Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats

doi:10.5847/wjem.j.1920-8642.2018.01.009

Abstract

Abstract:

BACKGROUND: Dexmedetomidine has already been used in septic patients as a new sedative agent, few studies have examined its effects on immunomodulation. Therefore, the authors have designed a controlled experimental study to characterize the immunomodulation effects of dexmedetomidine in the cecal ligation and puncture (CLP) model in rats.
METHODS: After CLP, 48 Wistar rats were randomly allocated into four groups: (1) CLP group; (2) small-dose treatment group (2.5 μg·kg ^-1·h^-1); (3) medium-dose treatment group (5.0 μg·kg ^-1· h^-1); and (4) large-dose treatment group (10.0 μg·kg ^-1·h^-1). HLA-DR and plasma cytokine (IL-4, IL-6, IL-10 and TNF-α) levels were measured, and the mean arterial blood pressure (MAP), heart rate (HR), arterial blood gases, lactate concentrations and mortality were also documented.
RESULTS: The HLA-DR level, inflammatory mediator levels, MAP and HR had no obvious changes among Dexmedetomidine treatment groups (DEX groups). Compared with the CLP group, the DEX groups exhibited decreased HLA-DR levels (P_group=0.0202) and increased IL-6 production, which was increased at 3 h (P= 0.0113) and was then attenuated at 5 h; additionally, the DEX groups exhibited decreased HR (P<0.001) while maintaining MAP (P_group=0.1238), and remarkably improving lactate (P<0.0001). All of these factors led to a significant decrease in the mortality, with observed rates of 91.7%, 66.7%, 25% and 18% for the CLP, DEX2.5, DEX5.0, DEX10.0 groups, respectively.
CONCLUSION: Dexmedetomidine treatment in the setting of a CLP sepsis rat model has partially induced immunomodulation that was initiated within 5 h, causing a decreased HR while maintaining MAP, remarkably improving metabolic acidosis and improving mortality dose-dependently.

Key words: Dexmedetomidine, Immunomodulation, Septic shock

Yan Ma, Xiang-you Yu, Yi Wang. Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats[J]. World Journal of Emergency Medicine, 2018, 9(1): 56-63.

Figures/Tables 5

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References 16

1	Ma Y, Yu XY. Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats. Chin J Emerg Med. 2016;25(9):1149-50.
2	Ma Y, Yu XY. Wang Y. Dose-related effects of dexmedetomidine on hemodynamics and mortality in sepsis shock: experiment with rats. Chin J Emerg Resusc Disaster Med. 2017;12(9):838-41.
3	Kawasaki T, Kawasaki C, Ueki M, Hamada K, Habe K, Sata T. Dexmedetomidine suppresses proinflammatory mediator production in human whole blood in vitro. J Trauma Acute Care Surg. 2013;74(5):1370-5. doi: 10.1097/TA.0b013e31828db978 pmid: 23609293
4	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(3):221-8. doi: 10.1007/s00540-008-0611-9
5	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(4):550-2. doi: 10.1093/bja/aem017 pmid: 17363413
6	Taniguchi T, Kidani Y, Kanakura H, Takemoto Y, Yamamoto K. Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med. 2004;32(6):1322-6. doi: 10.1097/01.ccm.0000128579.84228.2a pmid: 15187514
7	Ge Y, Huang M, Ma YF. The effects of microRNA-34a regulating Notch-1/NF-κB signaling pathway on lipopolysaccharide-induced human umbilical vein endothelial cells. World J Emerg Med. 2017;8(4):292-6. doi: 10.5847/wjem.j.1920-8642.2017.04.008 pmid: 29123608
8	Qiao H, Sanders RD, Ma D, Wu X, Maze M. Sedation improves early outcome in severely septic Sprague Dawley rats. Crit Care. 2009;13(4):R136. doi: 10.1186/cc8012 pmid: 19691839
9	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(1):R11. doi: 10.1186/cc7709 pmid: 19196475
10	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(2):R38. doi: 10.1186/cc8916 pmid: 20233428
11	Venn M, Newman J, Grounds M. A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med. 2003;29(2):201-7. Epub 2002 Nov 22. doi: 10.1007/s00134-020-06308-8 pmid: 33161451
12	Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009;301(5):489-99. doi: 10.1001/jama.2009.56 pmid: 19188334
13	Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA. 2007;298(22):2644-53. doi: 10.1001/jama.298.22.2644 pmid: 18073360
14	Tan JA, Ho KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: A meta-analysis. Intensive Care Med. 2010 ;36(6):926-39. doi: 10.1007/s00134-010-1877-6 pmid: 20376429
15	Marik PE, Baram M. Noninvasive hemodynamic monitoring in the intensive care unit. Crit Care Clin. 2007;23(3):383-400. doi: 10.1016/j.ccc.2007.05.002
16	Miranda ML, Balarini MM, Bouskela E. Dexmedetomidine attenuates the microcirculatory derangements evoked by experimental sepsis. Anesthesiology. 2015;122(3):619-30. doi: 10.1097/ALN.0000000000000491 pmid: 25313879

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