SURV1VE-Trial - Sustained Inflation and Chest Compression Versus 3:1 Chest Compression to Ventilation Ratio During Cardiopulmonary Resuscitation of Asphyxiated Newborns: A Randomized Controlled Trial
Phase: NA
Conditions: Heart Arrest, Birth Asphyxia, Bradycardia
Sponsor: University of Alberta

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Protocol 
 
SURV1VE-Trial  
 
Sustained inflation and chest compression versus 3:1 chest 
compression to ventilation ratio during cardiopulmonary resuscitation 
of asphyxiated newborns – a cluster randomized controlled trial 
 
 
 
Protocol: 
Protocol SURV1VE Phase II 
Trial phase 
Phase II 
Protocol date (version): 
Version 4.0, December 1st 2020 
Study sites:
Multi-centre; Multi-national

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Declaration of Commitment  
 
Name of investigator 
 
 
Institution 
 
 
 
Clinical trial 
Trial title 
SURV1VE-Trial - Sustained inflation and chest compression 
versus 3:1 chest compression to ventilation ratio during 
cardiopulmonary resuscitation of asphyxiated newborns – a 
cluster randomized control trial 
Inclusion criteria 
All infants (preterm and term infants) requiring chest 
compression at birth 
Exclusion criteria 
Congenital anomalies, Parents decline to consent for data 
use 
Recruitment period 
(months) 
24 months 
 
Strategy for the determination of recruitment figures 
How many neonates fulfilling entry criteria will be approximately 
eligible? 
 
Approximately how many patients will be recruited during the 
entire trial (anticipated 2 year recruitment period)? 
 
 
Will there be any other ongoing clinical trials/projects competing for the same patients 
 Yes 
 
 No 
 
If yes: How will this affect recruitment for the above-named clinical trial? 
 
Note: Reported recruitment will be checked if funding is provided (pre-trial visits). If 
inconsistencies exist between the estimated and verified numbers, the principal investigator will 
be asked to address this issue. 
 
Commitment to Participate 
I hereby agree to participate in the above-named clinical trial and support the trial by recruiting patients.  
 
 
 
___________________________ 
 
Date/Signature 
 
Conflicts of Interest 
I hereby declare that I have no conflict interest, neither personal nor commercial, with regard to the 
above-mentioned clinical trial and the investigational drugs that will be used.  
 
 
 
 
 
 
 
 
___________________________ 
 
Date/Signature 

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Protocol Summary  
Study Title 
SURV1VE-Trial - Sustained inflation and chest compression versus 
3:1 chest compression to ventilation ratio during cardiopulmonary 
resuscitation of asphyxiated newborns – a cluster randomized control 
trial 
Population 
Infants (preterm >28 weeks’ gestation and term) requiring chest 
compression in the delivery room. 
Primary Objective 
Chest Compression during sustained inflation (CC+SI) will improve 
short- and long-term outcomes in preterm and term newborns  
Primary Hypothesis 
By using CC+SI during cardiopulmonary resuscitation (CPR) the time 
needed to achieve return of spontaneous circulation (ROSC) 
compared to the current 3:1 compression to ventilation (C:V) will be 
reduced in asphyxiated newborns. 
Design and Sample Size 
This prospective multi-national randomized controlled trial (RCT) is a 
two-arm parallel design of two alternative courses of treatment. 218 
infants – 109 control / 109 intervention 
Inclusion Criteria 
Infants (preterm and term) requiring chest compression in the delivery 
room. 
Exclusion Criteria  
a) Congenital abnormality 
b) Condition that might have an adverse effect on breathing or 
ventilation (e.g. congenital diaphragmatic hernia) 
c) Congenital heart disease requiring intervention in the neonatal 
period)  
d) Parents’ refusal to give consent to this study 
Efficacy Endpoints  
Primary: 
• 
Time to achieve return of spontaneous circulation defined as 
a heart rate of >60/min for 60sec 
Secondary:  
• 
All mortality prior to discharge from hospital 
• 
Delivery room interventions (use of epinephrine) 
• 
Admission temperature 
• 
Use of therapeutic cooling 
• 
Mechanical ventilation 
• 
Use of inotropes 

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• 
Infection/sepsis 
• 
Necrotizing enterocolitis 
• 
Pneumothorax 
• 
Bronchoplumonary dysplasia 
• 
Retinopathy of prematurity  
• 
Brain injury as indicated by abnormal neuroimaging 
• 
Seizure  
• 
18-24 months neuro-developmental outcomes 
Safety Evaluations  
Adverse events 
 Statistical Methodology 
Interim analyses will be conducted when 10%, 25% and 50% of 
participants complete primary outcome. The final analysis will be 
conducted after the study is completed, unblinded, and the database 
is released for analysis. All analyses will be performed using IBM 
SPSS Statistics Ver. 24 (IBM Corp.) and SAS version 9.4 (SAS 
Institute Inc.) or later. 
 
 
Clinical Centers 
Multi-national sites (including Canada, Austria, Norway, Germany, 
Spain, Poland, Italy, The Netherlands, Ireland, United Kingdom, 
Australia and China), further sites are invited 
Enrollment Period 
2 years 
Study Duration  
3 years 
Webpage 
http://surv1ve.org 
ClinicalTrials.Gov Trial  
NCT02858583 

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Study flow diagram 
 
 
 
 

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Intervention flow diagram 
 
 
 
 

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Table of content 
PROTOCOL SUMMARY 
3 
STUDY FLOW DIAGRAM 
5 
INTERVENTION FLOW DIAGRAM 
6 
LIST OF ABBREVIATIONS 
9 
BACKGROUND 
10 
RESEARCH QUESTION 
10 
HYPOTHESES TO BE TESTED 
11 
KNOWLEDGE TO DATE 
11 
ASPHYXIA AT BIRTH 
11 
RATIONAL FOR USING CC+SI 
14 
METHODOLOGY 
18 
ETHICS 
18 
INCLUSION CRITERIA 
19 
EXCLUSION CRITERIA 
19 
PATIENT DISCONTINUATION AND WITHDRAWAL 
19 
RANDOMIZATION 
19 
SAMPLE SIZE AND POWER CALCULATION 
19 
BLINDING 
20 
TECHNIQUE OF RESUSCITATION 
20 
CONSTITUTION OF THE RESUSCITATION TEAM 
20 
DESCRIPTION OF GENERAL INTERVENTIONS 
20 
MASK VENTILATION 
21 
CARDIOPULMONARY RESUSCITATION 
21 
DETERMINATION OF ROSC 
22 
INTERVENTIONS 
22 
DISCONTINUING RESUSCITATION 
23 
RECORDING OF PHYSIOLOGICAL PARAMETERS 
23 
OUTCOME MEASURES 
23 
PRIMARY OUTCOME 
23 
SECONDARY OUTCOMES 
23 
OUTCOME ASSESSMENT TOOLS 
24 
COMPLIANCE WITH THE PROTOCOL 
24 
DATA COLLECTION 
24 
DATA ANALYSIS 
25 

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ASSESSMENT OF SAFETY 
26 
ADVERSE AND SERIOUS ADVERSE EVENTS 
26 
EXPECTED ADVERSE EVENTS 
26 
DATA AND SAFETY MONITORING BOARD 
26 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION 
27 
STOPPING RULES 
27 
OPT-OUT RULE 
28 
ETHICAL CONSIDERATIONS 
28 
PARENTAL CONSENT 
28 
DATA MANAGEMENT 
29 
DATA HANDLING AND ARCHIVING 
29 
DATA PROTECTION 
30 
QUALITY ASSURANCE 
30 
MONITORING 
30 
PUBLICATION PLAN 
31 
POTENTIAL SIGNIFICANCE 
31 
REFERENCES 
32 
 
 

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List of abbreviations 
CC 
 
- Chest compression  
DR 
 
- Delivery room  
CPR   
- Cardiopulmonary resuscitation 
SI 
 
- Sustained inflation 
CC+SI  
- Chest compression during sustained inflation 
ROSC  
- Return of spontaneous circulation 
C:V ratio  
- Compression to ventilation ratio 
DBP 
 
- Diastolic blood pressure  
CCaV   
- Continuous chest compression with asynchronous ventilations 
VT 
 
- Tidal volume 
RN 
 
- Registered Neonatal Nurse  
RRT 
 
- Registered Respiratory Therapist  
NNP 
 
- Neonatal Nurse Practitioner 
PIP  
 
- Peak inflation pressure  
PEEP  
- Peep expiratory pressure  
ECO2  
- Exhaled carbon dioxide 
eCRF   
- electronic Case Report Forms  
SD 
 
- Standard deviation 
IQR 
 
- Interquartile range 
SAE   
- Serious adverse event 
DSMB   
- Data and Safety Monitoring Board 
GCP 
 
- Good Clinical Practice 
NIRS  
-Near Infrared Spectroscopy 
aEEG  
-amplitude integrated electroencephalography 
 
 
 
 
 
 
 
 

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Background 
The majority of newborn infants successfully make the transition from fetal to neonatal life without 
any help1. However, an estimated 10% of newborns need help to establish effective ventilation, which 
remains the most critical step of neonatal resuscitation. Fortunately, the need for chest compression 
(CC) or medications in the delivery room (DR) is rare. Although, only about 0.1% of term infants and up 
to 15% of preterm infants2,3 receive these interventions, this will result in approximately 1 million newborn 
deaths annually worldwide. A recent cohort study at a level III center with a trained resuscitation team 
showed that only 6 per 10,000 infants received epinephrine4. However, the same study showed that 
those infants who received epinephrine during resuscitation had a high incidence of mortality (41%) and 
short-term neurologic morbidity (57% hypoxic-ischemic encephalopathy and seizures)4. A recent review 
of newborns who received prolonged CC and epinephrine but had no signs of life at 10 minutes following 
birth noted 83% mortality, with 93% of survivors suffering moderate-to-severe disability5. The poor 
prognosis associated with receiving CC alone or with medications in the DR raises questions as to 
whether improved cardiopulmonary resuscitation (CPR) methods specifically tailored to the newborn 
could improve outcomes. 
The inability to predict which newborns need CPR, and the infrequent use of CPR in the DR 
have limited neonatologists’ ability to perform rigorous clinical studies to determine the best method for 
delivering CC to newborn infants. The main cause of cardiovascular collapse in most newborns is 
asphyxia, which makes newborn infants distinctively different to the adult population. The International 
Liaison Committee on Resuscitation and the American Academy of Pediatrics/American Heart 
Association Neonatal Resuscitation Program have recognize this difference, however the guidelines 
almost exclusively rely on data from studies in the adult population or animal studies. Such data may 
not be wholly applicable to the neonatal population because the most common cause of cardiovascular 
collapse in the adult is ventricular fibrillation, not asphyxia. Thus, further studies are needed to determine 
the optimal method for improving hemodynamics and recovery during neonatal resuscitation. 
 
Research question 
In newborn infants (preterm infants >28 weeks’ gestation and term infants) requiring CPR, does 
CC during sustained inflation compared to 3:1 compression to ventilation ratio improves return of 
spontaneous circulation (ROSC)? 
 
  
Primary objective:  To prove that CC during sustained inflation will improve recovery from CPR 
in preterm and term newborns with faster ROSC than that by 3:1 CPR technique. 
  
Secondary objectives: To examine i) if CC during sustained inflation will improve short- and 

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long-term outcomes in preterm and term newborns, and ii) the value of feedback devices (e.g. ECO2, 
ECG and/or SpO2) in determining ROSC. 
Hypotheses to be tested 
Primary hypothesis: By using CC during sustained inflation (CC+SI) during CPR the time 
needed to achieve ROSC compared to the current 3:1 compression to ventilation (C:V) ratio will be 
reduced in asphyxiated newborns. 
Secondary hypotheses: The benefits associated with CC+SI will i) decrease death; ii) improve 
short- and long-term outcomes in preterm and term newborns; and iii) feedback devices help to 
determine ROSC. 
 
Knowledge to date  
Asphyxia at birth 
Asphyxia, a condition of impaired gas exchange with simultaneous hypoxia and hypercapnia 
leading to a mixed metabolic and respiratory acidosis, is the most common reason that newborns fail to 
make successful transition6. Asphyxia could result from either failure of placental gas exchange before 
delivery (e.g. abruption, chorioamnionitis), adverse events during delivery (e.g. dystocia/obstructed 
labor, cord prolapse), or deficient pulmonary gas exchange immediately after birth (e.g. apnea, airway 
obstruction, respiratory distress syndrome)6. Asphyxia depresses myocardial function leading to 
cardiogenic shock, pulmonary hypertension, mesenteric ischemia/reperfusion, and acute renal failure. 
Newborn infants either present with severe bradycardia or asystole at birth as a consequence of 
asphyxia. Current resuscitation guidelines recommend to initiate CC if the heart rate remains <60/min 
despite adequate ventilation for at least 30 seconds; CC should be then performed at a rate of 90/min 
and ventilations at a rate of 30/min, i.e. a 3:1 C:V ratio (Figure 1A) to achieve adequate oxygen delivery1. 
Chest compressions serve to mechanically pump the blood through the body until the return of 
myocardial function6. Blood expulsion from the ventricles during CPR is thought to occur by either direct 
compression of the heart between the sternum and vertebral column (cardiac pump theory), or phasic 
increases in intrathoracic pressure (thoracic pump theory). The “cardiac pump theory” postulates that 
CC directly eject blood from the heart into the circulation with each compression7. In comparison, the 
“thoracic pump theory” states that a phasic increase in intrathoracic pressure produced by compression 
of the chest creates a pressure gradient between the arterial and venous compartment8-12. This pressure 
gradient then serves as the driving force for antegrade blood flow. Optimized CC has been demonstrated 
to generate 30% of normal organ perfusion, with preferential (>50%) perfusion to the heart and brain8. 
During CC, coronary blood flow occurs during diastole with coronary perfusion pressure determined by 

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the difference between aortic blood pressure and right atrial pressure15. In adult animals and humans, 
uninterrupted CC and systemic vasoconstrictors such as epinephrine enhance diastolic blood pressure 
(DBP) during CPR. Studies using sudden cardiac collapse models in 2-3 month old asphyxiated pigs16 
as well as randomized trials during adult cardiac arrest17 have demonstrated that continuous CC without 
rescue breaths significantly reduce time to ROSC and increase survival due to improved 
hemodynamics. These studies led to a change in adult life support guidelines recommending that 
bystander CPR be performed without rescue breaths and that in lone rescuer advanced CPR, CC should 
be uninterrupted for the first few minutes18. In both adult and pediatric advanced life support, continuous 
CC with asynchronous ventilations are recommended after a secure airway has been established18,19. 
In contrast, current neonatal resuscitation guidelines recommend using a coordinated 3:1 C:V ratio if 
CC are needed, even after the placement of an endotracheal tube. This approach is composed of 90 
CC and 30 inflations per minute, with a pause after every 3rd CC to deliver one effective inflation (Figure 
1A). This approach may not be optimizing DBP during neonatal CPR as every interruption in CC results 
in a drop in DBP that needs to be regenerated during the next compression cycle. 
 
Figure 1A: Respiratory waveforms during 3:1 CPR13 
 
 
Rationale for using 3:1 compression to ventilation ratio 
The recommendation to use a 3:1 C:V ratio is based on expert opinion, extraction from animal 
data and consensus rather than strong scientific evidence form studies in newborn infants20. Rationales 

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for using a 3:1 C:V ratio include the higher physiological heart rate of 120-160/min and breathing rates 
of 40-60/min in newborns compared to adults. Furthermore, profound bradycardia or cardiac arrest in 
newborns is usually caused by hypoxia rather than primary cardiac compromise; therefore, providing 
ventilation is more likely to be beneficial in neonatal CPR compared to adult CPR1. However, the optimal 
C:V ratio that should be used during neonatal resuscitation to optimize coronary and cerebral perfusion 
while providing adequate ventilation of an asphyxiated newborn remains unknown14. 
Animal studies using cardiac arrest induced by asphyxia in newborn piglets demonstrated that 
combining CC with ventilations improves ROSC and neurological outcome at 24 hours compared to 
ventilations or CC alone16,21. Solevåg et al performed a study investigating alternating 9 CC and 3 
ventilations in asphyxiated piglets with cardiac arrest with the hypothesis that 9 CC would generate 
higher DBP during CPR than only 3 CC per series15. However, increasing the number of CC in a row 
should not be at the expense of ventilation, hence the ratio of CC to ventilation was maintained at 3:1. 
The time to ROSC was similar between the two approaches (median time of 150 and 148 sec for 3:1 
C:V and 9:3 C:V, respectively). In addition, there were no differences in DBP during CC15. Similarly, C:V 
ratios of 3:1 and 15:2 were compared using the same model16. Although the 15:2 C:V ratio provided 
higher mean CC per minute (75 versus 58 for 3:1), time to ROSC was similar between groups (median 
time of 195 and 150 sec for 15:2 and 3:1, respectively)16. These studies suggest that during neonatal 
CPR higher C:V ratios do not improve outcomes. 
Manikin studies have confirmed higher ventilation rates during simulated CPR using 3:1 C:V 
compared to higher C:V ratios17-19. A more recent neonatal manikin study examined respiratory 
parameters during neonatal CPR and reported that a 3:1 C:V ratio delivered significantly higher minute 
ventilation of 191 mL/kg compared to the minute ventilation at 9:3 and 15:2 C:V ratios (140 and 77 
mL/kg/min, respectively)20. A further manikin study compared 3:1 C:V with continuous CC with 
asynchronous ventilations (CCaV) using 90 CC and 30 non-synchronized inflations and reported 
significantly higher minute ventilation in the CCaV group compared to the 3:1 group (221 versus 191 
mL/kg/min, respectively)28. Schmölzer et al compared 3:1 C:V CPR with CCaV in a piglet model of 
neonatal asphyxia and reported similar minute ventilation (387 versus 275 mL/kg)21. However, there 
was a trend towards a reduced time to ROSC (143 and 114 sec for 3:1 and CCaV, respectively), and 
survival (3/8 and 6/8, respectively) in the CCaV group. The same manikin and animal study28,21 also 
reported similar tidal volume (VT) delivery between 3:1 C:V and CCaV (manikin study VT 6.4 and 5.6 
mL/kg, respectively28 and animal study VT 14.7 versus 11.0 mL/kg21). In a secondary analysis of the 
study by Schmölzer et al21, Li et al reported that during 3:1 C:V a cumulated loss of VT of 4.5 mL/kg 
occurs for each 3:1 C:V cycle (Figure 2A)22. Similarly, during CCaV a cumulated loss of VT of 9.1 mL/kg 
for each cycle of three CC and one inflation was observed22. This is concerning as a loss in VT could 
cause lung decruitment, which could hamper oxygenation and therefore ROSC. Further, an argument 
for synchronized CPR is the potential interference of non-synchronized CC with VT delivery, hence 

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impairment of oxygen delivery. However, the study by Schmölzer et al observed that a comparable 29% 
and 25% of manual inflations were affected during CC using CCaV or 3:1 C:V CPR21, respectively. 
These studies suggest no advantages (e.g. oxygen delivery, VT or minute ventilation) of using CCaV 
compared to 3:1 C:V. 
 
Figure 2A: Inspiratory and expiratory tidal volume (VT) during 3:1 C:V CPR22 
 
 
 
Rational for using CC+SI 
Reoxgenation and adequate blood flow are the cornerstones of neonatal CPR. Any effective 
resuscitative manoeuvre should increase blood flow and optimize oxygen delivery. In addition to 
standard CPR, manoeuvres that raise intrathoracic pressure can significantly increase carotid blood 
flow during CPR9,23. Chandra et al provided ventilation at high airway pressure while simultaneously 
performing CC in an animal model and demonstrated increased carotid flow without compromising 
oxygenation9. Further, studies in preterm lambs have demonstrated that a sustained inflation (SI) also 
increases intrathoracic pressure without impeding blood flow24. An experimental study using a 
ventricular fibrillation model of adult cardiac arrest demonstrated that emphasis on CC over ventilation 
increases neurologically intact survival in pigs25. In the resuscitation of asphyxiated newborn piglets, 

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Schmölzer et al recently reported that passive ventilation during CC, achieved by superimposing CC 
with a SI (CC+SI) (Figure 1B), significantly improved hemodynamics, minute ventilation, and time to 
ROSC compared to the currently recommended approach of using a 3:1 C:V ratio (mean arterial 
pressure: 51 versus 31 mmHg; pulmonary arterial pressure: 41 versus 31 mmHg; mean minute 
ventilation: 936 versus 623 mL/kg; median time to ROSC: 38 versus 143 sec, respectively)13. However, 
the study by Schmölzer et al used a CC rate of 120/min (in the CC+SI group), which is higher than the 
currently recommended CC rate of 90/min, which could have also added to the improved outcomes. 
 
Figure 1B: Respiratory waveforms during CC+SI CPR13 
 
 
 
 
A recent mathematical model suggests that higher CC rates than the currently recommended 90 
CC/min could optimize systemic perfusion26. This model further suggests that the most effective CC rate 
depends upon body size and weight, which would translate to 180 CC/min for term infants and even 
higher rates for preterm infants26. However, a recent simulation study comparing various CC rates (e.g. 
90/min versus 120/min) reported faster fatigue with increasing CC rates27. Overall, using CC rates of 
90/min was the least fatiguing and the most preferred method of neonatal CPR compared to using CC 
rates of 120/min27. This is further supported by a study by Solevåg et al who quantified the force used 
during CC and reported that fatigue occurs faster with increasing CC rates28. These studies suggest 
that a rate of 90/min will be the least fatiguing CC rate. Further, a recent randomized animal trial 

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compared CC+SI using CC rates of 90/min versus 120/min and reported similar time to ROSC, survival 
rates, and respiratory parameters during CPR29. During CC carotid blood flow, mean arterial pressure, 
and % change in ejection fraction and cardiac output were higher in the CC+SI 90/min group compared 
to CC+SI 120/min29. This further supports that higher CC rates do not improve systemic perfusion and 
that the current recommendation of 90 CC per minute is sufficient to achieve systemic perfusion. A 
further randomized animal trial comparing SI+CC 90/min with 3:1 C:V ratio (in review, Schmölzer last 
author) showed a significant reduction in median (IQR) time to ROSC 34 (28-156) sec versus  210 (72-
300) sec (p=0.05), less oxygen; 3/8 versus 8/8 required 100% oxygen during CPR (p=0.03), and 3/8 
versus 6/8 piglets received epinephrine (p=0.32) in the SI+CC 90/min group. In addition, improved 
respiratory and hemodynamic parameters were observed in the SI+CC 90/min group versus the 3:1 C:V 
ratio group. A recent pilot trial in preterm infants <32 weeks gestation showed similar results (in review, 
Schmölzer first author). Overall, the mean (SD) time to ROSC was significantly shorter in the CC+SI 
group with 31 (9) sec compared to 138 (72) sec in the 3:1 C:V group (p=0.011). Overall, 0/5 in the CC+SI 
group and 1/5 in the 3:1 C:V group received epinephrine. 
Providing adequate ventilation to achieve reoxgenation is a further cornerstone of neonatal CPR. 
Current best practice is to provide 90 CC and 30 ventilations that are coordinated with a pause in CC to 
deliver an inflation1. The purpose of inflations during CC is to deliver an adequate VT to facilitate gas 
exchange. However, delivery of an adequate VT during CPR remains difficult. Several DR studies 
reported that mask ventilation is the most difficult task during neonatal CPR. VT delivery could be 
compromised due to mask leak or airway obstruction30-38, causing inadequate oxygen delivery to the 
asphyxiated newborn. A recent case report by Li et al reported a large mask leak during mask ventilation 
in the DR, which resulted in severe bradycardia and the need for neonatal CC39. In addition, once CC 
were started mask leak further increased39. This is further supported by manikin studies, which reported 
decreased expiratory VT once CC were started20,40,41. Binder et al examined human or monitor feedback 
during simulated neonatal CPR using a leak-free manikin and reported lower expiratory VT in all groups 
compared with mask ventilation alone41. These studies suggest a decrease in expiratory VT once CCs 
are initiated. A loss in expiratory VT could cause lung decruitment, which could hamper oxygenation and 
therefore ROSC. This has been recently confirmed in an animal model of neonatal CPR. In a secondary 
analysis of the study by Schmölzer et al21, Li et al reported that during a significant loss of expiratory VT 
compared to inspiratory VT over each 3:1 C:V cycle (mean total inspiratory VT was 27.2mL/kg and mean 
total expiratory VT 31.7mL/kg = a loss of 4.5mL/kg per 3:1 C:V cycle) (Figure 2A)22. In contrast, no VT 
loss was observed in CC+SI. Instead a continued lung recruitment and establishment of functional 
residual capacity was observed (mean total inspired VT was 16.3mL/kg and mean total expiratory was 
14mL/kg = a gain of 2.3mL/kg/CC+SI cycle) (Figure 2B)22. This improvement in VT delivery may lead to 
better alveolar oxygen delivery and lung aeration. More importantly, the initial study by Schmölzer et 
al21 and secondary analysis by Li et al22 describe passive VT delivery during each chest compression 

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cycle. Similar observations have been reported by Tsui et al42 in children under the age of 17 years 
undergoing any surgery requiring general anesthesia and endotracheal intubation. Tsui et al compared 
VT after induction of general anesthesia before and after intubation by applying a downward force on 
the chest, which was not greater than the patient’s weight in seven infants42. Overall, median (IQR) VT 
generated before and after intubation was 2.4 (0.8-4.0) and 2.0 (0.4-3.6) mL/kg, respectively42. 
Although, Tsui et al only applied gentle chest pressure, they were able to achieve ~33% of an infants 
physiological VT of 5-7mL/kg. During CC the mean applied force is ~10kg (3-4 times the weight of the 
newborn infant)28, which would result in adequate VT delivery during CC+SI. Further, Solevåg et al 
determined the distending pressure needed to achieve sufficient VT delivery using different models 
(manikin and cadaver piglets) during CC+SI{Solevag:2017hd}. Distending pressure and VT correlated 
in cadaver piglets (r=0.83, p<0.001), manikin (r=0.98, p<0.001), and combined data (r=0.49, p<0.001). 
VT was delivered during chest recoil during CC in both models. In cadaver piglets a distending pressure 
~ 25cmH2O was needed to achieve an adequate VT. This study suggests that chest recoil generates VT 
depending on an adequate distending pressure, and that a pressure of ~25cmH2O will be needed to 
achieve adequate VT delivery. In a recent pilot trial comparing CC+SI versus 3:1 C:V CPR in 10 preterm 
infants <32 weeks gestation (5 in each group) Schmölzer et al used a distending pressure of 24cmH2O 
(local hospital policy during neonatal resuscitation) and showed adequate VT and significantly higher 
minute ventilation in the CC+SI group versus 3:1 C:V group (p<0.001) (under review, Schmölzer first 
author). These data suggest that CC+SI has the potential to improve ventilation and oxygen delivery 
during neonatal CPR.  
 
Successful resuscitation from cardiac arrest or severe bradycardia requires the delivery of high-
quality CC while providing adequate ventilation. However, no study has examined different chest 
compression techniques during neonatal resuscitation in asphyxiated newborn infants. 
 
 
 

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Figure 2B: Inspiratory and expiratory tidal volume (VT) during CC+SI CPR22 
 
 
 
Methodology 
Ethics 
This multi-center cluster randomized clinical trial will be reviewed by the appropriate Research Ethics 
Office at all participating sites. We will request a deferred consent model at all sites (see parental 
consent paragraph for details). Written consent will be sought from the parents of these infants as soon 
as possible after the birth so that acquired data could be utilized for research35. 
In the trial, participating centres will change their local hospital policy to either 3:1 C:V or CC+SI as 
per randomization to enrol for one year. To enrol the next 30 infants, participating centres will change 
their local hospital policy to the other arm with CC+SI or 3:1 C:V. After completion of enrollment, every 
centre will change to their original hospital policy. This approach will assure that all eligible infants 
are enrolled as the local hospital policy will be changed to match the study intervention. The order in 
which centres will start will be chosen randomly. 

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Inclusion criteria 
All infants (term or preterm infants >28 weeks’ gestation) requiring CC in the delivery room will 
be eligible for the trial. 
 
Exclusion criteria 
Infants will be excluded if they have a congenital abnormality or condition that might have an 
adverse effect on breathing or ventilation (e.g. congenital diaphragmatic hernia), or congenital heart 
disease requiring intervention in the neonatal period. Infants will be also excluded if their parents refuse 
to give consent to this study. 
 
Patient discontinuation and withdrawal 
The participant’s parents are free to withdraw the participant from the intervention or from the 
SURV1VE trial entirely at any time, and this will not have any consequences for the participant’s further 
treatment. When possible, the parents will be asked if they will allow their infant to participate in the 
remaining follow-up assessments, and allow their infants’ already collected data to be used in a 
database, a registry, and/or a publication.  
The attending clinician can withdraw the participant from the trial at any time. The reasons shall 
be documented. There are no pre-specified criteria for discontinuation of participants from the trial. The 
discontinuation of participants in the trial will not result in replacement with new participants. 
 
Randomization 
At the beginning of the trial participating sites will be randomized. Centers will be equally 
allocated to either CC+SI group (“intervention group”) or 3:1 C:V group (“control group”) for the first year. 
For the second year, after a wash out period of 2 months, centers in the intervention group will be 
changed to control and vice versa. 
 
Sample Size and Power calculation 
 
 Our primary outcome measure will be time to achieve ROSC. We hypothesize that the time to 
achieve ROSC will be reduced in the “CC+SI group”. A sample size of 208 infants, 104 in each group, 
would be sufficient to detect a clinically important 33% reduction in time to achieve ROSC using Cox 
proportional hazards regression with 80% power and a 2-tailed alpha error of 0.05. This 33% reduction 
represents 282 sec versus 420 sec of CC (based on the database of 30 term infants requiring CC in 
2014 and 2015 at the Royal Alexandra Hospital, Edmonton). To account for cluster randomization, the 

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sample size is multiplied by design effect of 1.045, so the total sample size is 218 infants, 109 in each 
group. 
 
Blinding 
There will be no blinding during the recruitment phase. Each hospital is allocated to one 
treatment arm and therefore the CC technique used at each particular site is known to the clinical team. 
The outcome assessor will be unaware of the group allocation. This blinding will be maintained until the 
data is locked for the final analysis and un-blinded. 
 
Technique of Resuscitation 
Infants will only be eligible and randomized if they require chest compressions. The methods 
described below also describe resuscitation interventions for infants prior to the start of chest 
compressions. 
 
Constitution of the Resuscitation Team 
The members of the resuscitation team will be site specific (for example in Edmonton it consists 
of a Registered Neonatal Nurse (RN), Respiratory Therapist (RT), Pediatric Resident or Neonatal Sub-
specialty Resident (Fellow) or Neonatal Nurse Practitioner (NNP) and/or Neonatologist). The most 
senior team member will act as the team leader, who will manage the protocol and guide the intervention 
during the trial. 
 
Description of general interventions 
Term infants 
The initial steps of the resuscitation will be according to the current neonatal resuscitation 
guidelines1. Delayed cord clamping should be performed as per local hospital policy (standard hospital 
practice guideline) at participating sites where eligible. Afterwards, dry and stimulate the infant, and 
open the airway. If heart rate is <100/min, the infant is gasping or has apnea, start positive pressure 
ventilation. At the same time consider attaching a pulse oximeter and also consider applying 
electrocardiography. If heart rate remains <100/min, perform MR. SOPA (Mask is tightly applied to the 
face, Re-position the head into the “sniffing” orientation, Suction the nares and the pharynx, Open the 
mouth, Pressure of PPV can be increased to a max of 40 cm H2O, Alternate airway (endotracheal tube 
or Laryngeal Mask Airway). If heart rate is <60/min or remains <60 despite all steps of MR. SOPA 
including alternate airway, start chest compressions and increase to 100% oxygen. 
 

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Preterm infants 
The initial steps of the resuscitation will be according to the current neonatal resuscitation 
guidelines1. Delayed cord clamping should be performed as per local hospital policy (standard hospital 
practice guideline) at participating sites where eligible. Immediately afterwards, preterm infants 
(according to local hospital policy - standard hospital practice guideline) will be either placed (without 
drying) in a polyethylene bag under radiant heat44 or dried and placed under radiant heat.  
A pulse oximeter will be used to monitor oxygen saturation immediately after birth and oxygen 
delivery will be guided by published norm values for oxygen saturation in preterm infants45.  
If heart rate is <100/min, the infant is gasping or has apnea, start positive pressure ventilation. 
Also consider applying electrocardiography at that time. If heart rate remains <100/min, perform MR. 
SOPA (Mask is tightly applied to the face, Re-position the head into the “sniffing” orientation, Suction 
the nares and the pharynx, Open the mouth, Pressure of PPV can be increased to a max of 40 cm H2O, 
Alternate airway (endotracheal tube or Laryngeal Mask Airway). If heart rate is <60/min or remains <60 
despite all steps of MR. SOPA start chest compression and increase to 100% oxygen. 
 
Mask Ventilation 
The clinical team will determine if an infant requires mask ventilation. If mask ventilation is 
required, it should be provided with a T-Piece device (e.g. Fisher & Paykel, Auckland, New Zealand or 
Giraffe Warmer, GE Health Care, Burnaby, BC, Canada), and appropriate face mask with default 
settings for peak inflation pressure (PIP) of 25 cmH2O, a peep expiratory pressure (PEEP) of 5 cm H2O, 
and a gas flow rate of 8-10L/min using a ventilation rate of 40-60 inflations/min. Initial respiratory support 
can include initial sustained inflations (instead of positive pressure ventilation alone) as per local hospital 
policy (standard hospital practice guideline). 
 
Cardiopulmonary Resuscitation 
If heart rate is <60/min or remains <60/min despite all steps of MR. SOPA start chest 
compressions. Prior to the start of CC intubation should be considered. However, in cases of intubation 
failure it is possible to start CC during mask ventilation. Compressions will be performed using the 2-
thumb encircling technique as recommended by current resuscitation guidelines46. Epinephrine will be 
administered according to current resuscitation guidelines either via umbilical vein catheter (0.01 mg/kg 
per dose – first line) or via endotracheal tube (0.05 mg/kg to 0.1 mg/kg) or every three to five minutes 
as needed44. Chest compressions and epinephrine will be continued until ROSC.  
 

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Determination of ROSC 
ROSC will defined as an increase in heart rate >60/min for 60sec determined by auscultation of 
the heart. Return of spontaneous circulation will be assessed after 60sec of a heart rate of >60/min. 
 
The current neonatal resuscitation guidelines do not recommend feedback devices (e.g. exhaled 
carbon dioxide (ECO2) monitors, electrocardiography (ECG), or pulse oximetry for detection of ROSC1. 
A secondary objective of the study will be to examine if either feedback device ECO2, ECG or pulse 
oximetry can be used for detection of ROSC. Participating centres (e.g. Edmonton, Graz, Winnipeg, 
Ulm, San Diego) are using either ECO2 monitors, ECG, and/or pulse oximetry routinely during neonatal 
resuscitation35,47-49. 
 
Interventions 
“3:1 C:V group”  
If the PIP has been increased >30 cm H2O during MR.SOPA, the PIP should be decreased to 
30 cmH2O prior start of chest compression. Infants randomized into the “3:1 C:V group” will receive CC 
at a rate of 90/min and ventilations at a rate of 30 /min in a 3:1 C:V ratio as recommended by the current 
resuscitation guidelines1 (study flow diagram). During CC, the inflations should be delivered using a PIP 
of 25-30 cmH2O (As per local hospital policy /standard hospital practice guideline). Heart rate should be 
reevaluated every 60sec according to current neonatal resuscitation guidelines1. 
 
“CC+SI group” 
If the PIP has been increased >30 cm H2O during MR.SOPA, the PIP should be decreased to 
30 cmH2O prior start of chest compression. Infants randomized into the “CC+SI group” will receive a SI 
with a PIP 25-30 cmH2O while receiving CC. CC will be performed at a rate of 90/min. The SI will be 
delivered over a period of 20 seconds. This will be followed by PEEP of 5-8 cm water as per local 
hospital policy (standard hospital practice guideline) for one second. Then the next SI for 20sec is started 
while CCs are continued. Again after 20sec there will be a 1sec pause with PEEP, which will be followed 
by another SI for 20sec with continuous CC. After 3x20sec SI+CC (total of 60sec) an assessment of 
heart rate should be performed. If heart rate is >60/min continue with standard care as per local hospital 
policy (standard hospital practice guideline). If heart rate remains <60/min continue with CC+SI for 
another 60sec (3x20sec SI+CC (total of 60sec) at which time a further assessment should be performed. 
If heart rate remains <60/min continue with CC+SI. If CPR is ongoing for 5 minutes using SI+CC, the 
clinical team must convert to the standard method of care using 3:1 C:V ratio. 
 

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Discontinuing Resuscitation  
 
Deciding how long resuscitative efforts should continue in any of the study infants will be solely at 
the discretion of the clinical team in accordance with the current neonatal resuscitation guidelines1 and 
per local hospital policy (standard hospital practice guideline) at every participating site. 
 
Recording of physiological parameters 
 
Participating sites who have the capability to record physiological parameters and/or video during 
neonatal resuscitations can include this if time permits prior to delivery38,48-51. Secondary objectives of 
the study will be recording physiological parameters during neonatal resuscitation to i) determine if either 
feedback device exhaled carbon dioxide (ECO2), Electrocardiograph (ECG), or pulse oximetery (SpO2) 
can be used for detection of ROSC, ii) examine changes of physiological parameters during neonatal 
resuscitation, and iii) examine respiratory function. 
 
18-24 months follow-up 
SI+CC might result in improved pCO2 during CPR. A more favourable pCO2 might be neuro-protective, 
and we hypothesize that SI+CC infants will have a better neurodevelopmental outcome compared to 
infants randomized to 3:1 C:V. Most infants who receive chest compressions are routinely assessed for 
neurodevelopmental outcomes at 18-24 months of age in the outpatient clinic in the study hospital. A 
Bayley III assessment (reference) will be performed by a psychologist or other professional with the 
relevant competence at the study site. This participant data will be collected at the 18-24 month follow 
up visit if this is part of routine care; it is not mandatory to collect.  
Outcome measures 
Primary outcome 
Time to achieve ROSC is defined as a heart rate of >60/min for 60sec determined by auscultation 
of the heart. Return of spontaneous circulation will be assessed after 60sec of a heart rate of >60/min.  
 
Secondary outcomes 
Secondary outcomes amongst others will include neonatal mortality (Neonatal death <28 days) 
and morbidities, for example, rates of brain injury (reported either via magnetic resonance imaging (MRI) 
or head ultrasound), changes in regional cerebral oxygen saturation using near-infrared spectroscopy 
(NIRS) monitoring started in the DR and discontinued when clinical stabilization is achieved, results of 
amplitude-integrated electroencephalograpy (aEEG) monitoring until normalization of background 

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patterns and occurrence of sleep-wake cycling, DR interventions (including the use of epinephrine), 
admission temperature, use of therapeutic cooling, mechanical ventilation, pneumothorax, use of 
inotropes, infection/sepsis, intraventricular hemorrhages, necrotizing enterocolitis, bronchopulmonary 
dysplasia, retinopathy of prematurity and long-term neurodevelopmental outcomes. We will also assess 
the value of ECO2, ECG and/or SpO2 in determining ROSC as described previously. 
 
Outcome assessment tools 
Mortality: All causes of mortality will be recorded. Cerebral injury will be assessed with either 
cerebral ultrasound or cerebral MRI if performed prior to discharge. If an infant dies prior to any neuro-
imaging, a request for autopsy should be made. Autopsy could include imaging alone or full autopsy. 
Morbidity: Case history until discharge or term age (for preterm infants). Secondary outcome 
parameters: Case history and output from feedback devices. 
 
Compliance with the Protocol 
The clinical investigation will be conducted in compliance with this protocol. Modifications to the 
protocol will not be implemented without agreement from the Principal Investigators and relevant ethics 
committee approval are obtained. 
Investigators are not allowed to deviate from the protocol except as specified above. Any major 
or safety related deviations will be recorded, analyzed and the ethics committees notified. If an 
investigator refuses to comply with the protocol he/she will be disqualified. 
 
Data collection 
Infants will be recruited over a period of 26 months. Approximately another six months will be 
required to collect hospital data on all infants enrolled. Resuscitation data will be collected on a standard 
form (Neonatal Resuscitation Record) that will form part of each infant’s hospital record. The Neonatal 
Resuscitation Record should be completed by the clinical team attending the resuscitation. Other 
medical data on each infant will be collected on an electronic Case Report Form (eCRF). The eCRF will 
be designed in collaboration with Women and Children's Health Research Institute, University of Alberta, 
Edmonton, Canada. Data will be entered into REDCap database from each site within one week after 
discharge or death of an infant. Long-term follow-up will be entered within two weeks after examination. 
All information entered into REDCap database will be used for analysis. 
 

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Data analysis 
The Clinical Research Informatics Core and Biostatistics Core of the Women and Children’s 
Health Research Institute, at the University of Alberta, will do data management and analysis. Additional 
information about the storage, management and analysis of study data is available.  
All analyses will be carried out according to the intention-to-treat principle. Statistical analyses 
will be performed using IBM SPSS Statistics Ver. 24 (IBM Corp.) and SAS version 9.4 (SAS Institute 
Inc.) or later.  
 
Interim Analysis 
Interim safety analysis will be performed at 10%, 25% and 50% of enrolment to review the primary 
outcome, ROSC, and severe adverse events (SAEs).  
Thus, three interim analyses will be performed at 22 patients (11 patients per group), 54 (27 patients 
per group), and 110 (55 patients per group) to evaluate the efficacy of the intervention. At each interim 
analysis posterior probability of SI+CC arm to reduce time to ROSC by 10% or more compared to the 
control arm will be calculated. If this probability is less than 0.5, the trial will be stopped for futility. If the 
posterior probability is greater than 0.98, the Data and Safety Monitoring Board will consider the trial to 
be stopped for superiority. Since no statistical tests will be performed at interim analyses, type I error 
(alpha) does not need adjustment. 
 
Final Analysis 
Primary Analysis 
The primary outcome is the time to achieve ROSC defined as a heart rate of >60/min for 60sec. Data 
will be analyzed on an intention-to treat basis and will include all randomized participants. A per protocol 
analysis will also be conducted using the data from the actual allocation of participating infants. A 
survival analysis will be used to analyze the difference in time to ROSC between intervention and control 
groups. To account for cluster randomization, Cox proportional hazards regression with time to ROSC 
as an outcome and allocation group as an independent variable will be created. Centers will be entered 
as clusters in the model and the statistical significance of the allocation group variable will be evaluated. 
The analysis will be 2-sided and p-value < 0.05 will be considered statistically significant. 
 
Secondary Analysis 
The data will be presented as mean (standard deviation, SD) for normally distributed continuous 
variables and median (interquartile range, IQR) when the distribution is skewed. The clinical 
characteristics and outcome parameters will be compared using Student’s t-test for parametric and 

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Mann-Whitney U-test for nonparametric comparisons of continuous variables, and χ2 for categorical 
variables. All p-values will be 2-sided and p <0.05 will be considered statistically significant.  
 
Assessment of safety  
Adverse and Serious Adverse Events  
Infants who require CPR in the DR are a very seriously ill patient group. Most adverse events 
may be of a serious nature with or without the SURV1VE-trial intervention, and both intervention groups 
are expected to have a very high proportion of serious adverse events (SAEs). Serious adverse events 
to be recorded are therefore mortality within the DR (e.g. did not achieve ROSC or did achieve ROSC 
but care was withdrawn), and within the NICU (any mortality). 
Given the global pandemic, all physical distancing, Personal Protective Equipment requirements and 
other requirements outlined by the local health authority will be strictly adhered to by study staff during 
consenting procedures. The consenting process is the only extra contact for the SURV1VE study.  
Parents will be made aware of this extra contact by a clinical staff member prior to contact with 
a research team member. Only once verbal consent is received from the parents will research staff 
begin the consent process. 
 
Expected adverse events 
Adverse events we expect to be related to the application of the treatment guideline include: No 
ROSC leading to death, accidental displacement of the endotracheal tube or extubation, accidental 
displacement of venous or arterial catheters, use of Nitric Oxide for pulmonary hypertension, sepsis, 
pneumothorax, and intraventricular hemorrhage (grades 1-4)52. 
 
Data and Safety Monitoring Board  
A Data and Safety Monitoring Board (DSMB) will monitor the study to: (1) protect all study 
patients, (2) safeguard the interests of all study patients, (3) monitor the overall conduct of the trial, (4) 
advise the investigators in order to protect the integrity of the trial, and (5) supervise the conduct and 
analysis of all interim analyses. To its end the DSMB will receive regular reports from the trial on any 
injuries or adverse events, any developments that jeopardize the continued success of the trial, and 
data by which to accomplish the evaluation of pre-determined early stopping rules. Serious Adverse 
Events to be reported (mortality) will be sent within 72 hours to the DSMB; reports of other/less serious 
adverse events and recruitment will be sent monthly; demographics and adverse events (including 
pneumothorax, and intraventricular hemorrhage grade 3 or higher according to Papile52) will be included 
with the interim and final safety and efficacy analyses. The DSMB will perform interim safety analysis at 

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10%, 25% and 50% of enrolment to review the primary outcome of ROSC, and SAEs. At the discretion 
of the DSMB further interim analyses can be requested. 
Members of the DSMB are Myra Wyckoff (current Chair of the International Liaison Committee 
on Resuscitation (ILCOR), Neil Finer (Professor Emeritus, University of California San Diego), and 
Maryna Yaskina (Statistician, Biostatistics Unit, Women and Children's Health Research Institute, 
University of Alberta, Edmonton, Canada). 
 
Suspension or premature termination of the clinical investigation  
The sponsor/principal investigator and the ethics committees can make decisions about trial 
discontinuation. If the trial is terminated or suspended the parents of all trial participants will be informed 
and appropriate follow-up will be assured. If sponsor/principal investigator terminates or suspends the 
trial the relevant ethics committees will be provided with a detailed written explanation of the termination 
or suspension. 
 
The sponsor/principal investigator can, upon completion of the analysis of the reason(s) for a 
suspension, decide to lift the suspension when the necessary corrective actions have been 
implemented. The investigators and ethics committees will be notified and provided with the relevant 
data supporting the decision. 
 
Stopping rules 
The DSMB will review the data at interim analyses at 10%, 25% and 50%. Predefined stopping 
rules will include: 
1) An increased mortality in the SI+CC group by 25% compared to the 3:1 C:V group at the predefined 
interim analysis at 10%, 25% and 50%. 
2) Increase in rate of morbidities including pneumothorax, intraventricular hemorrhage or the 
combination, in the SI+CC group by 25% compared to the 3:1 C:V group at the predefined interim 
analysis at 10%, 25% and 50%. 
3) Bayesian posterior probability of SI+CC group being better than the control is less than 0.5 or 
greater than 0.98. (Posterior probability of SI+CC arm to reduce time to ROSC by 10% or more 
compared to the control arm will be calculated. If this probability is less than 0.5, the trial will be 
stopped for futility. If the posterior probability is greater than 0.98, DSMB will consider the trial to be 
stopped for superiority. Since no statistical tests will be performed at interim analyses, type I error 
(alpha) does not need adjustment). 
 

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Opt-out Rule 
In any cases were CPR is ongoing for 5 minutes, the clinical team must convert to the standard 
method of care using the 3:1 C:V ratio. 
 
Ethical Considerations   
The SURV1VE-trial will be conducted in compliance with the guidelines of the Declaration of 
Helsinki in its latest form, the International Conference on Harmonization of Good Clinical Practice 
Guidelines. In case of modifications in the study protocol that are not merely of a formal nature but 
contain changes pertinent to the study participants, a renewed vote of the relevant ethics committees 
will be obtained. If applicable, the patients (parents) will be informed in the patient information and 
consent form about changes in the terms and conditions of the trial. The SURV1VE-trial will only start 
the randomization of participants after approvals from the relevant ethics committees have been 
obtained. 
 
Parental consent 
We aim to use a deferred consent approach as per Tri-Council Policy Statement in Human 
Research guidelines for research in "Individual Medical Emergencies". For these infants, retrospective 
consent will be sought from the parents as soon as possible after birth to use the data obtained. For this 
important study to be feasible, and enroll a representative sample, a deferred consent is important, as 
obtaining consent prior to delivery can be difficult.  
Guidelines for a deferred consent as laid down by Tri-Council Policy Statement state that, any study 
wishes to use deferred consent needs: 
a) “A serious threat to the prospective participant requires immediate intervention.” 
Infants participating in this trial will have cardiac arrest (or severe bradycardia), which in most 
cases is unforeseen prior to delivery; hence these infants will all need CPR and using chest 
compression will be therapeutic. However, only the 3:1 C:V ratio method (3:1 C:V group) is 
routinely used in all participating sites. It would not be feasible for a neonatal CPR study to ask 
permission prior to delivery from every parent delivering within the participating sites. 
b) “either no standard efficacious care exists or the research offers a realistic possibility of direct 
benefit to the participant in comparison with standard care.” 
The currently used approach of a 3:1 C:V ratio is extrapolated from animal studies and human 
adult studies. So far only one small pilot trial (Schmölzer PI) has examined CC in newborn 
infants. The available animal evidence and limited neonatal data suggest that the interventional 
approach has the potential to improve standards of care. 

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c) “either the risk is not greater than that involved in standard efficacious care, or it is clearly justified 
by 
the 
prospect 
for 
direct 
benefits 
to 
the 
participant.” 
Resuscitation is therapeutic and the currently available animal evidence and limited neonatal 
data suggest that the interventional approach has no higher risk of harm compared to the current 
standard of care (3:1 C:V group). 
d) “the prospective participant is unconscious or lacks capacity to understand the risks, methods 
and purposes of the research project.” A woman in labor cannot give a valid informed consent 
to a research study. The parents are not considered to be capable of receiving and 
understanding information about the trial immediately following the birth of a severely 
compromised child. Thus, the parents will be informed as soon as possible after stabilization of 
the infant about the study and asked to consent to the use of data that have been collected on 
their child.  
e) “third party authorization cannot be secured in sufficient time, despite diligent and documented 
efforts 
to 
do 
so;” 
The 
parents 
will 
be 
informed 
as 
soon 
as 
possible 
after 
birth/resuscitation/ROSC/death about the study and asked to consent to the use of data that 
have been collected on their child.  
f) “No relevant prior directive by the participant is known to exist.” 
 
There is an increasing use of the deferred consent approach within DR research. In fact, the PI 
of this application has ample experience with using deferred consent during neonatal resuscitation 
studies47,53. This study fulfills the criteria for a deferred consent in Europe, Canada and the United 
States. It also complies with the ethical requirements laid down by the National Health and Medical 
Research Council Australia for the ethical conduct of trials in neonatal intensive care research. 
Data management   
Data handling and archiving 
Source data will be registered in the participant’s medical records/CRF and into the eCRF. A 
common web-based eCRF will be devised to enable a central database (Women and Children's Health 
Research Institute, University of Alberta, Edmonton, Canada). Data entry into the central database and 
handling of medical records is the responsibility of the investigators. After the establishment of a ’clean 
file’, the database will be locked; The data will be locked after completion of patient recruitment and data 
entry. After long-term follow-up data entry this portion of the database will locked. Data will be stored for 
statistical analysis at the Biostatistics Unit, Women and Children's Health Research Institute, University 
of Alberta, Edmonton, Canada. The trial database will hereafter be kept according to the respective 
national laws. After the end of trial, the data will be archived for 25 years according to good clinical 

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practice guidelines. At each trial-site the data flow will be monitored according to the GCP principles by 
a locally appointed external monitoring committee. After completion of statistical data analysis, data will 
be pseudo-anonymized and stored at the University of Alberta, Edmonton, Canada. 
 
Data protection  
The investigator(s) permits trial-related monitoring, audits, and regulatory inspection(s) by 
providing direct access to the source data and other relevant documents. Trial data will be handled 
according to regulations of the data protection agency in the respective countries.   
 
Quality assurance 
The trial will be carried out in accordance with the Declaration of Helsinki in its latest form and 
the International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines.   
 
Monitoring 
The chief investigator consents to data evaluation being performed by the person in charge of 
monitoring in accordance with the monitoring plan, in order to ensure satisfactory data collection and 
adherence to the study protocol. Furthermore, the chief investigator states that he/she is willing to 
cooperate with this person and shall provide this person with all required information whenever 
necessary. This includes access to all documents related to the trial, including study-relevant medical 
files of patients in original form. The tasks of the investigator include maintenance of these patients' 
medical files as comprehensively as possible; this includes information concerning medical history, 
accompanying diseases, inclusion in the trial, data about visits, results of investigations, dispensing of 
medication, and adverse events. The monitor will also be permitted to perform data evaluation and draw 
comparisons with the relevant medical files in accordance with the standard operating procedures and 
ICH-GCP guidelines at predetermined intervals, in order to ensure adherence to the study protocol and 
continuous registration of data. All original medical reports required as sources for the information given 
in the CRF or the database shall be inspected. The study participants will have given their consent to 
such inspection by signing the consent form. The person in charge of monitoring is obliged to treat all 
information as confidential and to preserve the basic claims of the study participants in respect of 
integrity and protection of their privacy. 
 

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Publication plan  
The trial will be registered on ClinicalTrials.gov (NCT02858583) prior to the randomization of the 
first participant. Attempts will be sought to publish protocol, all results, positive, neutral, as well as 
negative, in peer-reviewed international journals. Authorship will be determined according to the 
International Committee of Medical Journal Editors. Attempts will be made to publish a list of all 
investigators with their contributions in all publications.   
 
Potential Significance 
Morbidity and mortality rates are extremely high for newborns requiring CC. We believe the 
combination of simultaneous CC and SI during CPR has the potential to significantly improve ROSC 
and survival. In addition, we believe that combining CC and SI might lead to improved pCO2, which has 
been demonstrated to be neuro-protective. This would be of considerable clinical relevance because 
improved respiratory and hemodynamic parameters potentially minimize morbidity and mortality in 
newborn infants. In addition, this will be the first randomized control trial to examine chest compression 
in the newborn period.  
 
 

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References 
1. 
Perlman JM, Wyllie JP, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal 
Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 
2015;132:S204–41.  
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Wyckoff MH, Perlman JM. Cardiopulmonary resuscitation in very low birth weight infants. 
Pediatrics 2000;106:618–20.  
3. 
Soraisham AS, Lodha AK, Singhal N, Aziz K, Yang J, Lee SK, et al. Neonatal outcomes 
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Barber CA, Wyckoff MH. Use and efficacy of endotracheal versus intravenous epinephrine 
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Kapadia V, Wyckoff MH. Chest Compressions for Bradycardia or Asystole in Neonates. Clin 
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Berg RA, Sanders AB, Kern KB, Hilwig RW, Heidenreich JW, Porter ME, et al. Adverse 
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Cardiopulmonary Resuscitation for Ventricular Fibrillation Cardiac Arrest. Circulation 
2001;104:2465–70.  
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Chandra N, Weisfeldt ML, Tsitlik J, Vaghaiwalla F, Snyder LD, Hoffecker M, et al. Augmentation 
of carotid flow during cardiopulmonary resuscitation by ventilation at high airway pressure 
simultaneous with chest compression. Am J Cardiol 1981;48:1053–63.  
10. 
Halperin HH, Tsitlik J, Guerci AD, Mellits ED, Levin HR, Shi AY, et al. Determinants of blood 
flow to vital organs during cardiopulmonary resuscitation in dogs. Circulation 1986;73:539–50.  
11. 
Rudikoff M, Maughan WL, Effron M, Freund P, Weisfeldt ML. Mechanisms of blood flow during 
cardiopulmonary resuscitation. Circulation 1980;61:345–52.  
12. 
Hevesi ZG, Thrush DN, Downs JB, Smith RA. Cardiopulmonary resuscitation: effect of CPAP 
on gas exchange during chest compressions. Anesthesiology 1999;90:1078–83.  
13. 
Schmölzer GM, O'Reilly M, LaBossiere J, Lee T-F, Cowan S, Qin S, et al. Cardiopulmonary 
resuscitation with chest compressions during sustained inflations: a new technique of neonatal 
resuscitation that improves recovery and survival in a neonatal porcine model. Circulation 
2013;128:2495–503.  
14. 
Wyckoff MH, Berg RA. Optimizing chest compressions during delivery-room resuscitation. 

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Semin Fetal Neonatal Med 2008;13:410–5.  
15. 
Solevåg AL, Wyckoff MH, Dannevig I, Saugstad OD, Nakstad B. Extended series of cardiac 
compressions during CPR in a swine model of perinatal asphyxia. Resuscitation 2010;81:1571–
6.  
16. 
Solevåg AL, Wyckoff MH, Dannevig I, Saugstad OD, Nakstad B. Return of spontaneous 
circulation with a compression:ventilation ratio of 15:2 versus 3:1 in newborn pigs with cardiac 
arrest due to asphyxia. Arch Dis Child Fetal Neonatal 2011;96:F417–21.  
17. 
Hemway RJ, Christman C, Perlman JM. The 3: 1 is superior to a 15: 2 ratio in a newborn 
manikin model in terms of quality of chest compressions and number of ventilations. Arch Dis 
Child 2012; 
18. 
Srikantan SK, Berg RA, Cox T, Tice L, Nadkarni V. Effect of one-rescuer 
compression/ventilation ratios on cardiopulmonary resuscitation in infant, pediatric, and adult 
manikins. Pediatric Critical Care Medicine 2005;6:293–7.  
19. 
Whyte SD, Sinha AK, Wyllie JP. Neonatal resuscitation--a practical assessment. Resuscitation 
1999;40:21–5.  
20. 
Solevåg AL, Madland JM, Gjærum E, Nakstad B. Minute ventilation at different compression to 
ventilation ratios, different ventilation rates, and continuous chest compressions with 
asynchronous ventilation in a newborn manikin. Scand J Trauma Resusc Emerg Med 
2012;20:73.  
21. 
Schmölzer GM, O'Reilly M, LaBossiere J, Lee T-F, Cowan S, Nicoll J, et al. 3:1 compression to 
ventilation ratio versus continuous chest compression with asynchronous ventilation in a 
porcine model of neonatal resuscitation. Resuscitation 2014;85:270–5.  
22. 
Li ES-S, Cheung P-Y, O'Reilly M, Schmölzer GM. Change in tidal volume during 
cardiopulmonary resuscitation in newborn piglets. Arch Dis Child Fetal Neonatal 
2015;100:F530–3.  
23. 
Chandra N, Rudikoff M, Weisfeldt M. SIMULTANEOUS CHEST COMPRESSION AND 
VENTILATION AT HIGH AIRWAY PRESSURE DURING CARDIOPULMONARY 
RESUSCITATION. The Lancet 1980;315:175–8.  
24. 
Sobotka KS, Hooper SB, Allison BJ, Pas te A, Davis PG, Morley CJ, et al. An initial sustained 
inflation improves the respiratory and cardiovascular transition at birth in preterm lambs. Pediatr 
Res 2011;70:56–60.  
25. 
Kern KB, Hilwig RW, Berg RA, Sanders AB, Ewy GA. Importance of continuous chest 
compressions during cardiopulmonary resuscitation: improved outcome during a simulated 
single lay-rescuer scenario. Circulation 2002;105:645–9.  
26. 
Babbs C, Meyer A, Nadkarni V. Neonatal CPR: room at the top--a mathematical study of 
optimal chest compression frequency versus body size. Resuscitation 2009;80:1280–4.  
27. 
Li ES-S, Cheung P-Y, O'Reilly M, Aziz K, Schmölzer GM. Rescuer fatigue during simulated 
neonatal cardiopulmonary resuscitation. J Perinatol 2015;35:142–5.  
28. 
Solevåg AL, Cheung P-Y, Li ES-S, Aziz K, O'Reilly M, Fu B, et al. Quantifying force application 
to a newborn manikin during simulated cardiopulmonary resuscitation. J Matern Fetal Neonatal 

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Med 2015;:1–3.  
29. 
Li ES-S, Cheung P-Y, Lee T-F, Lu M, O'Reilly M, Schmölzer GM. Return of spontaneous 
Circulation Is Not Affected by Different Chest Compression Rates Superimposed with Sustained 
Inflations during Cardiopulmonary Resuscitation in Newborn Piglets. PLoS ONE 
2016;11:e0157249–14.  
30. 
Schmölzer GM, Dawson JA, Kamlin COF, O'Donnell CP, Morley CJ, Davis PG. Airway 
obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch 
Dis Child Fetal Neonatal 2011;96:F254–7.  
31. 
Schmölzer GM, Kamlin COF, O'Donnell CP, Dawson JA, Morley CJ, Davis PG. Assessment of 
tidal volume and gas leak during mask ventilation of preterm infants in the delivery room. Arch 
Dis Child Fetal Neonatal 2010;95:F393–7.  
32. 
Poulton DA, Schmölzer GM, Morley CJ, Davis PG. Assessment of chest rise during mask 
ventilation of preterm infants in the delivery room. Resuscitation 2011;82:175–9.  
33. 
Finer N, Rich W, Wang C, Leone TA. Airway Obstruction During Mask Ventilation of Very Low 
Birth Weight Infants During Neonatal Resuscitation. Pediatrics 2009;123:865–9.  
34. 
Schilleman K, van der Pot CJM, Hooper SB, Lopriore E, Walther FJ, Pas te A. Evaluating 
manual inflations and breathing during mask ventilation in preterm infants at birth. J Pediatr 
2013;162:457–63.  
35. 
Cheung D, Mian QN, Cheung P-Y, Reilly MOA, Aziz K, van Os S, et al. Mask ventilation with 
two different face masks in the delivery room for preterm infants: a randomized controlled trial. 
2015;:1–5.  
36. 
Dawson JA, Schmölzer GM, Kamlin COF, Pas te A, O'Donnell CP, Donath S, et al. 
Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at 
birth: a randomized controlled trial. J Pediatr 2011;158:912–918.e1–2.  
37. 
Schmölzer GM, Kamlin COF, Dawson JA, Pas te A, Morley CJ, Davis PG. Respiratory 
monitoring of neonatal resuscitation. Arch Dis Child Fetal Neonatal 2010;95:F295–303.  
38. 
van Os S, Cheung P-Y, Pichler G, Aziz K, O'Reilly M, Schmölzer GM. Exhaled carbon dioxide 
can be used to guide respiratory support in the delivery room. Acta Paediatrica 2014;103:796–
806.  
39. 
Li ES-S, Cheung P-Y, Pichler G, Aziz K, Schmölzer GM. Respiratory function and near infrared 
spectroscopy recording during cardiopulmonary resuscitation in an extremely preterm newborn. 
Neonatology 2014;105:200–4.  
40. 
Roehr C-C, Schmölzer GM, Thio M, Dawson JA, Dold SK, Schmalisch G, et al. How ABBA may 
help improve neonatal resuscitation training: auditory prompts to enable coordination of manual 
inflations and chest compressions. J Paediatr Child Health 2014;50:444–8.  
41. 
Binder-Heschl C, Schmölzer GM, O'Reilly M, Schwaberger B, Pichler G. Human or monitor 
feedback to improve mask ventilation during simulated neonatal cardiopulmonary resuscitation. 
Arch Dis Child Fetal Neonatal 2014;99:F120–3.  
42. 
Tsui BCH, Horne S, Tsui J, Corry GN. Generation of tidal volume via gentle chest pressure in 
children over one year old. Resuscitation 2015;92:148–53.  

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43. 
Aziz K, Chadwick M, Downton G, Baker M, Andrews W. The development and implementation 
of a multidisciplinary neonatal resuscitation team in a Canadian perinatal centre. Resuscitation 
2005;66:45–51.  
44. 
Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J, et al. Part 15: neonatal 
resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation 
and Emergency Cardiovascular Care. Circulation 2010;122:S909–19.  
45. 
Dawson JA, Kamlin COF, Vento M, Wong C, Cole TJ, Donath S, et al. Defining the reference 
range for oxygen saturation for infants after birth. Pediatrics 2010;125:e1340–7.  
46. 
Wyckoff MH, Aziz K, Escobedo MB, Kapadia V, Kattwinkel J, Perlman JM, et al. Part 13: 
Neonatal Resuscitation: 2015 American Heart Association Guidelines Update for 
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart 
Association, Inc; 2015. pages S543–60. 
47. 
Pichler G, Urlesberger B, Baik N, Schwaberger B, Binder-Heschl C, Avian A, et al. Cerebral 
Oxygen Saturation to Guide Oxygen Delivery in Preterm Neonates for the Immediate Transition 
after Birth: A 2-Center Randomized Controlled Pilot Feasibility Trial. J Pediatr 2015; 
48. 
Fuchs H, Lindner W, Buschko A, Almazam M, Hummler HD, Schmid MB. Brain oxygenation 
monitoring during neonatal resuscitation of very low birth weight infants. J Perinatol 
2011;32:356–62.  
49. 
Fuchs H, Lindner W, Buschko A, Trischberger T, Schmid M, Hummler HD. Cerebral 
oxygenation in very low birth weight infants supported with sustained lung inflations after birth. 
Pediatr Res 2011;70:176–80.  
50. 
Kang LJ, Cheung P-Y, Pichler G, O'Reilly M, Aziz K, Schmölzer GM. Monitoring Lung Aeration 
during Respiratory Support in Preterm Infants at Birth. PLoS ONE 2014;9:e102729.  
51. 
Pichler G, Zotter H, Binder-Heschl C, Avian A, Schmölzer GM, Morris N, et al. aEEG and NIRS 
during transition and resuscitation after birth: Promising additional tools; an observational study. 
Resuscitation 2013;84:974–8.  
52. 
Papile L-A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and 
intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 
1978;92:529–34.  
53. 
Schmölzer GM, Morley CJ, Wong C, Dawson JA, Kamlin COF, Donath S, et al. Respiratory 
function monitor guidance of mask ventilation in the delivery room: a feasibility study. J Pediatr 
2012;160:377–381.e2.  
 
 
 
 
 
 
 
 
 

 
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Statistical Analysis Plan  
Based on JAMA. 2017; 318(23):2337-2343. doi:10.1001/jama.2017.18556 
 
Trial: 
SURV1VE-Trial 
 
Sustained inflation and chest compression versus 3:1 chest compression to ventilation ratio during cardiopulmonary resuscitation of 
asphyxiated newborns – a cluster randomized controlled trial 
 
 
Trial Registration: ClinicalTrials.gov Identifier: NCT02858583 
 
PI: Georg Schmölzer, MD, PhD 
 
Co-PI: 
Po-Yin Cheung 
Anne Solevåg 
Gerhard Pichler 
 
 
Protocol Number: Version 4.0 
 
Protocol Date: December 1st 2020 
 
 
 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
38 
 
Abbreviations 
 
Abbreviation Definition 
CC 
Chest Compression  
DR 
Delivery room 
CPR 
Cardiopulmonary resuscitation 
ROSC 
Return of spontaneous circulation  
CC+SI 
Chest compression with sustained inflation 
3:1 C:V 
Compression to ventilation ratio 
 
 
Section 1: Administrative Information 
1.1 SAP revisions  
 
Protocol 
version 
Updated 
SAP version no. 
Section number 
changed 
Description of and reason for 
change 
Date 
changed 
 
 
 
 
 
 
 
 
 
 
 
1.2 Roles and responsibility  
5 Names, affiliations, and roles of SAP contributors 
Contributor 
Affiliation 
Role of Contributor 
Georg Schmölzer 
University of Alberta 
PI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3 Signatures 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
39 
Author of SURV1VE-Trial Study SAP:  
 
Name (print):  
 
Dr. Maryna Yaskina 
 
Signature:  
 
 
 
Date 
(dd-mmm-
yyyy): 
 
 
 
Principal Investigator of the SURV1VE-Trial: Sustained inflation and chest compression versus 3:1 chest compression to ventilation ratio during 
cardiopulmonary resuscitation of asphyxiated newborns – a cluster randomized controlled trial 
 
Name (print):  
 
DDr. Georg Schmölzer 
 
Signature:  
 
 
 
Date 
(dd-mmm-
yyyy): 
19-Oct-2022 
 
 
Section 2: Introduction 
2.1 Background and rationale  
The majority of newborn infants successfully make the transition from fetal to neonatal life without any help1. However, an estimated 
10% of newborns need help to establish effective ventilation, which remains the most critical step of neonatal resuscitation. Fortunately, 
the need for chest compression (CC) or medications in the delivery room (DR) is rare. Although, only about 0.1% of term infants and up 
to 15% of preterm infants2,3 receive these interventions, this will result in approximately 1 million newborn deaths annually worldwide. A 
recent cohort study at a level III center with a trained resuscitation team showed that only 6 per 10,000 infants received epinephrine4. 
However, the same study showed that those infants who received epinephrine during resuscitation had a high incidence of mortality 
(41%) and short-term neurologic morbidity (57% hypoxic-ischemic encephalopathy and seizures)4. A recent review of newborns who 
received prolonged CC and epinephrine but had no signs of life at 10 minutes following birth noted 83% mortality, with 93% of survivors 
suffering moderate-to-severe disability5. The poor prognosis associated with receiving CC alone or with medications in the DR raises 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
40 
questions as to whether improved cardiopulmonary resuscitation (CPR) methods specifically tailored to the newborn could improve 
outcomes. 
The inability to predict which newborns need CPR, and the infrequent use of CPR in the DR have limited neonatologists’ ability to 
perform rigorous clinical studies to determine the best method for delivering CC to newborn infants. The main cause of cardiovascular 
collapse in most newborns is asphyxia, which makes newborn infants distinctively different to the adult population. The International 
Liaison Committee on Resuscitation and the American Academy of Pediatrics/American Heart Association Neonatal Resuscitation 
Program have recognized this difference, however the guidelines almost exclusively rely on data from studies in the adult population or 
animal studies. Such data may not be wholly applicable to the neonatal population because the most common cause of cardiovascular 
collapse in the adult is ventricular fibrillation, not asphyxia. Thus, further studies are needed to determine the optimal method for improving 
hemodynamics and recovery during neonatal resuscitation. 
 
Rationale for using 3:1 compression to ventilation ratio 
The recommendation to use a 3:1 C:V ratio is based on expert opinion, extraction from animal data and consensus rather than 
strong scientific evidence form studies in newborn infants20. Rationales for using a 3:1 C:V ratio include the higher physiological heart 
rate of 120-160/min and breathing rates of 40-60/min in newborns compared to adults. Furthermore, profound bradycardia or cardiac 
arrest in newborns is usually caused by hypoxia rather than primary cardiac compromise; therefore, providing ventilation is more likely to 
be beneficial in neonatal CPR compared to adult CPR1. However, the optimal C:V ratio that should be used during neonatal resuscitation 
to optimize coronary and cerebral perfusion while providing adequate ventilation of an asphyxiated newborn remains unknown14. 
Animal studies using cardiac arrest induced by asphyxia in newborn piglets demonstrated that combining CC with ventilations 
improves ROSC and neurological outcome at 24 hours compared to ventilations or CC alone16,21. Solevåg et al performed a study 
investigating alternating 9 CC and 3 ventilations in asphyxiated piglets with cardiac arrest with the hypothesis that 9 CC would generate 
higher DBP during CPR than only 3 CC per series15. However, increasing the number of CC in a row should not be at the expense of 
ventilation, hence the ratio of CC to ventilation was maintained at 3:1. The time to ROSC was similar between the two approaches (median 
time of 150 and 148 sec for 3:1 C:V and 9:3 C:V, respectively). In addition, there were no differences in DBP during CC15. Similarly, C:V 
ratios of 3:1 and 15:2 were compared using the same model16. Although the 15:2 C:V ratio provided higher mean CC per minute (75 
versus 58 for 3:1), time to ROSC was similar between groups (median time of 195 and 150 sec for 15:2 and 3:1, respectively)16. These 
studies suggest that during neonatal CPR higher C:V ratios do not improve outcomes. 
Manikin studies have confirmed higher ventilation rates during simulated CPR using 3:1 C:V compared to higher C:V ratios17-19. A 
more recent neonatal manikin study examined respiratory parameters during neonatal CPR and reported that a 3:1 C:V ratio delivered 
significantly higher minute ventilation of 191 mL/kg compared to the minute ventilation at 9:3 and 15:2 C:V ratios (140 and 77 mL/kg/min, 
respectively)20. A further manikin study compared 3:1 C:V with continuous CC with asynchronous ventilations (CCaV) using 90 CC and 
30 non-synchronized inflations and reported significantly higher minute ventilation in the CCaV group compared to the 3:1 group (221 
versus 191 mL/kg/min, respectively)28. Schmölzer et al compared 3:1 C:V CPR with CCaV in a piglet model of neonatal asphyxia and 
reported similar minute ventilation (387 versus 275 mL/kg)21. However, there was a trend towards a reduced time to ROSC (143 and 114 
sec for 3:1 and CCaV, respectively), and survival (3/8 and 6/8, respectively) in the CCaV group. The same manikin and animal study28,21 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
41 
also reported similar tidal volume (VT) delivery between 3:1 C:V and CCaV (manikin study VT 6.4 and 5.6 mL/kg, respectively28 and animal 
study VT 14.7 versus 11.0 mL/kg21). In a secondary analysis of the study by Schmölzer et al21, Li et al reported that during 3:1 C:V a 
cumulated loss of VT of 4.5 mL/kg occurs for each 3:1 C:V cycle22. Similarly, during CCaV a cumulated loss of VT of 9.1 mL/kg for each 
cycle of three CC and one inflation was observed22. This is concerning as a loss in VT could cause lung decruitment, which could hamper 
oxygenation and therefore ROSC. Further, an argument for synchronized CPR is the potential interference of non-synchronized CC with 
VT delivery, hence impairment of oxygen delivery. However, the study by Schmölzer et al observed that a comparable 29% and 25% of 
manual inflations were affected during CC using CCaV or 3:1 C:V CPR21, respectively. These studies suggest no advantages (e.g. oxygen 
delivery, VT or minute ventilation) of using CCaV compared to 3:1 C:V. 
 
Rational for using CC+SI 
Reoxgenation and adequate blood flow are the cornerstones of neonatal CPR. Any effective resuscitative manoeuvre should 
increase blood flow and optimize oxygen delivery. In addition to standard CPR, manoeuvres that raise intrathoracic pressure can 
significantly increase carotid blood flow during CPR9,23. Chandra et al provided ventilation at high airway pressure while simultaneously 
performing CC in an animal model and demonstrated increased carotid flow without compromising oxygenation9. Further, studies in 
preterm lambs have demonstrated that a sustained inflation (SI) also increases intrathoracic pressure without impeding blood flow24. An 
experimental study using a ventricular fibrillation model of adult cardiac arrest demonstrated that emphasis on CC over ventilation 
increases neurologically intact survival in pigs25. In the resuscitation of asphyxiated newborn piglets, Schmölzer et al recently reported 
that passive ventilation during CC, achieved by superimposing CC with a SI (CC+SI), significantly improved hemodynamics, minute 
ventilation, and time to ROSC compared to the currently recommended approach of using a 3:1 C:V ratio (mean arterial pressure: 51 
versus 31 mmHg; pulmonary arterial pressure: 41 versus 31 mmHg; mean minute ventilation: 936 versus 623 mL/kg; median time to 
ROSC: 38 versus 143 sec, respectively)13. However, the study by Schmölzer et al used a CC rate of 120/min (in the CC+SI group), which 
is higher than the currently recommended CC rate of 90/min, which could have also added to the improved outcomes. 
A recent mathematical model suggests that higher CC rates than the currently recommended 90 CC/min could optimize systemic 
perfusion26. This model further suggests that the most effective CC rate depends upon body size and weight, which would translate to 
180 CC/min for term infants and even higher rates for preterm infants26. However, a recent simulation study comparing various CC rates 
(e.g. 90/min versus 120/min) reported faster fatigue with increasing CC rates27. Overall, using CC rates of 90/min was the least fatiguing 
and the most preferred method of neonatal CPR compared to using CC rates of 120/min27. This is further supported by a study by Solevåg 
et al who quantified the force used during CC and reported that fatigue occurs faster with increasing CC rates28. These studies suggest 
that a rate of 90/min will be the least fatiguing CC rate. Further, a recent randomized animal trial compared CC+SI using CC rates of 
90/min versus 120/min and reported similar time to ROSC, survival rates, and respiratory parameters during CPR29. During CC carotid 
blood flow, mean arterial pressure, and % change in ejection fraction and cardiac output were higher in the CC+SI 90/min group compared 
to CC+SI 120/min29. This further supports that higher CC rates do not improve systemic perfusion and that the current recommendation 
of 90 CC per minute is sufficient to achieve systemic perfusion. A further randomized animal trial comparing SI+CC 90/min with 3:1 C:V 
ratio (in review, Schmölzer last author) showed a significant reduction in median (IQR) time to ROSC 34 (28-156) sec versus  210 (72-

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
42 
300) sec (p=0.05), less oxygen; 3/8 versus 8/8 required 100% oxygen during CPR (p=0.03), and 3/8 versus 6/8 piglets received 
epinephrine (p=0.32) in the SI+CC 90/min group. In addition, improved respiratory and hemodynamic parameters were observed in the 
SI+CC 90/min group versus the 3:1 C:V ratio group. A recent pilot trial in preterm infants <32 weeks gestation showed similar results (in 
review, Schmölzer first author). Overall, the mean (SD) time to ROSC was significantly shorter in the CC+SI group with 31 (9) sec 
compared to 138 (72) sec in the 3:1 C:V group (p=0.011). Overall, 0/5 in the CC+SI group and 1/5 in the 3:1 C:V group received 
epinephrine. 
Providing adequate ventilation to achieve reoxgenation is a further cornerstone of neonatal CPR. Current best practice is to provide 
90 CC and 30 ventilations that are coordinated with a pause in CC to deliver an inflation1. The purpose of inflations during CC is to deliver 
an adequate VT to facilitate gas exchange. However, delivery of an adequate VT during CPR remains difficult. Several DR studies reported 
that mask ventilation is the most difficult task during neonatal CPR. VT delivery could be compromised due to mask leak or airway 
obstruction30-38, causing inadequate oxygen delivery to the asphyxiated newborn. A recent case report by Li et al reported a large mask 
leak during mask ventilation in the DR, which resulted in severe bradycardia and the need for neonatal CC39. In addition, once CC were 
started mask leak further increased39. This is further supported by manikin studies, which reported decreased expiratory VT once CC 
were started20,40,41. Binder et al examined human or monitor feedback during simulated neonatal CPR using a leak-free manikin and 
reported lower expiratory VT in all groups compared with mask ventilation alone41. These studies suggest a decrease in expiratory VT 
once CCs are initiated. A loss in expiratory VT could cause lung decruitment, which could hamper oxygenation and therefore ROSC. This 
has been recently confirmed in an animal model of neonatal CPR. In a secondary analysis of the study by Schmölzer et al21, Li et al 
reported that during a significant loss of expiratory VT compared to inspiratory VT over each 3:1 C:V cycle (mean total inspiratory VT was 
27.2mL/kg and mean total expiratory VT 31.7mL/kg = a loss of 4.5mL/kg per 3:1 C:V cycle)22. In contrast, no VT loss was observed in 
CC+SI. Instead a continued lung recruitment and establishment of functional residual capacity was observed (mean total inspired VT was 
16.3mL/kg and mean total expiratory was 14mL/kg = a gain of 2.3mL/kg/CC+SI cycle)22. This improvement in VT delivery may lead to 
better alveolar oxygen delivery and lung aeration. More importantly, the initial study by Schmölzer et al21 and secondary analysis by Li et 
al22 describe passive VT delivery during each chest compression cycle. Similar observations have been reported by Tsui et al42 in children 
under the age of 17 years undergoing any surgery requiring general anesthesia and endotracheal intubation. Tsui et al compared VT after 
induction of general anesthesia before and after intubation by applying a downward force on the chest, which was not greater than the 
patient’s weight in seven infants42. Overall, median (IQR) VT generated before and after intubation was 2.4 (0.8-4.0) and 2.0 (0.4-3.6) 
mL/kg, respectively42. Although, Tsui et al only applied gentle chest pressure, they were able to achieve ~33% of an infants physiological 
VT of 5-7mL/kg. During CC the mean applied force is ~10kg (3-4 times the weight of the newborn infant)28, which would result in adequate 
VT delivery during CC+SI. Further, Solevåg et al determined the distending pressure needed to achieve sufficient VT delivery using 
different models (manikin and cadaver piglets) during CC+SI{Solevag:2017hd}. Distending pressure and VT correlated in cadaver piglets 
(r=0.83, p<0.001), manikin (r=0.98, p<0.001), and combined data (r=0.49, p<0.001). VT was delivered during chest recoil during CC in 
both models. In cadaver piglets a distending pressure ~ 25cmH2O was needed to achieve an adequate VT. This study suggests that chest 
recoil generates VT depending on an adequate distending pressure, and that a pressure of ~25cmH2O will be needed to achieve adequate 
VT delivery. In a recent pilot trial comparing CC+SI versus 3:1 C:V CPR in 10 preterm infants <32 weeks gestation (5 in each group) 
Schmölzer et al used a distending pressure of 24cmH2O (local hospital policy during neonatal resuscitation) and showed adequate VT 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
43 
and significantly higher minute ventilation in the CC+SI group versus 3:1 C:V group (p<0.001) (under review, Schmölzer first author). 
These data suggest that CC+SI has the potential to improve ventilation and oxygen delivery during neonatal CPR.  
 
Rationale 
The null hypothesis for this study is that the time to return of spontaneous circulation (ROSC) will be no different by using either 
chest compression with sustained inflation (CC+SI) or 3:1 compression to ventilation ratio (C:V) during CPR of newborn infants.  
 
2.2 Objectives  
 Primary objective:  To prove that CC during sustained inflation will improve recovery from CPR in preterm and term newborns with 
faster ROSC than that by 3:1 CPR technique. 
 Secondary objectives: To examine i) if CC during sustained inflation will improve short- and long-term outcomes in preterm and term 
newborns, and ii) the value of feedback devices (e.g. ECO2, ECG and/or SpO2) in determining ROSC. 
 
Section 3: Study Methods 
3.1 Trial design  
This study will be a cluster-crossover design, unmasked randomized controlled trial comparing two chest compression techniques 
during CPR. Participants will be randomized to receive either CC+SI or 3:1 C:V ratio during CPR with 1:1 ratio.  
 
3.2 Randomization  
In the trial, participating centres will change their local hospital policy to either CC+SI or 3:1 C:V ratio during CPR to enrol as many 
infants as possible.  
Description of study randomization procedure (REDCap, phone, internet) and allocation ratio. 
 
3.3 Sample size  
Our primary outcome measure will be time to achieve ROSC. We hypothesize that the time to achieve ROSC will be reduced in 
the “CC+SI group”. A sample size of 208 infants, 104 in each group, would be sufficient to detect a clinically important 33% reduction in 
time to achieve ROSC using Cox proportional hazards regression with 80% power and a 2-tailed alpha error of 0.05. This 33% reduction 
represents 282 sec versus 420 sec of CC (based on the database of 30 term infants requiring CC in 2014 and 2015 at the Royal Alexandra 
Hospital, Edmonton). To account for cluster randomization, the sample size is multiplied by design effect of 1.045, so the total sample 
size is 218 infants, 109 in each group. 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
44 
3.4 Framework  
Comparisons for the trial will be conducted under a superiority framework. 
 
3.5 Statistical interim analyses and stopping guidance 
Interim Analysis 
Interim safety analysis will be performed at 10%, 25% and 50% of enrolment to review the primary outcome, ROSC, and severe adverse 
events (SAEs). Thus, three interim analyses will be performed at 22 patients (11 patients per group), 54 (27 patients per group), and 110 
(55 patients per group) to evaluate the efficacy of the intervention. At each interim analysis, posterior probability of SI+CC arm to reduce 
time to ROSC by 10% or more compared to the control arm will be calculated. If this probability is less than 0.5, the trial will be stopped 
for futility. If the posterior probability is greater than 0.98, the Data and Safety Monitoring Board will consider the trial to be stopped for 
superiority. Since no statistical tests will be performed at interim analyses, type I error (alpha) does not need adjustment. 
 
Stopping rules 
The DSMB will review the data at interim analyses at 10%, 25% and 50%. Predefined stopping rules will include: 
4) An increased mortality in the SI+CC group by 25% compared to the 3:1 C:V group at the predefined interim analysis at 10%, 25% 
and 50%. 
5) Increase in rate of morbidities including pneumothorax, intraventricular hemorrhage or the combination, in the SI+CC group by 25% 
compared to the 3:1 C:V group at the predefined interim analysis at 10%, 25% and 50%. 
6) Bayesian posterior probability of SI+CC group being better than the control is less than 0.5 or greater than 0.98. (Posterior probability 
of SI+CC arm to reduce time to ROSC by 10% or more compared to the control arm will be calculated. If this probability is less than 
0.5, the trial will be stopped for futility. If the posterior probability is greater than 0.98, DSMB will consider the trial to be stopped for 
superiority. Since no statistical tests will be performed at interim analyses, type I error (alpha) does not need adjustment). 
 
3.6 Timing of final analysis 
The final analysis for the SURV1VE-Trial will take place in one stage. The main report of the trial will be prepared after hospital 
data of every patient have been completed and all data has been collected, cleaned and the database has been "closed". 
 
3.7 Timing of outcome assessments 
The Schedule of Activities is given in the Planned recruitment rate section of the trial protocol. Outcome data will be collected 
throughout hospital stay and at follow-up and entered in the REDCap data base. 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
45 
Section 4: Statistical Principles 
4.1 Confidence intervals and P values  
A two-sided level of 0.05 will be used to declare significance.  
 
4.2 Adjustments for multiplicity 
No multiplicity 
 
4.3 Confidence intervals to be reported 
A 95% confidence interval will be reported around estimates of the treatment effects of the primary and secondary outcomes.  
 
4.4 Adherence and protocol deviations  
4.4.1 Adherence  
 
Adherence will be determined by completion of MEASURE at TIME POINT. Non-adherence will be a dichotomous variable defined as ... 
 
4.4.1 Protocol deviations 
 
 Major protocol deviations are defined as: 
1. Enrollment of ineligible patient 
2. Failure to obtain informed consent or improper consent procedure 
3. Patient randomized but receives none of the study interventions. 
 
Protocol deviations are classified prior to unblinding of treatment. The number (and percentage) of patients with major and minor protocol 
deviations will be summarised by treatment group with details of type of deviation provided. The patients that are included in the ITT 
analysis data set will be used as the denominator to calculate the percentages. No formal statistical testing will be undertaken. 
 
4.5 Analysis populations  
 
All analyses will adhere to the principle of intention-to-treat. The ITT population will include all participants who were randomized in the 
trial. Additional analyses will be conducted on the per protocol populations.  The per protocol population will include all patients who were 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
46 
adherent to the treatment, i.e. This additional analysis will only be presented if there is a substantial difference in this population compared 
to the ITT population. 
 
Section 5: Trial Population 
5.1 Eligibility  
We will use the CONSORT extension for cluster trials flow diagram to provide details of the number of patients screened followed by a 
breakdown of how many patients were eligible and how many were excluded due to violating our inclusion/exclusion criteria outlined in 
the trial protocol. 
 
Inclusion criteria 
All infants (term or preterm infants >28 weeks’ gestation) requiring CC in the delivery room will be eligible for the trial. 
 
Exclusion criteria 
Infants will be excluded if they have a congenital abnormality or condition that might have an adverse effect on breathing or 
ventilation (e.g. congenital diaphragmatic hernia), or congenital heart disease requiring intervention in the neonatal period. Infants will be 
also excluded if their parents refuse to give consent to this study. 
 
The inclusion criteria are designed to be pragmatic and provide useful knowledge translation for most of the patient population in the 
future. Infants who meet study criteria will be enrolled. Sex, race, and ethnicity are not part of the exclusion criteria for this trial, and as 
such it should represent the combined demographics of all centers involved. A deferred consent approach as per Tri-Council Policy 
Statement in Human Research guidelines for research in "Individual Medical Emergencies" will be sought for all centres for data collection. 
 
5.2 Recruitment  
A CONSORT extension for cluster trials flow diagram will be used to summarise the number of patients were assessed for eligibility at 
screening for both trials. 
• eligible at screening 
• ineligible at screening* 
• eligible and randomised 
• eligible but not randomised* 
• received the randomised allocation 
• did not receive the randomised allocation* 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
47 
• lost to follow-up* 
• discontinued the intervention* 
• randomised and included in the primary analysis 
• randomised and excluded from the primary analysis* 
*reasons will be provided.   
 
5.3 Withdrawal/follow-up  
5.3.1 Timing of withdrawal/lost to follow-up 
Timing of withdrawal and lost to follow up data will be presented in CONSORT extension for cluster trials diagram format with 
numbers and reasons for withdrawal and/or exclusion from analysis given at each stage. 
 
5.3.2 Presentation of withdrawal data 
The numbers (with reasons) of losses to follow-up (drop-outs and withdrawals) over the course of the trial will be summarised by 
treatment arm. 
 
5.4 Baseline patient characteristics  
Patients will be described with respect to the following baseline variables: 
• gestational age 
• birth weight 
• sex 
• Apgar scores at 1, 5, and 10 minutes 
• Caesarean section 
• Cord pH 
• Cord pCO2 
• Cord base excess 
 
The demographic and clinical variables at baseline will be presented using the appropriate descriptive statistics, namely: means, standard 
deviations, medians and interquartile ranges for continuous variables, and frequency with proportions for discrete variables. These 
variables will be summarized by treatment group. 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
48 
Section 6: Analysis 
6.1 Outcome definitions List  
Primary Efficacy Outcome: 
The Primary Efficacy Endpoint will be time to achieve ROSC which is defined as a heart rate of >60/min for 60sec determined by 
auscultation of the heart. Return of spontaneous circulation will be assessed after 60sec of a heart rate of >60/min.  
 
 
Secondary Efficacy Outcomes: 
1. All-cause in-hospital mortality 
2. Severe brain injury 
 
Exploratory Outcomes 
See list below 
 
Safety Outcomes: 
1. Mortality 
2. Pneumothorax 
3. Intraventricular hemorrhage grade 3 or higher 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
49 
 
# Outcome 
Variable Name 
Description 
 
Gestation in weeks 
b_gaw 
Continuous Outcome 
 
Birth weight 
d_bw 
Continuous Outcome 
 
Gender (Sex) 
d_g 
Binary 
outcome 
1=male 
0=Female 
 
Multiple Birth 
d_mb 
Binary outcome 1=Yes 0=No 
 
Apgar at 1 Minute 
d_a1  
Continuous Outcome 
 
Apgar at 5 Minute 
d_a5 
Continuous Outcome 
 
Apgar at 10 Minute 
d_a10 
Continuous Outcome 
 
 
 
 
 
Mode of Delivery 
c_mod 
Outcome 
1=Vaginal, 
2=Instrumental 
3=Caesarean 
Section 
 
Meconium present 
c_mp 
Binary outcome 1=Yes 0=No 
 
Antenatal Steroids 
c_as c_ams 
Binary outcome 1=Yes 0=No 
 
Antenatal magnesium Sulphate 
c_as c_ams 
Binary outcome 1=Yes 0=No 
 
1. Presenting Antenatal Problems 
(choice=Premature Ruptures of 
Membranes (PROM))" 
"2. Presenting Antenatal Problems 
(choice=Pregnancy 
Induced 
Hypertension (PIH))" 
"3. Presenting Antenatal Problems 
(choice=Antepartum Hemorrhage 
(APH))" 
"4. Presenting Antenatal Problems 
(choice=Gestational 
Diabetes 
(GDM))" 
"5. Presenting Antenatal Problems 
(choice=Intrauterine 
Growth 
Restriction (IUGR)- less than 10th 
percentile)" 
"6. Presenting Antenatal Problems 
(choice=Fetal Distress)" 
c_pap___1  
c_pap___2 
c_pap___3 
c_pap___4 
c_pap___5 
c_pap___6 
c_pap___7 
c_pap___8 
c_pap___10 
c_pap_oth 
Each is a binary outcome 
1=Yes 0=No, please combine 
to 1 outcome and present as list 
n(%) 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
50 
"7. Presenting Antenatal Problems 
(choice=Chorioamnionitis)" 
"8. Presenting Antenatal Problems 
(choice=Shoulder Dystocia)" 
"10. 
Presenting 
Antenatal 
Problems (choice=Other)" 
 
Fetal Heart Rate Abnormality 
c_fhra 
Binary outcome 1=Yes 0=No 
 
Intrapartum Fever > 38∞ Celsius 
c_ipf 
Binary outcome 1=Yes 0=No 
 
 
 
 
 
 
 
 
 
Delayed Cord Clamping 
e_dcc  
Binary outcome 1=Yes 0=No 
 
Cord Milking 
e_cm_yn 
Binary outcome 1=Yes 0=No 
 
Duration of Delayed Cord Clamping 
e_ddcc 
Continuous outcome in sec 
please 
 
Number of Times Cord Milked 
e_ntcm 
Continuous outcome 
 
 
 
 
 
FiO2 at Start of Resuscitation   
e_opsr 
Continuous Outcome 
 
Maximum 
FiO2 
during 
Resuscitation  
e_mpor 
Continuous Outcome 
 
 
 
 
 
Method 
of 
determining 
bradycardia/asystole  
(choice=Auscultation) 
Method 
of 
determining 
bradycardia/asystole  
(choice=Palpation) 
Method 
of 
determining 
bradycardia/asystole  
(choice=ECG) 
Method 
of 
determining 
bradycardia/asystole  
(choice=Pulse Oximetry) 
Method 
of 
determining 
bradycardia/asystole  
(choice=Ultrasound) 
e_meth_dba___1 
e_meth_dba___2 
e_meth_dba___3 
e_meth_dba___4 
e_meth_dba___5 
Each is a binary outcome 
1=Yes 0=No, please combine 
to 1 outcome and present as list 
n(%) 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
51 
 
 
 
 
 
 
 
 
 
Compression 
Methods 
used 
(=group) 
e_cm 
This is the group variable 
 
What pressure was used to deliver 
the SI? 
e_si 
Continuous Outcome 
 
Intubation 
prior 
to 
Chest 
Compression 
e_icc 
Binary outcome 1=Yes 0=No 
 
Time to ROSC (Primary outcome) 
e_dur_cc 
Continuous Outcome 
 
Technique switched to 3:1 C:V for 
Compressions 
required 
longer 
than 5 minutes 
e_tcc 
Yes, No, Site Randomization is 
3:1 C:V 
 
ROSC 
e_rosc 
Binary outcome 1=Yes 0=No 
 
Subsequent 
need 
for 
Chest 
Compressions after ROSC initially 
achieved 
e_sccrosc 
No, Yes, Infant did not achieve 
ROSC 
 
Subject 
Alive 
at 
end 
of 
Resuscitation 
e_sar 
Binary outcome 1=Yes 0=No 
 
 
 
 
 
 
 
 
 
Epinephrine 
e_e_yn 
Binary outcome 1=Yes 0=No 
 
Endotracheal Epinephrine 
e_ee 
Binary outcome 1=Yes 0=No 
 
Number of Doses Endotracheal 
Epinephrine  
e_dette 
Continuous Outcome 
 
Intravenous Epinephrine 
e_ie 
Binary outcome 1=Yes 0=No 
 
Number of Doses Intravenous 
Epinephrine 
e_ndive 
Continuous Outcome 
 
UVC Epinephrine 
e_uvce  
Binary outcome 1=Yes 0=No 
 
Number 
of 
Doses 
UVC 
Epinephrine 
e_nduvce  
Continuous Outcome 
 
Intraosseous Epinephrine 
e_ioe 
Binary outcome 1=Yes 0=No 
 
Number of Doses Intraosseous 
Epinephrine 
e_ndioe 
Continuous Outcome  
 
Volume Expander 
e_ve 
Binary outcome 1=Yes 0=No 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
52 
 
Red Packed Blood Cells 
e_prbc 
Binary outcome 1=Yes 0=No 
 
 
 
 
 
pH (combine sample 1 and 2) 
f_ph1 & f_ph2 
Continuous Outcome 
 
pCO2 (combine sample 1 and 2) 
f_pco21 
& 
f_pco23 
Continuous Outcome 
 
BE (combine sample 1 and 2) 
f_be1 & f_be2  
Continuous Outcome 
 
Lactate (combine sample 1 and 2) f_l1 & f_l2 
Continuous Outcome 
 
Glucose 
f_glu 
Continuous Outcome 
 
 
 
 
 
Seizures 
f_s 
Binary outcome 1=Yes 0=No 
 
Pneumothorax 
During 
NICU 
Admission 
g_pnicua 
Binary outcome 1=Yes 0=No 
 
Hours after birth 
g_hpd 
Continuous Outcome in hours 
please 
 
Location of Pneumothorax 
g_lop 
Left, Right, Bilateral 
 
Inotropes 
g_it 
Binary outcome 1=Yes 0=No 
 
 
 
 
 
Initiation of Passive Cooling in the 
Delivery Room 
e_ipcdr  
Binary outcome 1=Yes 0=No 
 
Initiation of Active Cooling in the 
Delivery Room 
e_iacdr 
Binary outcome 1=Yes 0=No 
 
Active Cooling in NICU 
g_acnicu 
Binary outcome 1=Yes 0=No 
 
Duration of Cooling 
g_doc 
Continuous Outcome in hours 
please 
 
 
 
 
 
 
 
 
 
Death during NICU Admission 
h_dnicua 
Binary outcome 1=Yes 0=No  
 
Overall Death should combine 
Subject 
Alive 
at 
end 
of 
Resuscitation and Did the infant 
die during NICU Admission  
 
Both are Binary outcomes but 
Did the infant die during NICU 
Admission is a negative one 
(so the yes and no is reversed). 
 
 
Reason for Death 
 
h_rfd 
Should be a list of diagnoses 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
53 
 
Intraventricular Hemorrhage (IVH) 
 
g_ivh 
Binary outcome 1=Yes 0=No 
 
Grade of IVH 
g_g_ivh 
Papile Grade 3 or Papile Grade 
4  
 
 
Periventricular Leukomalacia 
g_pvl 
Binary outcome 1=Yes 0=No 
 
 
 
 
 
Amplitude EEG (aEEG) performed 
f_aeeg 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern after Stabilization/1h 
(choice=Normal) 
f_aeeg1___1 
Binary outcome 1=Yes 0=No 
 
laEEG Pattern after Stabilization/1h 
(choice=Moderate aEEG Depression) 
f_aeeg1___2 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern after Stabilization/1h 
(choice=Severe aEEG Depression) 
f_aeeg1___3 
Binary outcome 1=Yes 0=No 
 
Combine the three above to one 
variable  
 
Would be a three column list  
 
aEEG Pattern at 3 hours of age 
(choice=Normal) 
f_aeeg3___1 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern at 3 hours of age 
(choice=Moderate aEEG Depression) 
f_aeeg3___2 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern at 3 hours of age 
(choice=Severe aEEG Depression) 
f_aeeg3___3 
Binary outcome 1=Yes 0=No 
 
Combine the three above to one 
variable  
 
Would be a three column list  
 
aEEG Pattern at 5 hours of age 
(choice=Normal)" 
f_aeeg5___1 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern at 5 hours of age 
(choice=Moderate 
aEEG 
Depression)" 
f_aeeg5___2 
Binary outcome 1=Yes 0=No 
 
aEEG Pattern at 5 hours of age 
(choice=Severe 
aEEG 
Depression) 
f_aeeg5___3 
Binary outcome 1=Yes 0=No 
 
Combine the three above to one 
variable  
 
Would be a three column list  
 
MRI findings 
g_mri_r 
Should be a list of diagnoses 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
54 
 
 
 
 
 
 
 
 
 
Days of hospitalisation (= duration 
between day of birth and Day of 
discharge to home or transfer to other 
hospital/ Level 2 NICU 
Difference 
between 
b_dob  
and h_dod 
Continuous outcome in days 
please 
 
 
6.2 Analysis methods  
6.2.1 Analysis methods used  
Primary analysis 
The primary outcome is the time to achieve ROSC defined as a heart rate of >60/min for 60sec. Data will be analyzed on an 
intention-to treat basis and will include all randomized participants. A per protocol analysis will also be conducted using the data from the 
actual allocation of participating infants. A survival analysis will be used to analyze the difference in time to ROSC between intervention 
and control groups. To account for cluster randomization, Cox proportional hazards regression with time to ROSC as an outcome and 
allocation group as an independent variable will be created. Centers will be entered as clusters in the model and the statistical significance 
of the allocation group variable will be evaluated. The analysis will be 2-sided and p-value < 0.05 will be considered statistically significant. 
 
Secondary analysis 
The data will be presented as mean (standard deviation, SD) for normally distributed continuous variables and median (interquartile 
range, IQR) when the distribution is skewed. The clinical characteristics and outcome parameters will be compared using Student’s t-test 
for parametric and Mann-Whitney U-test for nonparametric comparisons of continuous variables, and χ2 for categorical variables. All p-
values will be 2-sided and p <0.05 will be considered statistically significant.  
 
Exploratory analysis 
Analysis of pre-specified secondary outcomes adjusted for relevant co-variates will be considered exploratory. 
 
Safety outcomes 
Analysis will be considered exploratory. 
 
6.2.2 Adjustment for covariates 
Due to the very small sample size, no adjustments will be performed. 
 

 
Protocol version 4.0, July 1st 2020 
 
 
 
 
 
 
55 
6.2.3 Sensitivity analyses 
None. 
 
6.3 Subgroups 
No subgroup analysis 
 
6.4 Missing data  
Since the intervention is performed in the delivery room, very low proportion of missing data is expected.  
 
6.5 Additional analyses  
None. 
 
6.6 Harms  
Severe adverse events will be coded using MedDRA and each SAE will be counted once only for a given participant. Severity, 
frequency and relationship of SAEs to study intervention will be presented. We will compare SAEs related to the oxygen administration 
using a chi-square test. A two-sided p-value of 0.05 or lower will be considered to indicate statistical significance for each safety outcome. 
 
6.7 Statistical software  
The statistical software SAS (SAS Institute Inc., Cary, NC, USA) and R (R Core Team, Vienna, Austria) will be used for the analysis. 
 
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