Carbon Monoxide Poisoning: From Microbes to Therapeutics

Abstract

Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.

Keywords: antidotes; carbon monoxide; carbon monoxide poisoning; heme; mitochondria.

Figure 1

Pathophysiological effects of acute CO exposure. In circulating red blood cells, CO binds to heme sites in Hb, diminishing O₂ carrying capacity and stabilizing the high-affinity R-state. In addition to binding Hb in circulation, CO may also bind myoglobin, causing a reduction in O₂ availability in tissue. In mitochondria, CO may directly bind the heme a₃ site in complex IV of the mitochondrial ETC, inhibiting the reduction of O₂ to water. This inhibition, coupled with reduced O₂ availability, leads to membrane depolarization, reduced ATP output, and accumulation of reducing equivalents in the ETC. These reducing equivalents may react with O₂ to form superoxide (O₂•−), which may propagate cellular damage directly or through conversion to other reactive oxygen species, such as hydrogen peroxide (H₂O₂). Abbreviations: CoQ, coenzyme Q/ubiquinone; Cyt c, cytochrome c; ETC, electron transport chain; Hb-R, relaxed-state hemoglobin; Hb-T, tense-state hemoglobin; P_O2, partial pressure of O₂. Figure adapted from images created with BioRender.com.

Figure 2

Summary of treatment strategies for acute CO poisoning. Treatment strategies fall into three categories: gas exchange, CO scavenging, and pharmacological mitigation. Normobaric oxygen therapy (NBOT), hyperbaric oxygen therapy (HBOT), and isocapnic hyperpnea (IH) therapy rely on gas exchange in the lungs with accelerated CO clearance driven by increased O₂ partial pressure or ventilation. Extracorporeal membrane oxygenation (ECMO) may facilitate CO clearance via gas exchange in cases of extreme illness or lung damage, and extracorporeal removal of CO with phototherapy (ECCOR-P) facilitates this clearance through CO photolysis. CO-scavenging therapeutics, including hemoprotein-based scavengers (Ngb-H64Q-CCC, StHb) and small molecule–based scavengers (hemoCD), may directly sequester CO from circulating hemoglobin (Hb) or cellular hemoproteins. These scavengers undergo rapid renal clearance to safely eliminate both scavenger and CO. A number of pharmacological compounds have been explored to mitigate the downstream pathophysiological damage incurred during acute CO poisoning, including steroids, anti-inflammatory drugs, and mitochondrial electron transport chain substrates. Figure adapted from images created with BioRender.com.