Carbon Monoxide Exerts Functional Neuroprotection After Cardiac Arrest Using Extracorporeal Resuscitation in Pigs

Abstract

Objectives: Neurologic damage following cardiac arrest remains a major burden for modern resuscitation medicine. Cardiopulmonary resuscitation with extracorporeal circulatory support holds the potential to reduce morbidity and mortality. Furthermore, the endogenous gasotransmitter carbon monoxide attracts attention in reducing cerebral injury. We hypothesize that extracorporeal resuscitation with additional carbon monoxide application reduces neurologic damage. Design: Randomized, controlled animal study. Setting: University research laboratory. Subjects: Landrace-hybrid pigs. Interventions: In a porcine model, carbon monoxide was added using a novel extracorporeal releasing system after resuscitation from cardiac arrest. Measurements and Main Results: As markers of cerebral function, neuromonitoring modalities (somatosensory-evoked potentials, cerebral oximetry, and transcranial Doppler ultrasound) were used. Histopathologic damage and molecular markers (caspase-3 activity and heme oxygenase-1 expression) were analyzed. Cerebral oximetry showed fast rise in regional oxygen saturation after carbon monoxide treatment at 0.5 hours compared with extracorporeal resuscitation alone (regional cerebral oxygen saturation, 73% ± 3% vs 52% ± 8%; p < 0.05). Median nerve somatosensory-evoked potentials showed improved activity upon carbon monoxide treatment, whereas post–cardiac arrest cerebral perfusion differences were diminished. Histopathologic damage scores were reduced compared with customary resuscitation strategies (hippocampus: sham, 0.4 ± 0.2; cardiopulmonary resuscitation, 1.7 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.3 ± 0.2; extracorporeal cardiopulmonary resuscitation with carbon monoxide application [CO-E-CPR], 0.9 ± 0.3; p < 0.05). Furthermore, ionized calcium-binding adaptor molecule 1 staining revealed reduced damage patterns upon carbon monoxide treatment. Caspase-3 activity (cardiopulmonary resuscitation, 426 ± 169 pg/mL; extracorporeal cardiopulmonary resuscitation, 240 ± 61 pg/mL; CO-E-CPR, 89 ± 26 pg/mL; p < 0.05) and heme oxygenase-1 (sham, 1 ± 0.1; cardiopulmonary resuscitation, 2.5 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.4 ± 0.2; CO-E-CPR, 1.4 ± 0.2; p < 0.05) expression were reduced after carbon monoxide exposure. Conclusions: Carbon monoxide application during extracorporeal resuscitation reduces injury patterns in neuromonitoring and decreases histopathologic cerebral damage by reducing apoptosis. This may lay the basis for further clinical translation of this highly salutary substance.

Neuroprotective effect of selective hypothermic cerebral perfusion in extracorporeal cardiopulmonary resuscitation: A preclinical study

“…Brain damage is a major cause of death and disability in patients with ECPR after CA. 17 In a meta-analysis of 6261 patients with ECPR, Migdady and colleagues 18 found that the favorable neurologic recovery rate was only 24% (95% confidence interval, 21%-28%). Two key points of restoring neuronal function are maintaining cerebral blood perfusion and reducing brain temperature.…”

The effects of ECMO on neurological function recovery of critical patients: A double-edged sword

“…The ECMO cannula retrograde input of oxygenated blood from the femoral artery is competition for deoxygenated blood from the natural circulation (46)(47)(48). Which results in inadequate coronary and head oxygenation and severe bilateral cerebral hypoxia (44,49). In addition, the clinical experience shows that the reduced "protective" lung ventilation used in ECMO patients may further contribute to varying degrees of hypoxemia (50).…”

“…The primary conditions such as the no and low blood flow state after CA and during CPR could cause initial hypoxic–ischemic damage to the brain ( 44 ), and inappropriate ECMO cannulation can exacerbate this pathological damage.…”

“…As well as CA patients treated with ECPR after ROSC usually accompanied with hyperoxia (usually defined as mild PaO 2 > 100 or 120 mmHg and severe PaO 2 > 300 mmHg) can also lead to acute cerebral IR injury. The underlying mechanism is that hyperoxia increases the production of ROS, which causes damage to lipid membranes, deoxyribonucleic acid and proteins ( 44 ), and neuronal damage. It also causes reactive vasoconstriction, leading to impaired cerebral microcirculation, and platelet dysfunction, which increases the risk of thrombosis and hemorrhage ( 56 , 57 ).…”

Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime

“…Advanced devices only released CO gas and kept all educts and by-and degradation products in the device. Successful applications were in organ transplantation 45 and pig studies of extracorporeal pulmonary resuscitation following cardiac arrest, 46 in which neuroprotection, 47 renal function improvement, 48 and improved hemodynamics 49 were reported. We are now expanding these designs for oral administration.…”