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Of mice and men (and sheep, swine etc.): The intriguing hemodynamic and metabolic effects of hydrogen sulfide (H2S)
Critical Carevolume 15, Article number: 146 (2011)
Whether the hydrogen sulfide (H2S)-induced metabolic depression observed in awake rodents exists in larger species is controversial. Therefore, Derwall and colleagues exposed anesthetized and ventilated sheep to incremental H2S concentrations by means of an extracorporeal membrane oxygenator. H2S caused pulmonary vasoconstriction and metabolic acidosis at the highest concentration studied. Oxygen uptake and carbon dioxide production remained in the physiological range. The authors concluded that, beyond the effect of temperature, H2S hardly modifies metabolism at all. Since the highest H2S concentration caused toxic side effects (possibly due to an inhibition of mitochondrial respiration), the therapeutic use of inhaled H2S should be cautioned.
In the previous issue of Critical Care, Derwall and colleagues  reported on the effects of gaseous hydrogen sulfide (H2S) (100 to 300 parts per million) in healthy, anesthetized, and mechanically ventilated sheep. To avoid any airway irritation, the authors used an elegant approach to circumvent inhaling H2S (that is, administration via an extracorporeal, veno-arterial membrane oxygenator). The major findings were that (a) whole body oxygen uptake (VO2), carbon dioxide production (VCO2), and cardiac output remained within the physiological range but that (b) H2S caused pulmonary vasoconstriction, which was (c) associated with a fall in blood pressure and metabolic acidosis at the highest doses administered.
In a landmark paper, Blackstone and colleagues  demonstrated that, in awake, spontaneously breathing mice, inhaling H2S induced a hibernation-like metabolic state characterized by reduced energy expenditure and hypothermia. Subsequently, Volpato and colleagues  reported that this metabolic depression was associated with bradycardia and reduced cardiac output but that blood pressure and stroke volume remained unaffected. Consequently, given the exciting prospect of pharmacologically reducing energy expenditure to protect against ischemia ('suspended animation' ) by application of a gaseous drug, the effects of inhaled H2S were investigated in various models. In fact, inhaled H2S protected rodents against otherwise lethal hypoxia  and hemorrhage  and attenuated murine kidney and lung injury [6–8]. Equivocal data, however, are available from large animals: inhaled H2S failed to show any metabolic effect in sheep or swine [9, 10], and the intravenous H2S donor sodium sulfide (Na2S) was reported either to reduce energy expenditure  or to have no effect at all .
What do we learn from the study by Derwall and colleagues ? The authors confirm previous data in the same species  that even a fivefold-higher concentration of inhaled H2S did not depress energy expenditure. Since the authors maintained the body temperature, they speculate that in larger species H2S can hardly affect metabolism at all beyond the effect of temperature per se (the 'Q10 effect': the fall of VO2 and VCO2 associated with a 10°C decrease), in particular when metabolism is already depressed. In fact, in anesthetized and mechanically ventilated mice subjected to deliberate hypothermia, inhaled H2S had no further metabolic and circulatory effects . Moreover, in larger adult animals, non-shivering thermogenesis is negligible and thus cannot be influenced such as in small animals (for example, mice) with a metabolic rate that is 15- to 20-fold higher than that of humans . Finally, any Na2S-related therapeutic effect in larger animals was independent of body temperature [14–16].
What is the future of H2S in critical care medicine? The vascular effects of H2S are still controversial: Derwall and colleagues  found a dose-dependent pulmonary vasoconstriction, which at first glance agrees with the hypoxia-sensing properties attributed to H2S . However, the mixed venous oxygen partial pressure (PO2) was 50 to 55 mm Hg (that is, clearly above the range that induced hypoxic vasoconstriction of isolated pulmonary arteries of cows ). In addition, the pulmonary vascular ***vasomotor response to H2S in vitro showed marked interspecies differences, so that any effect in the critically ill patient is difficult to anticipate . The systemic vasomotor effect of H2S is equally intriguing: endogenous H2S is a physiological vasodilator and thus assumes major importance in the control of blood pressure . Derwall and colleagues  report that the highest H2S concentration caused marked systemic vasodilation, whereas other authors [11, 16] found that Na2S reduced the noradrenaline doses required to achieve hemodynamic targets during reperfusion after porcine aortic balloon occlusion.
The appropriate H2S dose is also unknown: in the previous large animal studies, a 25-fold range of intravenous Na2S infusion rates was used [11, 12, 14–16], and, as in the present investigation, higher infusion rates over longer periods of time impaired pulmonary gas exchange [11, 12]. The significant metabolic acidosis affiliated with the highest H2S concentration deserves particular attention, but unfortunately the authors did not further elucidate this finding. It is tempting to speculate that inhibition of mitochodondrial respiration with subsequent reduction of aerobic capacity caused this metabolic acidosis: H2S is a well-established inhibitor of the cytochrome C oxidase, and the subtle increase in the respiratory quotient that can be derived from the mean VO2 and VCO2 values before and after exposure to 300 parts per million H2S, respectively, replicates data reported on the effects of H2S inhalation in exercising humans . Finally, as the authors themselves acknowledge, the fate of exogenous H2S remains unclear: they found, in the efferent blood of the extracorporeal membrane lung, sulfide levels that were associated with near-complete inhibition of the respiratory chain in vitro. The arterial blood concentrations, however, were in the same range as measured during Na2S infusion in swine, in which Na2S protected against myocardial  and renal  ischemia/reperfusion injury.
In conclusion, Derwall and colleagues performed an elegant ovine study to test whether a pharmacological (that is, H2S-induced) metabolic depression can be achieved in large animals. While the authors did not find any gross modifications of energy expenditure, they observed several intriguing hemodynamic and acid-base effects, which confirm the complex actions of this 'third gaseous mediator'.
carbon dioxide production
Derwall M, Francis RC, Kida K, Bougaki M, Crimi E, Adrie C, Zapol WM, Ichinose F: Administration of hydrogen sulfide via extracorporeal membrane lung ventilation in sheep with partial cardiopulmonary bypass perfusion: a proof of concept study on metabolic and vasomotor effects. Crit Care 2011, 15: R51. 10.1186/cc10016
Blackstone E, Morrison M, Roth MB: H 2 S induces a suspended animation-like state in mice. Science 2005, 308: 518. 10.1126/science.1108581
Volpato GP, Searles R, Yu B, Scherrer-Crosbie M, Bloch KD, Ichinose F, Zapol WM: Inhaled hydrogen sulfide: a rapidly reversible inhibitor of cardiac and metabolic function in the mouse. Anesthesiology 2008, 108: 659-668. 10.1097/ALN.0b013e318167af0d
Blackstone E, Roth MB: Suspended animation-like state protects mice from lethal hypoxia. Shock 2007, 27: 370-372. 10.1097/SHK.0b013e31802e27a0
Morrison ML, Blackwood JE, Lockett SL, Iwata A, Winn RK, Roth MB: Surviving blood loss using hydrogen sulfide. J Trauma 2008, 65: 163-168. 10.1097/TA.0b013e3181507579
Bos EM, Leuvenink HG, Snijder PM, Kloosterhuis NJ, Hillebrands JL, Leemans JC, Florquin S, van Goor H: Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol 2009, 20: 1901-1905. 10.1681/ASN.2008121269
Faller S, Ryter SW, Choi AM, Loop T, Schmidt R, Hoetzel A: Inhaled hydrogen sulfide protects against ventilator-induced lung injury. Anesthesiology 2010, 113: 104-115. 10.1097/ALN.0b013e3181de7107
Wagner F, Wagner K, Weber S, Stahl B, Knöferl MW, Huber-Lang M, Seitz DH, Asfar P, Calzia E, Senftleben U, Gebhard F, Georgieff M, Radermacher P, Hysa V: Inflammatory effects of hypothermia and inhaled H 2 S during resuscitated, hyperdynamic murine septic shock. Shock 2010, in press.
Haouzi P, Notet V, Chenuel B, Chalon B, Sponne I, Ogier V, Bihain B: H 2 S induced hypometabolism in mice is missing in sedated sheep. Respir Physiol Neurobiol 2008, 160: 109-115. 10.1016/j.resp.2007.09.001
Li J, Zhang G, Cai S, Redington AN: Effect of inhaled hydrogen sulfide on metabolic responses in anesthetized, paralyzed, and mechanically ventilated piglets. Pediatr Crit Care Med 2008, 9: 110-112. 10.1097/01.PCC.0000298639.08519.0C
Simon F, Giudici R, Duy CN, Schelzig H, Oter S, Gröger M, Wachter U, Vogt J, Speit G, Szabó C, Radermacher P, Calzia E: Hemodynamic and metabolic effects of hydrogen sulfide during porcine ischemia/reperfusion injury. 2008, 30: 359-364. 10.1097/SHK.0b013e3181674185
Drabek T, Kochanek PM, Stezoski J, Wu X, Bayir H, Morhard RC, Stezoski SW, Tisherman SA: Intravenous hydrogen sulfide does not induce hypothermia or improve survival from hemorrhagic shock in pigs. Shock 2011, 35: 67-73. 10.1097/SHK.0b013e3181e86f49
Baumgart K, Wagner F, Gröger M, Weber S, Barth E, Vogt JA, Wachter U, Huber-Lang M, Knöferl MW, Albuszies G, Georgieff M, Asfar P, Szabó C, Calzia E, Radermacher P, Simkova V: Cardiac and metabolic effects of hypothermia and inhaled hydrogen sulfide in anesthetized and ventilated mice. Crit Care Med 2010, 38: 588-595. 10.1097/CCM.0b013e3181b9ed2e
Esechie A, Enkhbaatar P, Traber DL, Jonkam C, Lange M, Hamahata A, Djukom C, Whorton EB, Hawkins HK, Traber LD, Szabó C: Beneficial effect of a hydrogen sulphide donor (sodium sulphide) in an ovine model of burnand smoke-induced acute lung injury. Br J Pharmacol 2009, 158: 1442-1453. 10.1111/j.1476-5381.2009.00411.x
Osipov RM, Robich MP, Feng J, Liu Y, Clements RT, Glazer HP, Sodha NR, Szabo C, Bianchi C, Sellke FW: Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion: comparison of different administration regimens and characterization of the cellular mechanisms of protection. J Cardiovasc Pharmacol 2009, 54: 287-297. 10.1097/FJC.0b013e3181b2b72b
Simon F, Scheuerle A, Gröger M, Stahl B, Wachter U, Vogt J, Speit G, Hauser B, Möller P, Calzia E, Szabó C, Schelzig H, Georgieff M, Radermacher P, Wagner F: Effects of intravenous sulfide during porcine aortic occlusion-induced kidney ischemia/reperfusion injury. Shock 2011, 35: 156-163. 10.1097/SHK.0b013e3181f0dc91
Olson KR, Whitfield NL: Hydrogen sulfide and oxygen sensing in the cardiovascular system. Antioxid Redox Signal 2010, 12: 1219-1234. 10.1089/ars.2009.2921
Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R: H 2 S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 2008, 322: 587-590. 10.1126/science.1162667
Bhambhani Y, Burnham R, Snydmiller G, MacLean I: Effects of 10-ppm hydrogen sulfide inhalation in exercising men and women. Cardiovascular, metabolic, and biochemical responses. J Occup Envrion Med 1997, 39: 122-129. 10.1097/00043764-199702000-00009
This commentary was supported by the Deutsche Forschungsgemeinschaft (DFG Ra 396/9-1, Klinische Forschergruppe 200 'Die Entzündungsantwort nach Muskulo-Skeletalem Trauma') and the Bundesministerium der Verteidigung (Forschungsvorhaben M/SABX/8A004).
PR received research grants from Ikaria, Inc. (Seattle, WA, USA), a company involved in the commercial development of hydrogen sulfide. The other authors declare that they have no competing interests.