CO2-related vasoconstriction superimposed on ischemic medullary brain autonomic nuclei may contribute to sudden death

Introduction: In 2015, a multinational randomized controlled phase IV clinical trial of adaptive servoventilation for the management of heart failure with central sleep apnea was halted in progress because more patients in the study group were dying than in the control group. One year later, another large clinical trial reported results on the effectiveness of continuous positive airway pressure (CPAP) in preventing sudden death and other cardiovascular events such as heart attack and stroke in patients with preexisting vascular disease as well as obstructive sleep apnea. Background: Sudden unexpected death has been associated with many types of small and nonmalignant medullary brain lesions, like demyelination plaques — largely asymptomatic until they caused sudden death. Many such medullary lesions, typically without hemorrhage or mass effect, have in themselves been previously considered relatively harmless — in cases where they have been known to be present. Discussion: Why did not the improved pulmonary ventilation and subsequently improved gas exchange provided during the CPAP and servoventilation clinical trials help to resolve any ischemic lesions that may have been present both in the heart and in the medulla, thereby tending to normalize interactions between the vagal neural structures and the heart? CO2 is a potent dilator of brain vasculature, thereby increasing blood flow to the brain. When ventilation is increased, even if only to improve it back toward normal from a depressed steady-state level, the alveolar partial pressure of carbon dioxide is decreased, likely resulting in a converse relative vasoconstriction in the brain, thereby reducing blood flow in the brain, especially in watershed areas like the solitary tract nucleus. In normal physiology, this is demonstrated impressively by the ability of hyperventilation to induce loss of consciousness. Conclusions: The findings of several clinical trials recently reported, taken together with neuropathology case studies reported elsewhere, suggest that additional research is warranted in regard to the mechanisms by which focal medullary autonomic brain ischemia may be related to sudden death in general medical illnesses — and how it may additionally be influenced by changes in arterial CO2 levels.