Chest compression superimposed with sustained inflation – translating preclinical findings into a neonatal clinical trial

Abstract

Neonatal cardiopulmonary resuscitation (CPR) remains associated with high mortality and significant risk of neurodevelopmental impairment. Current neonatal resuscitation guidelines recommend a 3:1 compression-to-ventilation (C:V) ratio, which inherently requires frequent interruptions in chest compressions, limits ventilation efficiency, and may delay return of spontaneous circulation (ROSC).

To address these limitations, we have examined chest compressions with sustained inflation (CC + SI) as an alternative approach. Preliminary data from animal studies and pilot human trials suggest (1) improved tidal volume delivery, (2) facilitation of passive ventilation during compressions, (3) uninterrupted chest compressions, and (4) more stable cerebral blood flow during resuscitation.

Experimental studies in asphyxiated animal models have demonstrated that CC + SI improves oxygenation, shortens time to ROSC, and reduces mortality without increasing pulmonary or cerebral injury when compared with standard 3:1 CPR. Two small pilot trials in human neonates support the feasibility of CC + SI. However, larger randomized controlled trials are required to validate these findings and determine whether CC + SI can safely and effectively replace the current 3:1 C:V approach as the standard of care in neonatal resuscitation.

Introduction

Approximately 0.1% of term and 10–15% of preterm infants (2–3 million globally) require cardiopulmonary resuscitation (CPR) at birth.1, 2 Chest compressions (CC) are recommended if the heart remains below 60/min after 30sec of adequate positive pressure ventilation.1, 2 The current neonatal resuscitation guidelines recommend a 3:1 compression-ventilation (C:V) ratio with 90 compressions and 30 inflations per minute.³ The mortality rate for infants who receive CPR in the delivery room is alarmingly high, with approximately 1 million newborns dying annually.1, 2, 4, 5, 6, 7 Survivors face significant short- and long-term neurological morbidity: 57% experience hypoxic-ischemic encephalopathy and seizures, and 73% suffer from moderate to severe disabilities.8, 9 As the primary cause of neonatal cardiac arrest is impaired gas exchange with hypoxemia and hypercapnia, establishing effective ventilation while providing high quality CC has the potential to improve coronary perfusion, and ultimately restore cardiac function.

In this report, we summarize data from our preclinical animal model and two small pilot trials, while were starting a multi-center randomized cluster trial.

Mechanism of chest compression

Severe hypoxia and acidosis impair cardiac function by reducing aortic peak blood flow and diastolic pressure, thereby diminishing coronary perfusion and exacerbating myocardial ischemia and hypoxia.10, 11 The purpose of CC is to restore adequate blood flow, hence oxygen delivery to vital organs during cardiac arrest.10, 11 This is thought to be achieved through two main mechanisms: the cardiac pump theory and the thoracic pump theory.12, 13, 14, 15, 16, 17, 18 The cardiac pump theory postulates that with every CC the heart is squeezed between the sternum and spine, hence the blood is ejected into the circulation¹⁸; The alternative mechanism, the thoracic pump theory, may account for most of the blood flow generated during CC. Chandra et al., described such a mechanism, in which CC create rhythmic increase in intrathoracic pressure, generating a pressure gradient between the arterial and venous compartments, resulting in forward blood flow into the circulation.19, 12, 13, 14, 15, 16, 17

How does CC + SI work?

For over a decade we have examined an alternative technique for neonatal CPR, where CC are given continuously and are superimposed by a constant high distending pressure (also called sustained inflation = CC + SI).20, 21, 22, 23, 24, 25, 26, 27, 28, 29 CC + SI delivers continuous CC at a rate of 90–120 compressions per min with a peak inflation pressure of at least 25 cmH₂O for up to 30 s. After each sustained inflation, the inflation is paused for 1sec, during which the airway pressure decreases to the level of positive end expiratory pressure, while CC are continued. With every CC air is forced out of the lung, and during chest recoil the high distending pressure (sustained inflation) allows gas to flow back into the lung. CC + SI leverages the thoracic pump theory by providing a high distending pressure, which has been shown to increase intrathoracic pressure,³⁰ as well as continuous CC, which also increase intrathoracic pressure.²⁹ By increasing the intrathoracic pressure, the generated pressure gradient drives forward blood flow, which can improve pulmonary blood flow, increase carotid blood flow, and facilitate venous return and preload during the compression-recoil. These CC + SI cycles are repeated until return of spontaneous circulation (ROSC) is achieved. CC + SI has been mentioned in the Consensus of Science and Treatment Recommendations from the International Liaison Committee on Resuscitation.1, 31, 32

Passive ventilation

An under-recognized adverse effect of the current standard approach of neonatal CPR (3:1 C:V technique) is lung de-recruitment. This technique forces air out of the lungs (a forced exhalation) during each compression, and the passive chest recoil only contributes to dead space ventilation, since the inflations are coordinated and do not occur at the same time as the CC.25, 33 In a neonatal piglet study, we measured the inspiration tidal volume and expiration tidal volume during CPR using the 3:1 C:V technique and the CC + SI technique.²⁵ For every 3:1 C:V cycle, the inspiration tidal volume was smaller than the expiration tidal volume, which ultimately led to a cumulated mean tidal volume loss of up to 4.5 mL/kg.²⁵ This is concerning as this could lead to alveolar de-recruitment and thereby prolong resuscitative efforts.²⁵ Therefore, CPR techniques, which combine high-quality CC with strategies that recruit the lung are needed. When CC + SI is performed, air moves in and out of the chest as there is a constant distending pressure being delivered (sustained inflation) that is not interrupted for CC. With every CC, air is forced out of the lung, and during chest recoil the sustained inflation allows gas to passively flow back into the lung. When tidal volume was measured during neonatal piglet CPR with CC + SI, we observed a mean tidal volume gain of up to 2.3 mL/kg for each CC + SI cycle; each inspiration tidal volume was greater than the expiration tidal volume, cumulating a gain in tidal volume.²⁵ The tidal volume gain helps prevent lung collapse and improves lung aeration, resulting in increases in pulmonary blood flow. This can lead to increases in oxygenated blood flow returning from the lungs, which can restore cardiac function and result in improved tissue oxygen delivery during CPR. CC + SI thereby allows for higher minute ventilation, enhancing gas exchange and hemodynamic recovery.

Preclinical studies with CC + SI

CC rates

The current neonatal resuscitation guidelines recommend a CC rate of 90/min, however, the optimal CC rate remains unknow.31, 34 A mathematical model suggests that a CC rate of 180/min will result in improved blood flow and maximal systemic perfusion pressure.³⁵ In a recent study in neonatal piglets by our group, we compared CC rates of 60–180/min and demonstrated a gradual increase in stroke volume, minimum and maximum rate of left ventricle pressure change, and carotid blood flow until a CC rate of 150/min, with a level-off effect at a CC rate of 180/min.³⁶ However, cardiac output continued to increase with the highest being at a CC rate of 180/min.³⁶ Further randomized animal trials comparing various CC rates (90/min vs 120/min, 90/min vs 60/min, 90/min vs 180/min) combined with the CC + SI technique showed no differences in time to ROSC, mortality, hemodynamic, or respiratory parameters.26, 37, 38 While CC + SI with rates of 60, 90, 120, and 180/min have been studied in neonatal animal studies, no study has examined 150/min and the optimal CC rate remains unknown.

Peak inflation pressure

The current neonatal resuscitation guidelines recommend an initial peak inflation pressure (PIP) of 20–25 cmH₂O during mask ventilation, which can be increased to 30–40 cmH₂O if necessary.1, 2 In our original animal study that described the CC + SI technique, we used a PIP of 30 cmH₂O, which resulted in a mean tidal volume of 14 mL/kg.²⁰ In an animal cadaver study, we identified a PIP of 25 cmH₂O to be sufficient to deliver an adequate tidal volume when using CC + SI.³⁹ In a subsequent animal study, we compared PIPs of 10, 20, and 30 cmH₂O with CC + SI and reported that different PIPs resulted in similar time to ROSC.⁴⁰ However, a PIP of 30 cmH₂O resulted in larger tidal volume delivery, lower exhaled CO₂, and was associated with increased brain inflammatory markers.⁴⁰

Oxygen concentration

There is uncertainty as to what the optimal oxygen concentration might be for term and preterm infants.1, 2, 41 The current neonatal resuscitation guidelines state that the initial oxygen concentration should be either 21% (for term infants), 21–30% (for preterm infants >32 weeks), or 30–100% (for preterm infants <32 weeks).1, 2 Regardless, once CC are started, the oxygen concentration should be increased to 100% oxygen.1, 2 While there is no study that has examined different oxygen concentrations during CC in newborns, animal studies comparing 21% with 100% oxygen using the CC + SI technique as well as other techniques showed no difference in time to ROSC, short-term survival, and hemodynamic recovery.42, 43

Injury markers

There are concerns, that the sustained distending pressure during CC + SI might cause lung injury or air leaks (e.g., pneumothorax) as well as impaired venous return resulting in intraventricular hemorrhage. However, none of the preclinical animal studies has reported pneumothorax on autopsy. Furthermore, analysis of pulmonary and cerebral injury markers including interleukin-1β (IL), IL-6, IL-8, and tumor necrosis factor-alpha (TNF‑α) were not different with CC + SI compared to 3:1 C:V.²³ Furthermore, both pilot trials in newborn infants comparing CC + SI with 3:1 C:V reported no increase in intraventricular hemorrhage or air leaks.22, 44

Human trials

Our laboratory fundings have been successfully translated into two pilot trials in newborn infants at birth.22, 44 Our initial pilot trial was a single center feasibility trial, which confirmed our preclinical findings with a significantly shorter mean (SD) time to ROSC with CC + SI with 31 (9) s vs 138 (72) s.²² This was followed by the SURV1VE Trial, a cluster crossover trial, at four centers in Canada and Austria.⁴⁴ The SURV1VE Trial was planned to recruit 218 infants, however, due to the COVID-19 pandemic – which prevented the start of new studies, several ethics committees postponed approval until the first interim analysis to have more safety data, and insurance companies refused to provide international trial insurance – it took over 3 years to sign contracts. These delays (patient recruitment occurred between October 2017 and September 2022) and hurdles resulted in the trial being stopped after 5 years, with only 25 infants (n = 11, CC + SI; n = 14, 3:1 C:V) enrolled.⁴⁴ The primary outcome was time to ROSC, and the median (IQR) time to ROSC was 90 (60–270) s and 615 (174–780) s (p = 0.0502 (log rank), p = 0.16 (cox proportional hazards regression)) with CC + SI and 3:1 C:V, respectively. Mortality was 2/11 (18.2%) with CC + SI versus 8/14 (57.1%) with 3:1 C:V (p = 0.10 (Fisher’s exact test), OR (95% CI) 0.17; (0.03–1.07)).⁴⁴ Furthermore, a recent meta-analysis of both trials reported that the pooled data suggests no difference in infant mortality between CC + SI versus 3:1 C:V during neonatal CPR (Relative Risk 0.64, 95% Confidence Interval 0.21,1.7, p = 0.33, I² = 63%).⁴⁵ The pooled data further suggested a significant reduction in time to ROSC with CC + SI versus 3:1 C:V during neonatal CPR (mean difference 115 (from 184.75 to 45.36) s, p = 0.001, I² = 26%).⁴⁵

Outlook

Preliminary data form several animal and two small human pilot trials suggest that CC + SI improves tidal volume delivery, allows for passive ventilation during CC, provides uninterrupted CC, and improves stability of carotid blood flow during CPR by returning and maintaining it to baseline levels (Table 1, Table 2). While the preclinical and early human data are promising, a large trial comparing CC + SI with 3:1 C:V to assess mortality and long-term neurodevelopmental outcomes is needed. We have recently published a call to participate in a SURV1VE-2 Trial,⁴⁶ which received funding from the Canadian Institute of Health Research in 2025. The SURV1VE-2 Trial aims to recruit 554 infants (277 infants per group) in centers in Canada, USA, Chile, India, Pakistan, Zimbabwe, South Africa, UK, Europe, Australia, and New Zealand. Further sites are welcome to join to ensure this trial, which will be the largest CPR trial in newborn infants, will be successful.

Table 1.

Comparison of CC + SI vs 3:1 C:V during neonatal CPR.

Domain	CC + SI (Chest Compressions + Sustained Inflation)	3:1 C:V (Compression-to-Ventilation Ratio)	References
Mechanism	Combines continuous CC (90–120/min) with sustained inflation (≥25 cmH2O for up to 30 s), maintains high intrathoracic pressure and passive ventilation.	Alternates 3 compressions: 1 ventilation (90 CC + 30 inflations/min), interrupts compressions for ventilations.	20, 21
Ventilation Efficiency	Neonatal piglet model: Enables passive ventilation during CC. Two-fold increase in minute ventilation, increases gas exchange. Mean tidal volume gain ≈2.3 mL/kg per cycle, helps prevent lung collapse.	Neonatal piglet model: Causes lung de-recruitment with each CC cycle. Mean tidal volume loss ≈4.5 mL/kg per cycle, risking alveolar collapse.	22, 23, 24
Circulatory mechanics	Adult dog, adult pig, adult baboon models: Enhances intrathoracic pressure and forward blood flow via thoracic pump effect. Neonatal piglet model: Increases cardiac output and carotid blood flow, which improves coronary perfusion.	Repeated pauses for ventilation may reduce mean intrathoracic pressure and perfusion efficiency.	19, 20, 12, 13, 14, 15, 16, 17
Hemodynamics	Neonatal piglet model: Carotid blood flow returns to baseline value after CPR and maintains baseline value during recovery. Increases diastolic blood pressure, mean systemic arterial pressure, and pulmonary arterial pressure.	Neonatal piglet model: Reduces mean systemic arterial pressure and diastolic pressure, likely due to interruption of CC for ventilations.	25, 26, 27
Time to ROSC (Return of Spontaneous Circulation)	Neonatal piglet model: Faster time to ROSC, less than half of that of 3:1 C:V. Clinical studies: Significantly shorter time to ROSC (Pilot trial 31 s vs 138 s; SURV1VE trial median 90 s vs 615 s; Meta-analysis mean difference 115 s).	Neonatal piglet model, clinical studies: Longer time to ROSC; interrupted CC may delay hemodynamic recovery.	20, 22, 44, 45
Mortality	Neonatal piglet model: Lower mortality after ROSC (∼12% vs ∼62%). Clinical studies: Trend toward lower mortality (18% vs 57%, OR 0.17 [0.03–1.07]); pooled data RR 0.64 [0.21–1.7]).	Neonatal piglet model, clinical studies: Higher mortality in preclinical piglet model and early clinical comparisons.	20, 21, 44
Lung and brain injury markers	Neonatal piglet model: No increase in pulmonary or cerebral inflammatory markers (IL-1β, IL-6, IL-8, TNF-α). Neonatal piglet model, clinical studies: No pneumothorax or intraventricular hemorrhage in preclinical piglet model or pilot clinical trials.	Neonatal piglet model: Baseline comparison; similar injury markers but greater risk of lung de-recruitment.	21, 22, 44, 45, 46
Oxygenation	Neonatal piglet model: Two-fold increase in minute ventilation supports better oxygenation and CO2 clearance; maintains lung inflation during CC.	Neonatal piglet model: Lower exhaled CO2 during CC (less than half of that of CC + SI); indicates limited gas exchange during compressions; oxygen delivery fluctuates.	42, 47
Ease of implementation	Simulation study: Requires pressure-controlled device capable of sustained inflation with simultaneous CC.	Simulation study: Standard NRP technique, universally taught and simple to perform.	48
Clinical translation	Clinical studies: Feasible and safe in pilot human trials; large multinational SURV1VE-2 Trial (n = 554) underway.	Clinical studies: Established standard of care in current NRP guidelines.	22, 44, 45, 46

Abbreviations: CC, chest compressions; CC + SI, chest compressions with sustained inflation; C:V, compression-to-ventilation ratio; IL, interleukin; NRP, Neonatal Resuscitation Program; ROSC, return of spontaneous circulation; TNF, tumor necrosis factor.

Table 2.

Results from animal studies comparison of CC + SI vs 3:1 C:V.

CRediT authorship contribution statement

Si Chen: Writing – original draft, Methodology, Investigation, Data curation. Megan O’Reilly: Writing – review & editing, Validation, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Tze-Fun Lee: Writing – review & editing, Validation, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Georg M. Schmölzer: Writing – review & editing, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

SC, MOR, and TFL have no competing interests.

GMS has no finical conflicts. However, he has developed CC+SI and has received funding form the Sick Kids Foundation, Toronto Canada, Heart and Stroke Foundation, Canada, Canadian Institute of Health Research, and Thrasher Research Fund to conduct experimental or clinical trials.