Midazolam Efficacy Against Acute Hydrogen Sulfide-Induced Mortality and Neurotoxicity

Abstract

Hydrogen sulfide (H2S) is a colorless, highly neurotoxic gas. It is not only an occupational and environmental hazard but also of concern to the Department of Homeland Security for potential nefarious use. Acute high-dose H2S exposure causes death, while survivors may develop neurological sequelae. Currently, there is no suitable antidote for treatment of acute H2S-induced neurotoxicity. Midazolam (MDZ), an anti-convulsant drug recommended for treatment of nerve agent intoxications, could also be of value in treating acute H2S intoxication. In this study, we tested the hypothesis that MDZ is effective in preventing/treating acute H2S-induced neurotoxicity. This proof-of-concept study had two objectives: to determine whether MDZ prevents/reduces H2S-induced mortality and to test whether MDZ prevents H2S-induced neurological sequelae. MDZ (4 mg/kg) was administered IM in mice, 5 min pre-exposure to a high concentration of H2S at 1000 ppm or 12 min post-exposure to 1000 ppm H2S followed by 30 min of continuous exposure. A separate experiment tested whether MDZ pre-treatment prevented neurological sequelae. Endpoints monitored included assessment of clinical signs, mortality, behavioral changes, and brain histopathological changes. MDZ significantly reduced H2S-induced lethality, seizures, knockdown, and behavioral deficits (p < 0.01). MDZ also significantly prevented H2S-induced neurological sequelae, including weight loss, behavior deficits, neuroinflammation, and histopathologic lesions (p < 0.01). Overall, our findings show that MDZ is a promising drug for reducing H2S-induced acute mortality, neurotoxicity, and neurological sequelae.

Intramuscular aminotetrazole cobinamide as a treatment for inhaled hydrogen sulfide poisoning in a large swine model

“…11 doi: 10.1111/nyas.14339 Long-term neurologic sequelae can occur and the adverse neurological effects of H 2 S toxicity can persist after the initial exposure. 12,13 The specific mechanism of neurotoxicity remains poorly understood. 12 H 2 S is a mitochondrial poison that interrupts the mitochondrial electron transport chain by inhibiting cytochrome c oxidase, causing hyperlactatemia and metabolic acidosis.…”

“…[14][15][16] Additionally, inhibition of L-type calcium channels in the heart can cause pulseless electrical activity. [13][14][15][16][17] Although H 2 S has a potent "rotten egg" odor, olfactory fatigue occurs quickly, resulting in people being unaware they are being exposed to the gas. 18 H 2 S is easily made by combining readily available chemicals that contain an acid (i.e., disinfectants) with those that contain sulfur (i.e., pesticides), and is used frequently as a suicidal agent.…”

“…Several other countermeasures against H 2 S are also currently under investigation, including methylene blue, methemoglobin inducers, anticonvulsive medications, epinephrine, oxygen, and cobalamin derivatives. [13][14][15][16] Several of these agents were studied in animal models using intraperitoneal or intravenous injection of a solution of sodium hydrogen sulfide (NaHS) to induce sulfide toxicity. 15,22,23,26 Since most human sulfide exposures are from inhalation of H 2 S gas, the development of an inhalational model of sulfide poisoning would be beneficial in the study of countermeasure development.…”

JMT’s Research Concepts Section: a 5-Year Evaluation

“…The Journal of Medical Toxicology launched the Research Concepts section in 2010 to allow investigators to advance their research more quickly [1]. The goals of this section are threefold: (1) to provide a forum for rapid publication of peerreviewed research; (2) to obtain high-level critical reviews from established funded investigators; and (3) to support future grant applications for extramural funding. To meet these goals, this section was open to pilot data as well as novel study concepts to give investigators an opportunity to reach a larger audience with high-risk ideas that had the potential for high impact if carried through to the next step.…”

“…From 2014 through 2018, the JMT Research Concepts section published eight articles: each was reviewed by a minimum of two previously funded peer reviewers. Time from submission to first decision averaged 14.1 days; 6 manuscripts required one revision and 2 required multiple revisions before publication [2][3][4][5][6][7][8][9]. Institutional affiliation for the first author included 5 manuscripts for the University of Massachusetts, 2 manuscripts for the University of Pennsylvania, and one manuscript for Iowa State University.…”