Cardiogenic shock induced reduction in cellular O₂ delivery as a hallmark of acute H₂S intoxication

To the Editor:

One of the main mechanisms of hydrogen sulfide toxicity is thought to relate to the ability of H₂S/HS⁻ to block the activity of the mitochondrial electron transport chain, preventing the creation of a proton gradient across the mitochondrial membrane, and in turn impeding ATP regeneration in all cells.^1,2 The corollary of the impediment in ATP production is a reduction in cellular O₂ utilization, leading to a reduction in peripheral O₂ extraction and thus an increase in venous and tissular O₂ content (and partial pressure), akin to the well-documented rise in venous PO2 (and paradoxical reddish color of tissues) during cyanide poisoning-induced cellular “anoxia”.³

Fernandes et al.⁴ have recently argued that this mechanism is difficult to reconcile with the data published by Brenner et al.⁵ depicting a drop, instead of an increase, in “tissular” oxyhemoglobin during sulfide intoxication, that is, in the setting of an inhibition of oxidative phosphorylation. However, we have found that H₂S intoxication dramatically decreases cardiac contractility and cardiac output, ⁶ as soon as the concentration of free H₂S/HS⁻ reaches levels of about 3 microM, before major signs of toxicity can be observed,^6–8 leading to fatal pulseless electrical activity within minutes.⁹ No significant peripheral vasodilation was observed during sulfide-induced circulatory failure.⁶ This striking and very rapid depression in cardiac contractility has been previously suggested to result from the blockade of L-type Ca channels in cardiomyocytes.^10,11 The “poisoning” of the cardiomyocytes appears very early,⁶ possibly through non-ATP-related mechanisms¹⁰ at a time when the cytochrome C oxidase activity is not yet, or not dramatically, impeded in most tissues. As a consequence, a decrease in venous/peripheral O₂ saturation/content is not unexpected. To clarify this matter, we have recomputed (Fig. 1), from data previously obtained in 7 sedated rats,⁶ the relationship between cardiac output (determined from aortic or pulmonary blood flow), V.O₂ (determined by pulmonary gas exchange), the change in O₂ extraction (computed as V.O₂/cardiac output ratio), during the first minutes of H₂S/HS⁻ infusion at a rate, which is fatal within 5–6 min (2 mg/kg/min).⁶ Such a H₂S infusion produced a rapid decrease in cardiac output/O₂ delivery, which was proportionally much more severe and rapid than the reduction in O₂ consumption. As a result, O₂ extraction rises (Fig. 1), reflecting a larger fall in the rate of O₂ delivery than in the rate of cellular O₂ utilization. Incidentally, a similar reduction in tissular/venous O₂ saturation has also been documented during cyanide poisoning, wherein acute cardiac failure occurs.¹²

Fig. 1. Panel A. Original recording of the changes in arterial blood pressure, cardiac output, and left ventricular pressure, during H₂S infusion in a 500-g rat receiving a solution of sulfide made from NaHS (1 mg/min). There was a rapid decrease in cardiac output, arterial pressure, and left ventricular pressure, which led to asystole, within 5 min. The horizontal bracket shows the period at which of cardiac output was determined for the computations shown in B. Panel B. V.O₂ (left panel) and the change in O₂ extraction as % from baseline (Right panel) as a function of cardiac output. Ten-second-averaged data obtained from 7 rats during the first minutes of an infusion of H2S at toxic levels (2 mg/min) are shown. Cardiac output dropped dramatically, while oxygen extraction increases reflecting a proportionally higher fall in O₂ delivery than in O₂ utilization. Note that PaO₂, and thus the arterial O₂ content, was prevented to decrease by mechanical ventilation throughout the period of infusion.

These data support the view that a rapid cardiogenic shock leading to a profound reduction in O₂ delivery to peripheral tissues is a one of the dreadful and early effects of H₂S intoxication. The proper identification of this cardiogenic shock, in a clinical setting of patients exposed to mitochondrial “poisons” presenting with circulatory failure and tissue hypoxia, has crucial therapeutic implications.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant Number: 1R21NS080788-02 and 1R21NS090017-01