The effects of methylene blue on hemodynamic parameters and cytokine levels in refractory septic shock

Byung-Kyu Park, Tae-Sun Shim, Chae-Man Lim, Sang-Do Lee, Woo-Sung Kim, Dong-Soon Kim, Won-Dong Kim, Younsuck Koh, Byung-Kyu Park, Tae-Sun Shim, Chae-Man Lim, Sang-Do Lee, Woo-Sung Kim, Dong-Soon Kim, Won-Dong Kim, Younsuck Koh

Abstract

Background: Endogenous nitric oxide (NO) induces the peripheral vasodilation via the activation of guanylate cyclase in patients with septic shock. The purpose of this study was to assess the acute effects of methylene blue (MB), which is an inhibitor of guanylate cyclase, on the hemodynamics and on the production of pro-inflammatory cytokines and nitric oxide (NO) in patients with refractory septic shock.

Methods: Twenty consecutive patients with refractory septic shock, which was defined as shock refractory to a dopamine infusion of more than 20 microg/kg/min with the appropriate use of antibiotics and adequate volume replacement, received MB infusion of 1 mg/kg intravenously. The hemodynamic and respiratory variables were measured at baseline, 30, 60 and 120 min after an infusion of MB (1 mg/kg). The blood levels of NO, IL-1, IL-10 and TNF-alpha were measured at baseline, 30 and 120 min after MB infusion.

Results: The administration of MB induced an increase in the systemic vascular resistance (SVR) that resulted in an increase of the mean arterial pressure (MAP) in patients with refractory septic shock, and this was without a decrease in cardiac output. The administered MB induced an increase in pulmonary vascular resistance (PVR) that resulted in an increase of pulmonary arterial pressure (PAP), without any deterioration of gas exchange. However, the increases in SVR and PVR were not associated with the alteration of endogenous production of NO, IL-1, IL-10 and TNF- alpha.

Conclusion: MB transiently elevated the MAP by increasing the SVR without altering the endogenous productions of NO, IL-1, IL-10 and TNF- alpha during the study period in patients with refractory septic shock.

Figures

Figure 1
Figure 1
Changes in mean arterial pressure (MAP) after the infusion of MB (mean±SEM, n=20 in each group) in refractory septic shock patients. MAP significantly increased from baseline at 30, 60 and 120 minutes. *p<0.01 vs. baseline **p<0.05 vs. baseline
Figure 2
Figure 2
Changes in mean pulmonary arterial pressure (MPAP) after the infusion of MB (mean ±SEM, n=20 in each group) in refractory septic shock patients. MPAP significantly increased from baseline at 30, 60 and 120 minutes. *p<0.01 vs. baseline **p<0.05 vs. baseline

References

    1. Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991;115:457–469.
    1. Daemen-Gubbels CR, Groeneveld PH, Groeneveld AB, van Kamp GJ, Bronsveld W, Thijs LG. Methylene blue increases myocardial function in septic shock. Crit Care Med. 1995;23:1363–1370.
    1. Fink MP, Payen D. The role of nitric oxide in sepsis and ARDS: synopsis of a roundtable conference held in Brussels on 18-20 March 1995. Intensive Care Med. 1996;22:158–165.
    1. Symeonides S, Balk RA. Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin North Am. 1999;13:449–463.
    1. Lorente JA, Landin L, Renes E, de Pablo R, Jorge P, Rodena E, Liste D. Role of nitric oxide in the hemodynamic changes of sepsis. Crit Care Med. 1993;21:759–767.
    1. Cobb JP, Danner RL. Nitric oxide and septic shock. JAMA. 1996;275:1192–1196.
    1. Furchgott RF. The discovery of endotheilium-derived relaxing factor and its importance in the definition of nitric oxide. JAMA. 1996;276:1186–1188.
    1. Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med. 1994;120:771–783.
    1. Murad F. Signal transduction using nitric oxide and cyclic guanosine monophosphate. JAMA. 1996;276:1189–1192.
    1. Preiser JC, Lejeune P, Roman A, Carlier E, de Backer D, Leeman M, Kahn RJ, Vincent JL. Methylene blue administration in septic shock: a clinical trial. Crit Care Med. 1995;23:259–264.
    1. Driscoll W, Thurin S, Carrion V, Steinhorn RH, Morin FC., 3rd Effect of methylene blue on refractory neonatal hypotension. J Pediatr. 1996;129:904–908.
    1. Gachot B, Bedos JP, Veber B, Wolff M, Regnier B. Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Med. 1995;21:1027–1031.
    1. Andresen M, Dougnac A, Diaz O, Hernandez G, Castillo L, Bugedo G, Alvarez M, Dagnino J. Use of methylne blue in patients with refractory septic shock: impact on hemodynamics and gas exchange. J Crit Care. 1998;13:164–168.
    1. Schneider F, Lutun P, Hasselmann M, Stoclet JC, Tempe JD. Methylene blue increases systemic vascular resistance in human septic shock. Intensive Care Med. 1992;18:309–311.
    1. Zhang H, Rogiers P, Preiser JC, Spapen H, Manikis P, Metz G, Vincent JL. Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock. Crit Care Med. 1995;23:1711–1721.
    1. Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertnaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001;29:1860–1867.
    1. Brown G, Frankl D, Phang T. Continuous infusion of methylene blue for septic shock. Postgrad Med J. 1996;72:612–614.
    1. Keaney JF, Jr, Puyana JC, Francis S, Loscalzo JF, Stamler JS, Loscalzo J. Methylene blue reverses endotoxin-induced hypotension. Circ Res. 1994;74:1121–1125.
    1. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochem Pharmacol. 1993;45:367–374.
    1. Raychaudhuri B, Dweik R, Connors MJ, Buhrow L, Malur A, Drazba J, Arrolign AC, Erzurum SC, Kavuru MS, Thomaassen MJ. Nitric oxide blocks nuclear factor -κB activation in alveolar macrophages. Am J Respir Cell Mol Biol. 1999;21:311–316.
    1. van Dervort AL, Yan L, Madara PJ, Cobb JP, Wesley RA, Corrieau CC, Tropea MM, Danner RL. Nitric oxide regulates endotoxin-induced TNF-α production by human neutrophils. J Immunol. 1994;152:4102–4109.
    1. Eigler A, Sinha B, Endres S. Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells. Biochem Biophys Res Commun. 1993;196:494–501.
    1. Paya D, Gray GA, Stoclet JC. Effects of methylene blue on blood pressure and reactivity to norepinephrine in endotoxemic rats. J Cardiovasc Pharmacol. 1993;21:926–930.
    1. Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth. 1996;77:110–117.
    1. Harbrecht BG, Wang SC, Simmons RL, Billiar TR. Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-α sysnthesis. J Leukoc Biol. 1995;57:297–302.
    1. Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care. 2002;30:755–762.
    1. Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, Wolff SM, Wilmore DW. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988;318:1481–1486.
    1. Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, van der Meer JW, Endres S, Lonnemann G, Corsetti J, Chetnow B. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis. 1990;161:79–84.
    1. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovasc JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989;321:280–287.
    1. Evgenov OV, Sager G, Bjertnaes LJ. Methylene reduces lung fluid filtration during the early phase of endotoxemia in awake sheep. Crit Care Med. 2001;29:374–379.
    1. Martin W, Orazan KM, Newby CA. Methylene blue but not changes in cyclic GMP inhibits resting and bradykinin-stimulated production of prostacyclin by pig aortic endothelial cells. Br J Pharmacol. 1989;97:51–56.
    1. Wolin MS, Cherry P, Rodenburg JM, Messina EJ, Kaley G. Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the generation of superoxide anion. J Pharmacol Exp Ther. 1990;254:872–876.
    1. Marczin N, Ryan US, Catravas JD. Methylene blue inhibits nitrovasodilator-and endotheilium-derived relaxing factor-induced cyclic GMP accumulation in cultured pulmonary arterial smooth muscle cells via generation of superoxide anion. J Pharmacol Exp Ther. 1992;263:170–179.
    1. Galili Y, Kluger Y, Mianski Z, Iaina A, Wollman Y, Marmur S, Soffer D, Chernikovsky T, Klausner JP, Rabau MY. Methylene blue: a promising treatment modality in sepsis induced by bowel perforation. Eur Surg Res. 1997;29:390–395.
    1. Martin W, Villani GM, Jothianandan D, Furchgott RF. Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther. 1985;232:708–716.
    1. Beasley D. Interleukin-1 and endotoxin activate soluble guanylate cyclase in vascular smooth muscle. Am J Physiol. 1990;259:R38–R44.
    1. Schneider F. Methylene blue infusion in septic shock. Crit Care Med. 1995;23:1935–1936.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi