Jason J. Rose

Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy

&NA; Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long‐term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long‐term neurocognitive deficits occur in 15‐40% of patients, whereas approximately one‐third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire‐related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development.

Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning

A mutant five-coordinate neuroglobin with a very high carbon monoxide binding affinity acts as an antidote to bind and eliminate CO. Antidote for an invisible foe We cannot see it, taste it, or smell it. Nevertheless, carbon monoxide is a deadly poison; it is a frequent cause of poisoning all over the world. This gaseous product of incomplete combustion displaces the oxygen molecules carried by hemoglobin throughout the body, thereby starving tissues of oxygen and causing death. Now, Azarov et al. have reengineered neuroglobin, a hemoglobin-like protein from the brain, so that it binds carbon monoxide more quickly and tightly than does hemoglobin. When CO-poisoned mice are infused with the artificial neuroglobin, it scavenges the CO, freeing hemoglobin to perform its oxygen delivery duty. The engineered neuroglobin ensures the survival of CO-poisoned mice. The half-life of CO in human red blood cells treated with neuroglobin is only 25 s, compared with a published half-life of 20 min with hyberbaric oxygen, the best treatment currently available. Engineered globins show encouraging promise as antidotes for this lethal gas. Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P50 (partial pressure of O2 at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ≥200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.

Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Background Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI. Methods A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status. Results In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04). Conclusions A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

Bosentan for Sarcoidosis-associated Pulmonary Hypertension, Age-adjusted D-Dimer Levels in Pulmonary Embolism, and Mean Arterial Blood Pressure Targets in Septic Shock

Pulmonary hypertension (PH) is present in a significant number of patients with advanced sarcoidosis, and is associated with increased mortality. Baughman and colleagues (1) performed a double-blind, randomized, placebo-controlled trial to determine whether bosentan is effective in treating sarcoidosis-associated PH. A total of 39 patients with sarcoidosis and pulmonary artery (PA) hypertension were randomized to receive either bosentan or placebo in a 2:1 ratio. Patients were excluded if they had severe exercise limitation (New York Heart Association class IV), severe airway obstruction, or significant heart failure. Right heart catheterization was performed before and after 16 weeks of therapy. Outcomes included the changes in mean PA pressure, 6-minute walk distance (6MWD), dyspnea, and quality of life as assessed by validated questionnaires. In the 30 patients with serial hemodynamic data, mean PA pressure decreased by 4 (66.6) mm Hg in the bosentan group (P , 0.02), and increased by 1 (63.7) mm Hg (P . 0.05) in the placebo group. There was no significant change in 6MWD, dyspnea, or quality of life scores in either group. Themajor limitation of this study is its emphasis on PA pressure. Changes in PA pressure correlate poorly with clinical outcomes. Contemporary studies of PH therapy generally emphasize functional outcomes, such as 6MWD (2). In this study, 6MWD decreased in the bosentan group (223 6 69.5 m; P . 0.05), whereas it increased in the placebo group (176 44.1; P. 0.05). Although not statistically significant, this difference, together with more frequent desaturation in the bosentan group, suggests that bosentan worsened gas exchange in some patients (3). In this study, 18 of 35 patients had fibrosis on chest radiograph, a forced vital capacity of less than 60%, or both. However, even a subgroup analysis of patients with forced vital capacity greater than 50% failed to demonstrate an increased 6MWD. Given the modest PH in this study (mean PA pressure, z35 mm Hg; mean right atrial pressure, 5 mm Hg), it is possible that patients with more severe PH (i.e., out of proportion to their fibrosis) would have experienced an increase in their exercise capacity. Until additional studies are performed, however, patients with sarcoidosis-associated PH should be referred to centers with expertise in PH and monitored closely for response to vasodilator therapy, if it is initiated (3). n

Left Bundle Branch Block in Non-ST Segment Elevation Acute Coronary Syndromes: Incidence, Angiographic Characteristics and Clinical Outcomes

To the Editor: Acute coronary syndrome (ACS) patients presenting with left bundle branch block (LBBB) have higher mortality rates and worse overall outcomes than patients without LBBB ([1,2][1]). We compared clinical characteristics of 29,176 patients with and without LBBB enrolled in non–ST-

A 53-Year-Old Woman with Severe Carbon Monoxide Poisoning

A 60-year-old woman with amedical history of depression, anxiety, and prior suicide attempts presented after being found unconscious in an enclosed garage with the car engine running. Carbon monoxide (CO) levels in the garage were in the range of 120 ppm at the time of her discovery, and the duration of her exposure was unknown. She required intubation in the field for airway protection. On arrival in the emergency room, her heart rate was 120–130 beats per minute and her blood pressure was 78/57 mm Hg. Her initial arterial blood gas analysis was notable for a pH of 7.32, PCO2 of 33 mm Hg, PO2 of 380 mm Hg, bicarbonate of 16 mEq/L, and a carboxyhemoglobin level of 24.0%, which decreased to 1.3% after 5 hours of 100% oxygen administration. Due to her initial clinical instability, including her ongoing need for mechanical ventilation, hyperbaric oxygen therapy was not initiated. Labs were notable for lactate 4.5 mmol/L, anion gap of 16, and toxicology screen negative for volatile alcohols, ethanol, acetaminophen, or salicylate. Complete blood count was within normal limits, and urine drug screen was only positive for benzodiazepines. Her initial troponin level was 0.98 ng/ml (normal ,0.012 ng/ml), and her ECG was notable only for sinus tachycardia.