Microcirculation and Critical Care Medicine
Date Issued
2012
Date
2012
Author(s)
Yeh, Yu-Chang
Abstract
Despite early goal-directed therapy and Surviving Sepsis Campaign have been developed for many years, the mortality of severe sepsis and septic shock is still high. Recent advances in imaging technology have enabled the observation of microcirculation, and several studies have demonstrated that derangements in microvascular flow play a role in sepsis-induced multiple organ dysfunction syndrome and death. The systemic inflammatory response syndrome may cause excess vasodilation and result in hypotension. The endothelial cells may secrete inflammatory adhesion molecules, cytokines, and chemokines, and these may increase microvascular permeability and result in capillary leakage and tissue edema. Moreover, endotoxin may activate the coagulatory function of endothelial cells and inhibit the anti-coagulation activity of endothelial cells and endogenous fibrinolysis, and it may result in microvascular thrombosis. Excess vasodilation, capillary leakage, and microvascular thrombosis can result in microcirculatory dysfunction, and it will lead to tissue hypoperfusion and finally to multiple organ dysfunction syndrome and death. The first aim of this thesis is to investigate the relation between severity of severe sepsis and septic shock and the severity of sublingual microcirculatory dysfunction in critically ill patients using a sidestream dark-field (SDF) video microscope. Furthermore, we also investigated the relation between severity of endotoxemia and the severity of intestinal microcirculatory dysfunction in a rat model. The following two devices were used to investigate the microcirculation in animal research: (1) full-field laser perfusion imager was used to continuously measure the change of microcirculatory blood flow intensity; and (2) SDF video microscope was used to investigate total small-vessel (< 20 μm) density (TSVD), perfused small-vessel density (PSVD), microvascular flow index (MFI), and heterogeneity index (HI). Because the interaction between lipopolysaccharide (LPS, from gram-negative bacteria) and Toll-like receptor 4 (TLR4) induces sepsis and subsequent microcirculatory dysfunction, this thesis hypothesized that antagonizing LPS-related signaling pathway by a TLR4 antagonist, eritoran tetrasodium (E5564), might reduce endotoxemia-related microcirculatory dysfunction. The second aim of this thesis is to investigate whether eritoran can improve intestinal microcirculation using the endotoxemic rat model. Moreover, interaction between inflammation and coagulation system may induce microvascular thrombosis during sepsis, and the third aim of this thesis is to investigate whether enoxaparin can improve intestinal microcirculation using the endotoxemic rat model.
The results of clinical research of sepsis revealed that TSVD, PSVD, and MFI were higher in the 28-day survival group than in the 28-day non-survival group. The results of animal research of endotoxemia revealed that intestinal microcirculatory blood flow intensity were significantly lower in the high dose (15 mg/kg) LPS group than the other groups. Moreover, microcirculatory blood flow intensity, PSVD, MFI, and HI were better in the eritoran treatment group than the LPS group. Eritoran also reduced blood level of tumor necrosis factor α, interleukin-1β, and D-dimer and microthrombosis formation. This thesis also revealed that enoxaparin can restore intestinal microcirculation by reducing microthrombosis formation and maintaining higher PSVD.
Surgical stress and pain may induce excess inflammation and activation of sympathetic nervous system and lead to tissue hypoperfusion. Both hypoperfusion-related anaerobic glycolysis and excess inflammation-related pyruvate overproduction can cause hyperlactemia. Because microcirculatory dysfunction may lead to tissue hypoperfusion and excess inflammation, the fourth aim of this thesis is to compare the perioperative microcirculation between critically ill surgical patients with blood lactate level ≧ 3 mmol/L and those with blood lactate level < 3 mmol/L at 24h after surgery. Because dexmedetomidine can induce sympatholytic vasodilation, inhibit inflammation, and produce hypocoagulation, it has the potential to improve surgical stress and pain-related microcirculatory dysfunction. The fifth aim of this thesis is to establish a rat model and investigate whether dexmedetomidine can improve intestinal microcirculatory dysfunction resulting from surgical stress and pain.
The results of clinical research of critically ill surgical patients revealed that perioperative TSVD and PSVD were lower in patients with blood lactate level ≧ 3 mmol/L than in patients with blood lactate level < 3 mmol/L at 24h after surgery. There were significant correlations between postoperative 1h TSVD and PSVD and postoperative 24h blood lactate level. The results of animal research of surgical stress and pain revealed that the microcirculatory blood flow intensity and PSVD in intestinal mucosa and serosal-muscular layer decreased during surgical stress and pain. Moreover, it also revealed that dexmedetomidine can attenuate tachycardia and hypertension and restore the intestinal microcirculatory blood flow intensity and PSVD.
Microcirculation will play a more important role in the future medicine. More researches are required to investigate how to early diagnose and treat microcirculatory dysfunction in patients, and further to evaluate the clinical benefit of maintain good microcirculation on reducing multiple organ injury. Wish gaining more time to conduct multimodal therapy for the patient can improve survival and quality of life.
Subjects
sepsis
microcirculation
endotoxin
Toll-like receptor 4 antagonist
low molecular weight heparin
surgery
lactate
alpha-2 adrenoceptors agonist
Type
thesis
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