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Explorations of the therapeutic potential of influencing metabolism during critical
illness
Aslami, H.
Publication date
2013
Link to publication
Citation for published version (APA):
Aslami, H. (2013). Explorations of the therapeutic potential of influencing metabolism during
critical illness.
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Summary and discussion
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Summary and discussion
Systemic inflammatory response syndrome (SIRS) and sepsis are characterized by a hyper– metabolic response. Traditional treatment consists of trying to keep up with high energy demands by maintaining adequate cardiac output and oxygenation. In this thesis, instead of increasing oxygen delivery, we reasoned to reduce energy demands. We hypothesized that inducing a hypo–metabolic state may limit organ injury, thereby restoring the dysbalance between oxygen delivery and consumption, providing a novel therapeutic approach towards critically ill patients (chapter 2–4).
We found that in pneumosepsis, enhanced inflammation was associated with mitochondrial dysfunction and ensuing bio–energetic failure, as reflected by low ATP levels, as well as with low respiration (chapter 6 and 10). Hypothermia or H2S reduced lung injury, shown by a decrease in pulmonary protein loss together with a decrease in pulmonary levels of pro–inflammatory mediators and a reduction in the sequestration of activated immune cells at the site of injury (chapter 9–11). Also kidney injury was reduced, reflected by a decrease in kidney protein loss and decrease in plasma creatinin levels. Protection against organ damage was associated with restored bio–energetic failure. Also, mitochondrial biogenesis was increased, i.e. the regenerative capacity of mitochondria (chapter 10). As noted, multiple organ failure has been hypothesized to be an adaptive response which might improve survival by preservation of vital mitochondria, which may repopulate organs when the inflammatory insult has abated (1). Our experiments suggest however that reduced mitochondrial capacity and low bio–energetic failure are due to damage inflicted by excessive inflammation (chapter 10).
Hypothermia and H2S reduced metabolism, reflected by a reduction in heart rate, body temperature and exhaled carbon dioxide (chapter 6 and 10). Both strategies may have exerted a protective effect on mitochondria by reducing inflammation and oxidative damage. H2S may have also improved mitochondrial integrity as free mitochondrial (mt) DNA levels tended to be reduced (chapter 10). Similarly, hypothermia reduced circulating mtDNA levels in patients with out of hospital cardiac arrest (chapter 8). These results may point towards mitochondria as fundamental players in the course of organ failure and that strategies to preserve or maintain its function may improve organ function in the critically ill.
H2S acts as a anti–inflammatory agent, but is also a toxic compound (chapter 4). We show that prolonged H2S infusion does not enhance protection compared to a short course of infusion in a model of endotoxemia with organ injury (chapter 11). Although we were not able to measure H2S concentrations in the tissues, H2S accumulation may have clouded the protective effects in the prolonged H2S infusion group. The question is whether lower doses of H2S (which do not induce a hibernation–like state) may suffice for an anti–inflammatory effect, as shown before (2;3). Slow releasing H2S molecules may have less detrimental effects
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as compared to the compound used in the various experiments described here (4). Slow H2S release may not accumulate in the organs. It remains questionable whether slow releasing H2S molecules reduces metabolism.
We showed that the protective effect of H2S are to some extend irrespective of the reduction in body temperature. Thereby, we believe that H2S and hypothermia exert differential effects. However, hypothermia is a clinically relevant intervention, whereas the toxic nature of H2S limits its clinical applicability. We found that induced hypothermia improved ventilation in mechanically ventilated cardiac arrest patients who do not have lung injury (chapter 7). Similar findings were found in patients with sepsis induced ARDS (5). We also found that hypothermia reduces inflammation inflicted by mechanical ventilation (chapter 5).
There is caution as to whether reducing metabolism may impair host defense and thereby increase the risk of infection or aggravate ongoing infection. However, in a pneumosepsis model, hypothermia protected against dissemination of bacteria to distant organs (chapter 10). Also, suspended animation–like state did not result in increased bacterial loads (chapter 6). Although it is not known whether bacterial replication increases again after cessation of hypothermia in this short model, this finding suggest that a short period of inducing hypo– metabolism does not enhance bacterial infection. These results may open the door to trials investigating the effect of hypothermia on organ injury and mortality in ARDS patients. Surprisingly, pharmacological induction of hypo–metabolism by 3–iodothyronamine (T1am) did not reduce lung inflammation in a mouse model of LPS induced lung injury (chapter 12). T1am reduces metabolism dose dependently by effects opposite of those of T3. T1am reduced infarct size with approximately 40% in a rat stroke model, an effect which required hypothermia (6). In our experiments, we did not measure body temperature in the animals, however CO2 and O2 consumption where both significantly reduced in the animals. Further exploring the effects of T1am on thyroid metabolism revealed that T3 concentrations were 4–10 times higher than normal in the T1am groups, which may have been caused by trace amounts of T3 in the T1am compound itself. Therefore we cannot accept or reject our hypothesis that T1am reduces metabolism and thereby inflammation. Induction of hypo– metabolism with pure T1am and boosting up metabolism with T3 would be an interesting experiment to further unravel the common pathways between metabolism on one side and inflammation on the other.
In conclusion, our experiments suggests that reducing inflammation might be a promising therapeutic strategy to reduce organ damage in the critically ill patient. Hypothermia seems to be the perfect strategy as shown in our experiments. As hypo–metabolism and hypothermia are linked, we cannot conclude that reducing metabolism per se is associated with organ protection. Although induction of a suspended animation–like state with H2S seems futuristic, the anti–inflammatory effect of the compound is interesting and promising. Future research direction should focus on slow releasing H2S molecules and on discontinuous H2S injection to reduce accumulation and toxicity in organs.
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References
(1) Singer M, De S, V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine–mediated, metabolic response to overwhelming systemic inflammation. Lancet 2004 August 7;364(9433):545– 8.
(2) Francis RC, Vaporidi K, Bloch KD, Ichinose F, Zapol WM. Protective and Detrimental Effects of Sodium Sulfide and Hydrogen Sulfide in Murine Ventilator–induced Lung Injury. Anesthesiology 2011 November;115(5):1012–21.
(3) Esechie A, Kiss L, Olah G, Horvath EM, Hawkins H, Szabo C, Traber DL. Protective effect of hydrogen sulfide in a murine model of acute lung injury induced by combined burn and smoke inhalation. Clin Sci (Lond) 2008 August;115(3):91–7.
(4) Li L, Salto–Tellez M, Tan CH, Whiteman M, Moore PK. GYY4137, a novel hydrogen sulfide–releasing molecule, protects against endotoxic shock in the rat. Free Radic Biol Med 2009 July 1;47(1):103–13. (5) Villar J, Slutsky AS. Effects of induced hypothermia in patients with septic adult respiratory distress
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(6) Doyle KP, Suchland KL, Ciesielski TM, Lessov NS, Grandy DK, Scanlan TS, Stenzel–Poore MP. Novel thyroxine derivatives, thyronamine and 3–iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury. Stroke 2007 September;38(9):2569–76.
