Matt Harmon

157 Chapter eight Background Out-of-hospital cardiac arrest (OHCA) is a common reason for critical care admission. 1-3 Despite increasing survival after OHCA with initial shockable rhythm in the last decades 4,5 , overall survival is still low 6,7 , and brain injury continues to be the principal cause of death and disability. 5,8 Guidelines recommend ventilation to normal carbon dioxide levels after return of spontaneous circulation (ROSC) .9,10 However, unintended hyperventilation during and after resuscitation frequently occurs and variability in ventilation leading to dyscarbia is a prevalent finding in the post cardiac arrest phase. 11,12 Elevated arterial carbon dioxide partial pressure (PaCO 2 ), hypercapnia, may lead to cerebral vasodilatation and increased cerebral blood flow (CBF), while a decrease in PaCO 2 , hypocapnia, can exert the opposite effect. 13 PaCO 2 is also a central variable in acid-base homeostasis encompassing hypercapnic acidosis or hypocapnic alkalosis. 14 In recent studies, PaCO 2 was associated with neurological outcome after OHCA; hypocapnia was related to poor neurological outcome 15-17 , whilst hypercapnia was associated with good as well as poor neurological outcome. 16-21 As hypercapnia has been associated to good neurological outcome 16 , the novel concept of targeted therapeutic mild hypercapnia (TTMH) has been tested in the pilot randomized Carbon Control and Cardiac Arrest (CCC)-trial and shown to be safe, feasible to perform, lowering biomarkers of brain damage and a tendency of improved global functional outcome. 21 A phase-III randomized clinical trial has recently started recruiting patients to further investigate the impact of TTMH on neurological outcome (NCT03114033) and there are active plans to co-enrol patients with the ongoing TTM2-trial (NCT02908308) comparing hypothermia to normothermia after cardiac arrest. 22 We conducted this exploratory sub-study of the TTM-trial to describe the evolution of PaCO 2 in serial measurements at predefined time points during the first hours after ROSC, to explore the role that PaCO 2 may have in the neurological outcome of OHCA patients and to specifically analyze the interaction between mild hypercapnia and targeted temperature management in relation to neurological outcome. To further strengthen the analyzes, we investigated the association of PaCO 2 to a surrogate marker of neurological outcome: peak levels of serum-protein tau, a marker of neuronal damage, that has shown to be more accurate than neuron specific enolase (NSE) in predicting outcome. 23