**8. Contribution of the porcine model of neonatal hypoxia-asphyxia to current knowledge**

The porcine model of neonatal hypoxia-asphyxia has proven to be an invaluable tool through which new resuscitation techniques can be studied pre-clinically. It has also proven to be a crucial element in increasing our understanding of physiological and pharmacological changes surrounding neonatal resuscitation. Below is a summary of studies that have utilized the model to gain further knowledge in various aspects of neonatal resuscitation. Knowledge gained from the below described studies are key in shaping the future neonatal resuscitation guidelines [24, 25].

## **8.1 Sustained inflations**

The current neonatal resuscitation guidelines and the previous guidelines in 2010 [2–4, 26] recommend using a 3:1 C:V ratio when CC are needed, however these recommendations are not based on strong scientific evidence and the most effective C:V ratio in newborns remains controversial. Using our porcine model, Schmölzer et al. investigated an alternative approach to providing ventilation during CPR in the means of sustained inflations (SI) [27]. Rather than the standard coordinated 3:1 C:V technique, Schmölzer et al. proposed that SI during CC would passively deliver an adequate tidal volume into the lungs and improve survival. SI was delivered with a peak inflating pressure of 30 cmH2O for duration of 30 s. During the SI, CC was delivered at a rate of 120/min; SI was interrupted after 30 s for 1 s before a further 30 s of SI was provided [27]. The results showed that piglets resuscitated with SI during CC not only achieved ROSC faster than piglets resuscitated with the standard 3:1 C:V technique, but also had improved hemodynamic recovery and survival [27]. Following that study, Li et al. investigated the optimal rate of CC during SI by comparing CC rates of 90/min and 120/min [28]. Both groups had a similar time to ROSC, survival rates, and hemodynamic and respiratory parameters during CPR, and the hemodynamic recovery in the subsequent 4-hours was also similar in both groups. This leads the authors to suggest that resuscitation with a CC rate of 120/min during SI did not show a significant advantage compared to 90/min and higher CC rates are not necessarily an advantage [28]. To assure this suggestion, another study by Li et al. compared SI with CC at a rate of 90/min to the standard 3:1 C:V technique [29]. Piglets resuscitated with SI during CC at 90/min had significantly improved time to ROSC and also a reduced requirement for 100% oxygen and improved respiratory parameters compared to piglets resuscitated with 3:1 C:V [29]. Mustofa et al. investigated the optimal length of SI during CC by comparing

**175**

*A Porcine Model of Neonatal Hypoxia-Asphyxia to Study Resuscitation Techniques in Newborn…*

resuscitation with SI duration of either 20 s or 60 s [30]. Using SI duration of 60 s resulted in a similar time to ROSC as SI duration of 20 s, as well as similar survival rate and hemodynamic recovery [30]. Furthermore, Mustofa et al. showed no significant differences in lung and brain pro-inflammatory cytokine concentrations between the SI groups and the 3:1 C:V group, suggesting that the SI technique does not promote more acute brain and lung injuries that the currently practiced tech-

Using the porcine model of neonatal hypoxia-asphyxia, Schmölzer et al. investigated a different approach to neonatal resuscitation with asynchronous ventilation during continuous CC; the rationale being that giving continuous CC without pausing for ventilation (as with 3:1 C:V) may avoid interruption in coronary perfusion and may improve minute ventilation during CPR [31]. Piglets were resuscitated with either the standard 3:1 C:V technique or the asynchronous ventilation technique, which delivered continuous CC at a rate of 90/min with asynchronous ventilation at a rate of 30 inflations/min [31]. Both groups had a similar time to ROSC, survival rates, epinephrine and oxygen administration, and hemodynamic and respiratory parameters during CPR; systemic and regional hemodynamic recovery in the subsequent 4-hour recovery period was also similar. This suggests that asynchronous ventilation during continuous CC is not more beneficial to the standard 3:1 C:V technique. In a following study, Patel et al. examined whether the outcome will improve by using different CC rates with asynchronous ventilation, namely 90/min, 100/min, and 120/min [32]. Even though rate and time to ROSC were similar between groups, increasing the CC rate to 120/min with asynchronous ventilation significantly improved hemodynamic recovery, as indicated by CBF, and

Current neonatal resuscitation guidelines recommend the use of 100% oxygen when CC are needed, however this is based on minimal evidence and 100% oxygen is also associated with increased oxidative stress [2–4, 33], and increased morbidity and mortality [34, 35]. Solevåg et al. examined the effect of using 21% oxygen (air) or 100% oxygen during resuscitation using either the 3:1 C:V technique or continuous CC with asynchronous ventilation (rate of 90/min) [36]. Time to achieve ROSC was similar between groups, however resuscitation with air was associated with a higher left ventricular stroke volume after ROSC and less myocardial oxidative stress compared to resuscitation with 100% oxygen [36]. This suggests that air during CC may reduce myocardial oxidative stress and improve cardiac function compared to 100% oxygen. However, the use of continuous CC with asynchronous ventilation in this study was less effective than the standard 3:1

Pasquin et al. used the porcine model of neonatal hypoxia-asphyxia to examine different ratios of CC to ventilations; the standard 3:1 C:V technique was compared to a C:V ratio of 2:1 and 4:1 [37]. Time to ROSC, mortality, oxygen requirements, epinephrine administration, and hemodynamic recovery were similar between all groups, indicating no difference in the efficacy of various C:V ratios in asphyxial-

*DOI: http://dx.doi.org/10.5772/intechopen.89171*

nique of 3:1 C:V [30].

**8.2 Asynchronous ventilation**

cerebral and renal perfusion [32].

**8.3 Oxygen**

C:V technique [36].

**8.4 Chest compressions**

induced cardiac arrest of neonatal piglets.

*A Porcine Model of Neonatal Hypoxia-Asphyxia to Study Resuscitation Techniques in Newborn… DOI: http://dx.doi.org/10.5772/intechopen.89171*

resuscitation with SI duration of either 20 s or 60 s [30]. Using SI duration of 60 s resulted in a similar time to ROSC as SI duration of 20 s, as well as similar survival rate and hemodynamic recovery [30]. Furthermore, Mustofa et al. showed no significant differences in lung and brain pro-inflammatory cytokine concentrations between the SI groups and the 3:1 C:V group, suggesting that the SI technique does not promote more acute brain and lung injuries that the currently practiced technique of 3:1 C:V [30].

## **8.2 Asynchronous ventilation**

*Animal Models in Medicine and Biology*

model.

[24, 25].

**current knowledge**

**8.1 Sustained inflations**

primary cardiac compromise/ventricular fibrillation observed in adult patients. Furthermore, using our newborn piglet model, we are able to describe an increasingly important clinical situation in the laboratory setting – PEA, which is not well described in newborns in the delivery room. However, the asphyxia model uses piglets that have already undergone the transition from fetal to neonatal circulation and have cleared their lung fluid, which may present as a limitation. Furthermore, our model requires piglets to be intubated with a tightly sealed endotracheal tube to prevent any endotracheal tube leak. This may not occur in the delivery room where infants are either intubated (larynx bypassed, leak present) or receive respiratory support via a facemask, resulting in the possibility of airway obstruction or mask leaks. Nevertheless, many of its advantages make up for the few limitations of the

**8. Contribution of the porcine model of neonatal hypoxia-asphyxia to** 

The porcine model of neonatal hypoxia-asphyxia has proven to be an invaluable tool through which new resuscitation techniques can be studied pre-clinically. It has also proven to be a crucial element in increasing our understanding of physiological and pharmacological changes surrounding neonatal resuscitation. Below is a summary of studies that have utilized the model to gain further knowledge in various aspects of neonatal resuscitation. Knowledge gained from the below described studies are key in shaping the future neonatal resuscitation guidelines

The current neonatal resuscitation guidelines and the previous guidelines in 2010 [2–4, 26] recommend using a 3:1 C:V ratio when CC are needed, however these recommendations are not based on strong scientific evidence and the most effective C:V ratio in newborns remains controversial. Using our porcine model, Schmölzer et al. investigated an alternative approach to providing ventilation during CPR in the means of sustained inflations (SI) [27]. Rather than the standard coordinated 3:1 C:V technique, Schmölzer et al. proposed that SI during CC would passively deliver an adequate tidal volume into the lungs and improve survival. SI was delivered with a peak inflating pressure of 30 cmH2O for duration of 30 s. During the SI, CC was delivered at a rate of 120/min; SI was interrupted after 30 s for 1 s before a further 30 s of SI was provided [27]. The results showed that piglets resuscitated with SI during CC not only achieved ROSC faster than piglets resuscitated with the standard 3:1 C:V technique, but also had improved hemodynamic recovery and survival [27]. Following that study, Li et al. investigated the optimal rate of CC during SI by comparing CC rates of 90/min and 120/min [28]. Both groups had a similar time to ROSC, survival rates, and hemodynamic and respiratory parameters during CPR, and the hemodynamic recovery in the subsequent 4-hours was also similar in both groups. This leads the authors to suggest that resuscitation with a CC rate of 120/min during SI did not show a significant advantage compared to 90/min and higher CC rates are not necessarily an advantage [28]. To assure this suggestion, another study by Li et al. compared SI with CC at a rate of 90/min to the standard 3:1 C:V technique [29]. Piglets resuscitated with SI during CC at 90/min had significantly improved time to ROSC and also a reduced requirement for 100% oxygen and improved respiratory parameters compared to piglets resuscitated with 3:1 C:V [29]. Mustofa et al. investigated the optimal length of SI during CC by comparing

**174**

Using the porcine model of neonatal hypoxia-asphyxia, Schmölzer et al. investigated a different approach to neonatal resuscitation with asynchronous ventilation during continuous CC; the rationale being that giving continuous CC without pausing for ventilation (as with 3:1 C:V) may avoid interruption in coronary perfusion and may improve minute ventilation during CPR [31]. Piglets were resuscitated with either the standard 3:1 C:V technique or the asynchronous ventilation technique, which delivered continuous CC at a rate of 90/min with asynchronous ventilation at a rate of 30 inflations/min [31]. Both groups had a similar time to ROSC, survival rates, epinephrine and oxygen administration, and hemodynamic and respiratory parameters during CPR; systemic and regional hemodynamic recovery in the subsequent 4-hour recovery period was also similar. This suggests that asynchronous ventilation during continuous CC is not more beneficial to the standard 3:1 C:V technique. In a following study, Patel et al. examined whether the outcome will improve by using different CC rates with asynchronous ventilation, namely 90/min, 100/min, and 120/min [32]. Even though rate and time to ROSC were similar between groups, increasing the CC rate to 120/min with asynchronous ventilation significantly improved hemodynamic recovery, as indicated by CBF, and cerebral and renal perfusion [32].

#### **8.3 Oxygen**

Current neonatal resuscitation guidelines recommend the use of 100% oxygen when CC are needed, however this is based on minimal evidence and 100% oxygen is also associated with increased oxidative stress [2–4, 33], and increased morbidity and mortality [34, 35]. Solevåg et al. examined the effect of using 21% oxygen (air) or 100% oxygen during resuscitation using either the 3:1 C:V technique or continuous CC with asynchronous ventilation (rate of 90/min) [36]. Time to achieve ROSC was similar between groups, however resuscitation with air was associated with a higher left ventricular stroke volume after ROSC and less myocardial oxidative stress compared to resuscitation with 100% oxygen [36]. This suggests that air during CC may reduce myocardial oxidative stress and improve cardiac function compared to 100% oxygen. However, the use of continuous CC with asynchronous ventilation in this study was less effective than the standard 3:1 C:V technique [36].

#### **8.4 Chest compressions**

Pasquin et al. used the porcine model of neonatal hypoxia-asphyxia to examine different ratios of CC to ventilations; the standard 3:1 C:V technique was compared to a C:V ratio of 2:1 and 4:1 [37]. Time to ROSC, mortality, oxygen requirements, epinephrine administration, and hemodynamic recovery were similar between all groups, indicating no difference in the efficacy of various C:V ratios in asphyxialinduced cardiac arrest of neonatal piglets.

#### **8.5 Respiratory parameters**

The purpose of inflations during CC is to deliver an adequate tidal volume to facilitate gas exchange [38], however limited information exists regarding tidal volume delivery during CC. Therefore, Li et al. examined the changes in tidal volume during CC and their effect on lung aeration in the porcine model of hypoxiaasphyxia [39]. Li et al. shows that when resuscitating using the SI with CC technique, passive lung ventilation/aeration can be achieved. In contrast, although use of the 3:1 C:V technique delivered tidal volume, it also resulted in a relative loss of tidal volume per 3:1 C:V cycle of up to 4.5 mL/kg [39]. This suggests that tidal volume delivery is greater when using SI with CC to resuscitate compared to the standard 3:1 C:V technique; this may lead to better alveolar oxygen delivery and lung aeration [39].

Using an objective method to evaluate recovery or predict the outcome of resuscitation may help decision-making during resuscitation. Therefore, Li et al. examined the temporal changes in end-tidal CO2 (ETCO2), volume of expired CO2 (VCO2), and the partial pressure of exhaled CO2 (PECO2) and their relationship with survivability and hemodynamic changes during CPR in the neonatal porcine model [40]. Li et al. reported that surviving piglets had significantly higher values of ETCO2, VCO2, and PECO2 during CPR compared to non-surviving piglets, suggesting that continuously monitoring ETCO2, VCO2, and PECO2 during CC has the potential to be a non-invasive method to indicate ROSC [40]. To further investigate if other parameters could be used as early outcome predictors after CPR, Solevåg et al. examined if cerebral and renal tissue oxygen saturation was different between surviving piglets and non-surviving piglets that were resuscitated after asphyxiainduced cardiac arrest [41]. The relationship of the tissue oxygen saturations with cardiac output, blood pressure, and biochemical variables was also examined [41]. No correlation between cardiac output or blood pressure and cerebral or renal tissue oxygen saturation was observed.

#### **8.6 Hemodynamics**

Espinoza et al. examined the changes in HR during adequate PPV following severe bradycardia in the porcine model of hypoxia-asphyxia [42]. The Neonatal Resuscitation Program (NRP) states that if adequate PPV is given for low HR, then the infant's HR should increase within the first 15 s of PPV. However in contrast to the NRP, Espinoza et al. showed that adequate PPV does not increase HR within 15 s of ventilation in piglets with asphyxia-induced bradycardia; after 30 s of PPV only half of piglets had an increase in HR. This study challenges the current NRP statement and suggests that clinicians should not expect an increase in HR after 15 s of PPV if there is severe bradycardia [42].

#### **8.7 Epinephrine**

Current neonatal resuscitation guidelines recommend the administration of intravenous epinephrine during if HR persists below 60 bpm despite CC and 100% oxygen [2–4]. However there is currently a lack of data evaluating the hemodynamic effects of epinephrine during neonatal resuscitation. Wagner et al. utilized the porcine model of hypoxia-asphyxia to examine hemodynamic changes after epinephrine administration during resuscitation and compare surviving and non-surviving piglets; epinephrine was administered at a dose of 0.01 mg/kg [43]. Epinephrine had no effect on either HR or cardiac output in survivors versus non-survivors during resuscitation; it did not increase survival rates or ROSC [43].

**177**

**Author details**

Edmonton, Alberta, Canada

Alberta, Edmonton, Alberta, Canada

provided the original work is properly cited.

Health Research Institute, University of Alberta.

*A Porcine Model of Neonatal Hypoxia-Asphyxia to Study Resuscitation Techniques in Newborn…*

The abovementioned studies highlight the practicality of this neonatal animal model not only in driving progress in our understanding of neonatal resuscitation,

Animal models that reliably reproduce the events surrounding neonatal resuscitation in the delivery room are imperative to improve the outcome of newborn infants requiring CPR and may also lead to benefits for the pediatric population. Due to its many advantages, the porcine model of neonatal hypoxia-asphyxia is one of the most commonly used large animal models for neonatal resuscitation studies. Not only has this model provided a further understanding of the effects of various resuscitation interventions, but it has also enabled the study of an increasingly important clinical situation in the laboratory setting – pulseless electrical activity. Using this animal model will further accelerate knowledge on neonatal resuscitation

We would like to thank the public for donating money to our funding agencies: GMS is a recipient of the Heart and Stroke Foundation/University of Alberta Professorship of Neonatal Resuscitation, a National New Investigator of the Heart and Stroke Foundation Canada and an Alberta New Investigator of the Heart and Stroke Foundation Alberta. The study was supported by a Grant from the SickKids

Foundation in partnership with the Canadian Institutes of Health Research (CIHR - Institute of Human Development, Child and Youth Health (IHDCYH)), New Investigator Research Grant Program (Grant number - No. NI17-033) and a Grant-in-Aid from the Heart and Stroke Foundation Canada (Grant Number: G-15- 0009284). We would like to acknowledge support from the Women and Children's

but also in paving the way for new techniques into the delivery room.

Megan O'Reilly1,2, Po-Yin Cheung1,2, Tze-Fun Lee1,2 and Georg M. Schmölzer1,2\*

2 Department of Pediatrics, Faculty of Medicine and Dentistry, University of

\*Address all correspondence to: georg.schmoelzer@me.com

1 Centre for the Studies of Asphyxia and Resuscitation, Royal Alexandra Hospital,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*DOI: http://dx.doi.org/10.5772/intechopen.89171*

that will ultimately benefit patients.

**Acknowledgements**

**9. Conclusions**

*A Porcine Model of Neonatal Hypoxia-Asphyxia to Study Resuscitation Techniques in Newborn… DOI: http://dx.doi.org/10.5772/intechopen.89171*

The abovementioned studies highlight the practicality of this neonatal animal model not only in driving progress in our understanding of neonatal resuscitation, but also in paving the way for new techniques into the delivery room.
