, Safety, and Indications/Contraindications 
 
Both the Deltex Medical CardioQ-EDM (Deltex Medical Limited; K172457; June 28, 2018), and the 
CipherOx CRI, (Flashback Technologies, Inc.; K173929; July 24, 2018), have been cleared through 
Class II/Traditional 510(k)s.   
 
The CardioQ-EDM has been used in over 400,000 patients worldwide. To date, there have been no 
serious adverse events associated with EDM. Extrapolating data from nasogastric tube and 
transesophageal echocardiography probe placement, the incidence of esophageal perforation is 
exceedingly low and only described in case reports and small case series.  Nonetheless, the risk of 
esophageal perforation will be discussed during the informed consent process.   The co-investigator 
in the operating room will be responsible for reporting any adverse events to the PI.  In the event of 
an adverse event, the PI will fully disclose details to the participants family, COMIRB, Children’s 
Hospital Research Institute, and Deltex Medical.    
 
To minimize risk associated with CardioQ-EDM placement, the PI or Co-investigators (Drs. Shahi or 
Phillips) who all have experience placing similar objects will place the device by applying jaw thrust 
in the standard fashion.  Proper positioning of the device will be confirmed by Doppler waveform, 
negating the need for radiographic confirmation.  Specific pediatric CardioQ-EDM probes (KDP72) 
which are indicated in children age 15 and younger will be placed through the oral cavity. Although 
the device has not been used at CHCO previously, the insertion is identical to an orogastric tube 
placement and thus the investigators do not believe that a bioengineering review is necessary.  
 
One additional risk is the potential for extubation with probe manipulation.  To minimize this risk, 
probes will be placed while the anesthesiologist maintains the airway.  If at any point during the 
case, the probe becomes mal-positioned, no repositioning will be performed, and the study is 
terminated for this individual in an effort to avoid inadvertent extubation.  Furthermore, the probe 

Protocol #: 18-2513 
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Version date: 07/01/2019 
 
will remain in place until the time of extubation to again minimize the risk of inadvertent 
extubation.    
 
 
The CipherOx-CRI probe was cleared by the FDA for patients with a finger thickness of 0.3 to 1 inch.  
There were no warnings, precautions or contraindications in the product brochure. 
  
4.9.1 CardioQ-EDM Details 
• The Deltex Medical Doppler KDP72 probe is for use in patients aged 15 
years or younger for up to 72 hours. 
• The KDP probe is 28 in (72 cm) long and has maximum usage time which is 
defined on the probe packaging. 
• It is only approved for ORAL placement into the esophagus of a single 
patient over 5.5 lb. (2.5 kg) in weight. 
• The patient should be under full sedation or general anesthesia. 
• The probe shaft has six depth markers visible through the transparent 
cover starting at 6 in (15 cm) through to 16 in (40 cm) incrementing in 
steps of 2 in (5 cm). These markers act as a guide to facilitate correct probe 
placement.  
• Nasal placement of any probes in patients aged 15 years or younger is not 
approved nor is usage of the CardioQ-EDM for patients below 5.5 lb. (2.5 
kg) in weight. 
 
4.9.2 CardioQ-EDM Contraindications 
• Doppler probes (DP240 and I2n) should not be placed in patients under 16 
years of age. We will be using the KDP72 probe 
• Do not use where nasal injuries are apparent or may have occurred. 
• Do not use where nasal polyps exist. 
• Do not use where there are circumstances of facial trauma. 
• Do not use where there is a risk of brain injury. 
• Do not use in patients undergoing intra-aortic balloon pumping. 
• Do not use with carcinoma of the pharynx, larynx or esophagus. 
• Do not use with aneurysms of the thoracic aorta. 
• Do not use with tissue necrosis of the esophagus or nasal passage. 
• Do not use in close proximity to laser surgery. 
• Do not use in patients with pharyngo-oesophago-gastric pathology and/or 
severe bleeding diatheses. 
 
 

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5. Specific Aims: 
 
Aim I: Define fluid responders based on aortic DVpeak: Among infants undergoing cranial vault 
reconstruction for craniosynostosis, we aim to determine the proportion who respond to clinically 
administered fluid or blood products defined by pre- and post-fluid challenge EDM ΔVPeak >10%. 
 
Mock-up Table 1:  Demographics of Responders and Non-Responders to Initial 10 mL/kg 
bolus prior to surgical incision  
 
Variable 
Responders 
Non-Responders 
P-value 
Demographics 
     Age  
     Weight 
     Height  
     BMI 
     Gender 
     Ethnicity 
Duration of NPO status 
Associated syndrome 
 
 
 
Legend:  BMI, body mass index; npo, nil per os 
 
Aim II:  Calculate the PPV, NPV, sensitivity, specificity, and optimal threshold for CRI and 
collapsibility index as tools to prediction fluid responder 
 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
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Performance will also be calculated for heart rate, systolic blood pressure, mean arterial pressure, 
pulse pressure variability and stroke volume variability. Two separate analyses will be performed – 
one for the 10 ml/kg protocolized bolus provided immediately after induction and one accounting 
for all boluses provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
 
 
Mock-up Figure 
 
 
 
 
Mock-up Table 2 – Performance at predicting fluid responsiveness 
 
Variable 
Correlation (r) 
AUC 
IVC CI 
 
 
CRI 
 
 
SBP 
 
 
PPV 
 
 
SVV 
 
 
MAP 
 
 
HR 
 
 
 
 
 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
Aim III: Evaluate confounding variables that may influence CRI or collapsibility index 
 
Variable 
Scale of 
Measurement 
Data Point 
Location 
Analysis 
Method 
Outcome Variable 
 
    IVC CI, CRI, PPV, SVV, HR,      
    SBP, MAP AUROC 
 
     
 
 
 
 
Interval 
 
 
 
 
Pre-bolus 
measurements 
Multivariable 
Linear 
Regression 
Confounding Variables 
   Age 
   Weight 
   BMI 
   Gender 
   Ethnicity 
   Associated syndrome 
   Preoperative Hemoglobin 
   Duration of NPO status 
   Core temperature at time of     
     bolus 
   Paralysis provided (Y/N) 
   Blood transfusion (Y/N) 
   Total blood volume 
   Total Crystalloid 
   Total Colloid 
   Vasopressor requirement 
   Total amount of vasopressor   
   Ventilation  
        Tidal volume 
        PEEP 
        PIP 
        Spontaneous breaths 
 
Interval 
Interval 
Interval 
Dichotomous 
Ordinal 
Dichotomous 
Interval 
Interval  
Interval  
 
Dichotomous 
Dichotomous 
Interval Interval 
Interval 
Dichotomous 
Interval 
 
Interval 
Interval 
Interval 
Dichotomous 
 
Demographics 
Demographics 
Demographics 
Demographics 
Demographics 
Demographics 
Preop results 
 Anesthesia Rec 
Anesthesia Rec 
 
Anesthesia Rec 
Anesthesia Rec 
Anesthesia Rec 
Anesthesia Rec 
Anesthesia Rec 
Anesthesia Rec 
Anesthesia Rec 
 
Ventilator 
Ventilator 
Ventilator 
Ventilator 
 
 
Figure or Table will depend on results found.  If neither of the outcome variables are affected by the 
confounding variables may only report this finding in the text. 
Two separate analyses will be performed – one for the 10 ml/kg protocolized bolus provided 
immediately after induction and one accounting for all boluses provided. 
 
 

Protocol #: 18-2513 
PI: Sarkis C Derderian 
Version date: 07/01/2019 
 
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