Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock

Glenn Hernández, Pablo Tapia, Leyla Alegría, Dagoberto Soto, Cecilia Luengo, Jussara Gomez, Nicolas Jarufe, Pablo Achurra, Rolando Rebolledo, Alejandro Bruhn, Ricardo Castro, Eduardo Kattan, Gustavo Ospina-Tascón, Jan Bakker, Glenn Hernández, Pablo Tapia, Leyla Alegría, Dagoberto Soto, Cecilia Luengo, Jussara Gomez, Nicolas Jarufe, Pablo Achurra, Rolando Rebolledo, Alejandro Bruhn, Ricardo Castro, Eduardo Kattan, Gustavo Ospina-Tascón, Jan Bakker

Abstract

Background: Persistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock.

Methods: Eighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 μg/k/h) or endotoxin-esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments.

Results: Dexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups.

Conclusions: Dexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics.

Keywords: Dexmedetomidine; Esmolol; Lactate; Lactate clearance; Septic shock.

Figures

Fig. 1
Fig. 1
General scheme of the protocol. Complete hemodynamic, respiratory, and systemic and regional perfusion measurements were performed at points A, B, C, and D, except for lactate clearance that was performed at point D. LPS lipopolysaccharide, DEX dexmedetomidine, ESM esmolol, HR heart rate
Fig. 2
Fig. 2
Comparison of dexmedetomidine, esmolol and controls in exogenous lactate clearance (A), cardiac output (B), and total hepatic blood flow (C) at the end of experiments. Both DEX and ESM were associated with less impairment in lactate clearance when compared to controls despite comparable systemic and regional hemodynamics. DEX dexmedetomidine, ESM esmolol

References

    1. Hernandez G, Bruhn A, Castro R, Regueira T. The holistic view on perfusion monitoring in septic shock. Curr Opin Crit Care. 2012;18:280–6. doi: 10.1097/MCC.0b013e3283532c08.
    1. Hernandez G, Castro R, Romero C, de la Hoz C, Angulo D, Aranguiz I, et al. Persistent sepsis-induced hypotension without hyperlactatemia: is it really septic shock? J Crit Care. 2011;435:e9–14.
    1. Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40:1795–815. doi: 10.1007/s00134-014-3525-z.
    1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. doi: 10.1007/s00134-012-2769-8.
    1. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18:503. doi: 10.1186/s13054-014-0503-3.
    1. Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, et al. When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care. 2014;4:30. doi: 10.1186/s13613-014-0030-z.
    1. Ospina-Tascón GA, Umaña M, Bermúdez W, Bautista-Rincón DF, Hernandez G, Bruhn A, et al. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med. 2015;41:796–805. doi: 10.1007/s00134-015-3720-6.
    1. Jansen TC, Van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, Van der Klooster JM, Lima AP, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752–61. doi: 10.1164/rccm.200912-1918OC.
    1. Hernandez G, Bruhn A, Luengo C, Regueira T, Kattan E, Fuentealba A, et al. Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive Care Med. 2013;39:1435–43. doi: 10.1007/s00134-013-2982-0.
    1. Levy B, Perez P, Gibot S, Gerard A. Increased muscle-to-serum lactate gradient predicts progression towards septic shock in septic patients. Intensive Care Med. 2010;36:1703–9. doi: 10.1007/s00134-010-1938-x.
    1. Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock. 2008;30:417–21. doi: 10.1097/SHK.0b013e318167378f.
    1. Levraut J, Ciebiera JP, Chave S, Rabary O, Jambou P, Carles M, et al. Mild hyperlactatemia in stable septic patients is due to impaired lactate clearance rather than overproduction. Am J Respir Crit Care Med. 1998;157:1021–6. doi: 10.1164/ajrccm.157.4.9705037.
    1. Tapia P, Soto D, Bruhn A, Alegría L, Jarufe N, Luengo C, et al. Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion. Crit Care. 2015;19:188. doi: 10.1186/s13054-015-0928-3.
    1. Vincent JL. Serial blood lactate levels reflect both lactate production and clearance. Crit Care Med. 2015;43:e209. doi: 10.1097/CCM.0000000000000906.
    1. Spink WW, Reddin J, Zak SJ, Peterson M, Starzecki B, Seljeskog E. Correlation of plasma catecholamine levels with hemodynamic changes in canine endotoxin shock. J Clin Invest. 1966;45:78–85. doi: 10.1172/JCI105325.
    1. Moran JL, O’Fathartaigh MS, Peisach AR, Chapman MJ, Leppard P. Epinephrine as an inotropic agent in septic shock: a dose-profile analysis. Crit Care Med. 1993;21:70–7. doi: 10.1097/00003246-199301000-00015.
    1. Minneci PC, Dens KJ, Banks SM, Costello R, Csako G, Eichacker PQ, et al. Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model of septic shock. Am J Physiol Heart Circ Physiol. 2004;287:H2545–54. doi: 10.1152/ajpheart.00450.2004.
    1. Levy B, Bollaert PE, Charpentier C, Nace L, Audibert G, Bauer P, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997;23:282–7. doi: 10.1007/s001340050329.
    1. De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med. 2003;31:1659–67. doi: 10.1097/01.CCM.0000063045.77339.B6.
    1. Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, Spies CD, Hannemann L. Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med. 1997;25:399–404. doi: 10.1097/00003246-199703000-00005.
    1. Di Giantomasso D, Bellomo R, May CN. The haemodynamic and metabolic effects of epinephrine in experimental hyperdynamic septic shock. Intensive Care Med. 2005;31:454–62. doi: 10.1007/s00134-005-2580-x.
    1. Irving MH. Sympatho-adrenal hyperactivity--the key to irreversible shock? Postgrad Med J. 1969;45:523–9. doi: 10.1136/pgmj.45.526.523.
    1. Dunser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med. 2009;24:293–316. doi: 10.1177/0885066609340519.
    1. Hofer S, Steppan J, Wagner T, Funke B, Lichtenstern C, Martin E, et al. Central sympatholytics prolong survival in experimental sepsis. Crit Care. 2009;13:R11. doi: 10.1186/cc7709.
    1. Rudiger A. Beta-block the septic heart. Crit Care Med. 2010;38:S608–12. doi: 10.1097/CCM.0b013e3181f204ca.
    1. Andreis DT, Singer M. Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum. Intensive Care Med. 2016. [Epub ahead of print].
    1. Geloen A, Chapelier K, Cividjian A, Dantony E, Rabilloud M, May CN, et al. Clonidine and dexmedetomidine increase the pressor response to norepinephrine in experimental sepsis: a pilot study. Crit Care Med. 2013;41:e431–8. doi: 10.1097/CCM.0b013e3182986248.
    1. Venn RM, Bryant A, Hall GM, Grounds RM. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. Br J Anaesth. 2001;86:650–6. doi: 10.1093/bja/86.5.650.
    1. Memiş D, Hekimoğlu S, Vatan I, Yandim T, Yüksel M, Süt N. Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients. Br J Anaesth. 2007;98:550–2. doi: 10.1093/bja/aem017.
    1. Memiş D, Kargi M, Sut N. Effects of propofol and dexmedetomidine on indocyanine green elimination assessed with LIMON to patients with early septic shock: a pilot study. J Crit Care. 2009;24:603–8. doi: 10.1016/j.jcrc.2008.10.005.
    1. Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38. doi: 10.1186/cc8916.
    1. Taniguchi T, Kurita A, Kobayashi K, Yamamoto K, Inaba H. Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats. J Anesth. 2008;22:221–8. doi: 10.1007/s00540-008-0611-9.
    1. Yeh YC, Sun WZ, Ko WJ, Chan WS, Fan SZ, Tsai JC, et al. Dexmedetomidine prevents alterations of intestinal microcirculation that are induced by surgical stress and pain in a novel rat model. Anesth Analg. 2012;115:46–53. doi: 10.1213/ANE.0b013e318253631c.
    1. Miranda ML, Balarini MM, Bouskela E. Dexmedetomidine attenuates the microcirculatory derangements evoked by experimental sepsis. Anesthesiology. 2015;122:619–30. doi: 10.1097/ALN.0000000000000491.
    1. Hamzaoui O, Teboul JL. The role of beta-blockers in septic patients. Minerva Anestesiol. 2015;81:312–9.
    1. Jacquet-Lagrèze M, Allaouchiche B, Restagno D, Paquet C, Ayoub JY, Etienne J, et al. Gut and sublingual microvascular effect of esmolol during septic shock in a porcine model. Crit Care. 2015;19:241. doi: 10.1186/s13054-015-0960-3.
    1. Kimmoun A, Louis H, Al Kattani N, Delemazure J, Dessales N, Wei C, et al. β1-adrenergic inhibition improves cardiac and vascular function in experimental septic shock. Crit Care Med. 2015;43:e332–40. doi: 10.1097/CCM.0000000000001078.
    1. Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study. Crit Care Med. 2013;41:2162–8. doi: 10.1097/CCM.0b013e31828a678d.
    1. Aboab J, Sebille V, Jourdain M, Mangalaboyi J, Gharbi M, Mansart A, et al. Effects of esmolol on systemic and pulmonary hemodynamics and on oxygenation in pigs with hypodynamic endotoxin shock. Intensive Care Med. 2011;37:1344–51. doi: 10.1007/s00134-011-2236-y.
    1. Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310:1683–91. doi: 10.1001/jama.2013.278477.
    1. Dubin A, Edul VS, Pozo MO, Murias G, Canullán CM, Martins EF, et al. Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia. Crit Care Med. 2008;36:535–42. doi: 10.1097/01.CCM.0000300083.74726.43.
    1. Hagiwara S, Iwasaka H, Maeda H, Noguchi T. Landiolol, an ultrashort-acting beta1-adrenoceptor antagonist, has protective effects in an LPS-induced systemic inflammation model. Shock. 2009;31:515–20. doi: 10.1097/SHK.0b013e3181863689.
    1. Dünser MW, Gradwohl-Matis I. α(2)-agonists to restore adrenergic vasoconstrictor responsiveness in septic shock: thinking outside of the box or fishing in the wrong pond? Crit Care Med. 2013;41:2838–40. doi: 10.1097/CCM.0b013e31829caf7a.
    1. Lankadeva YR, Booth LC, Kosaka J, Evans RG, Quintin L, Bellomo R, et al. Clonidine restores pressor responsiveness to phenylephrine and angiotensin II in ovine sepsis. Crit Care Med. 2015;43:e221–9. doi: 10.1097/CCM.0000000000000963.
    1. Mizock BA. The hepatosplanchnic area and hyperlactatemia: a tale of two lactates. Crit Care Med. 2001;29:447–9. doi: 10.1097/00003246-200102000-00047.
    1. Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, et al. Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care. 2012;2:44. doi: 10.1186/2110-5820-2-44.
    1. Bellomo R, Kellum JA, Pinsky MR. Transvisceral lactate fluxes during early endotoxemia. Chest. 1996;110:198–204. doi: 10.1378/chest.110.1.198.
    1. Michaeli B, Martinez A, Revelly JP, Cayeux MC, Chioléro RL, Tappy L, et al. Effects of endotoxin on lactate metabolism in humans. Crit Care. 2012;16:R139. doi: 10.1186/cc11444.
    1. Severin PN, Uhing MR, Beno DW, Kimura RE. Endotoxin-induced hyperlacta- temia results from decreased lactate clearance in hemodynamically stable rats. Crit Care Med. 2002;30:2509–14. doi: 10.1097/00003246-200211000-00017.
    1. Santak B, Radermacher P, Adler J, Iber T, Rieger KM, Wachter U, et al. Effect of increased cardiac output on liver blood flow, oxygen exchange and metabolic rate during long-term endotoxin-induced shock in pigs. Br J Pharmacol. 1998;124:1689–97. doi: 10.1038/sj.bjp.0701998.
    1. Samsel RW, Cherqui D, Pietrabissa A, Sanders WM, Roncella M, Emond JC, et al. Hepatic oxygen and lactate extraction during stagnant hypoxia. J Appl Physiol. 1991;70:186–93.
    1. Tashkin DP, Goldstein PJ, Simmons DH. Hepatic lactate uptake during decreased liver perfusion and hyposemia. Am J Physiol. 1972;223:968–74.
    1. Naylor JM, Kronfeld DS, Freeman DE, Richardson D. Hepatic and extrahepatic lactate metabolism in sheep: effects of lactate loading and pH. Am J Physiol. 1984;247:E747–55.
    1. Creteur J, De Backer D, Sun Q, Vincent JL. The hepatosplanchnic contribution to hyperlactatemia in endotoxic shock: effects of tissue ischemia. Shock. 2004;21:438–43. doi: 10.1097/00024382-200405000-00007.
    1. Edul VS, Ince C, Navarro N, Previgliano L, Risso-Vazquez A, Rubatto PN, et al. Dissociation between sublingual and gut microcirculation in the response to a fluid challenge in postoperative patients with abdominal sepsis. Ann Intensive Care. 2014;4:39. doi: 10.1186/s13613-014-0039-3.
    1. Brienza N, Ayuse T, Revelly JP, O’Donnell CP, Robotham JL. Effects of endotoxin on isolated porcine liver: pressure-flow analysis. J Appl Physiol (1985) 1995;78:784–92.

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