Pediatric Extracorporeal Cardiopulmonary Resuscitation: Development of a Porcine Model and the Influence of Cardiopulmonary Resuscitation Duration on Brain Injury

Abstract

Background The primary objective was to develop a porcine model of prolonged (30 or 60 minutes) pediatric cardiopulmonary resuscitation (CPR) followed by 22- to 24-hour survival with extracorporeal life support, and secondarily to evaluate differences in neurologic injury. Methods and Results Ten-kilogram, 4-week-old female piglets were used. First, model development established the technique (n=8). Then, a pilot study was conducted (n=15). After 80% survival was achieved in the final 5 pilot animals, a proof-of-concept randomized study was completed (n=11). Shams (n=6) underwent anesthesia only. Severe neurological injury was determined by a composite score of mitochondrial function, neuropathology, and cerebral metabolism: scale of 0-6 (severe: >3). Among 15 piglets in the pilot study, overall survival was 10 (67%); of the final 5, overall survival was 4 (80%). Eleven piglets were then randomized to 60 (CPR60, n=5) or 30 minutes of CPR (CPR30, n=5); 1 animal was excluded from prerandomization for intra-abdominal hemorrhage (10/11, 91% survival). Three of 5 animals in the CPR60 group had severe neurological injury scores versus 1 of 5 in the CPR30 group (P=0.52). During ECMO, CPR60 animals had lower pH (CPR60: 7.4 [IQR 7.4-7.4] versus CPR30: 7.5 [IQR 7.4-7.5], P=0.022), higher lactate (CPR60: 6.8 [IQR 6.8-11] versus CPR30: 4.2 [IQR 4.1-4.3] mmol/L; P=0.012), and higher ICP (CPR60: 19.3 [IQR 11.7-29.3] versus CPR30: 7.9 [IQR 6.7-9.3] mm Hg; P=0.037). Both groups had greater mitochondrial injury than shams (CPR60: P<0.001; CPR30: P<0.001). CPR60 did not differ from CPR30 in mitochondrial respiration, neuropathology, or cerebral metabolism. Conclusions A pediatric porcine model of extracorporeal cardiopulmonary resuscitation after 60 and 30 minutes of CPR consistently resulted in 24-hour survival with more severe lactic acidosis in the 60-minute cohort.

Keywords: cardiac arrest; cardiopulmonary resuscitation; extracorporeal membrane oxygenation; mitochondria; pediatric.

Figure 1. Experimental methods.

CPR indicates cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalogram; HD‐CPR, hemodynamic‐directed CPR; MAP, mean arterial pressure; and SBP, systolic blood pressure.

Figure 2. Model development and study population.

CPR indicates cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; and HD‐CPR, hemodynamic‐directed CPR.

Figure 3. Intra‐arrest physiology over 30 (n=5) or 60 (n=5) minutes of CPR.

Data shown are from a mixed effects model comparing predicted values for each group, 30‐minutes CPR and 60‐minutes CPR. Values are predicted difference (standard error) between 60‐minutes CPR versus 30‐minutes CPR. Time was coded differently for variables measured at different frequencies. CBF indicates cerebral blood flow; CoPP, coronary artery perfusion pressure; DBP, diastolic blood pressure; EtCO₂, end tidal carbon dioxide; ICP, intracranial pressure; L/P, lactate/pyruvate ratio; MD, cerebral microdialysis; PbtO₂, brain tissue oxygenation; and SBP, systolic blood pressure,

Figure 4. Mitochondrial respiration at 24 hours following cardiac arrest.

Wilcoxon rank‐sum test was used for nonnormally distributed data. Values are median (interquartile range). CI indicates complex I; CII, complex II; CPR30, treatment group that received CPR for 30 minutes; CPR60, treatment group that received CPR for 60 minutes; ICH, intracerebral hemorrhage; LEAK, state 4^o respiration without ATP production; OXPHOS, oxidative phosphorylating capacity; and RCR, respiratory control ratio.