Impaired Microcirculatory Blood Flow Research Articles

Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis.

Sepsis is a persistent systemic inflammatory condition involving multiple organ failures resulting from a dysregulated immune response to infection, and one of the hallmarks of sepsis is endothelial dysfunction. During its progression, neutrophils are the first line of innate immune defence against infection. Aside from traditional mechanisms, such as phagocytosis or the release of inflammatory cytokines, reactive oxygen species and other antibacterial substances, activated neutrophils also release web-like structures composed of tangled decondensed DNA, histone, myeloperoxidase and other granules called neutrophil extracellular traps (NETs), which can efficiently ensnare bacteria in the circulation. In contrast, excessive neutrophil activation and NET release may induce endothelial cells to shift toward a pro-inflammatory and pro-coagulant phenotype. Furthermore, neutrophils and NETs can degrade glycocalyx on the endothelial cell surface and increase endothelium permeability. Consequently, the endothelial barrier collapses, contributing to impaired microcirculatory blood flow, tissue hypoperfusion and life-threatening organ failure in the late phase of sepsis.

Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats.

To study the effect of electroacupuncture (EA) on oxaliplatin-induced peripheral neuropathy (OIPN) in rats. Male Sprague-Dawley rats were equally divided into 3 groups using a random number table: the control group, the OIPN group, and the EA (OIPN + EA) group, with 10 rats in each. The time courses of mechanical, cold sensitivity, and microcirculation blood flow intensity were determined. The morphology of the dorsal root ganglion (DRG) was observed by electron microscopic examination. The protein levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the transient receptor potential (TRP) protein family in DRGs were assayed by Western blot. EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats (P<0.01). Notably, oxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs (P<0.01). EA treatment increased the microcirculation blood flow and attenuated the pathological changes induced by oxaliplatin (P<0.01). In addition, the expression levels of Nrf2 and HO-1 were down-regulated, and the TRP protein family was over-expressed in the DRGs of OIPN rats (P<0.01). EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG (P<0.05 or P<0.01). EA may be a potential alternative therapy for OIPN, and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

Mucosal and cutaneous capnometry for the assessment of tissue hypoperfusion.

In critically ill patients, tissue hypoperfusion is an important cause leading to multi-organ dysfunction and death, and it cannot always be detected by measuring standard global hemodynamic and oxygen-derived parameters. Gastric intramucosal partial pressure of carbon dioxide (PCO2) as measured by gastric tonometry has been recognized to be of clinical value as a prognostic factor, in assessing the effects of particular therapeutic interventions, and as an end-point of resuscitation. However, this technique has several limitations that have hampered its implementation in clinical practice. The sublingual tissue bed has been shown to be damaged in models of shock, and microcirculatory changes in this area may indicate imminent changes in other important organs. The measurement of sublingual mucosal PCO2 (PslCO2) by sublingual capnography is technically simple, noninvasive and gives near instantaneous results. Clinical studies have established that high PslCO2 values and, more especially, high PslCO2 gap (PslCO2 - arterial PCO2) values are correlated with impaired microcirculatory blood flow and a poor outcome in critically ill patients. Sublingual capnography seems to be the ideal noninvasive monitoring tool to evaluate the severity of shock states and the adequacy of tissue perfusion. However, clinical studies are needed to determine the clinical utility of PslCO2 gap monitoring as end-point target to guide resuscitation in critically ill patients.

Epinephrine for Cardiac Arrest

Epinephrine for Cardiac Arrest: Are We Doing More Harm Than Good? Vijay Krishnamoorthy;Monica Vavilala;Michael Fettiplace;Guy Weinberg; Anesthesiology

Sublingual and muscular microcirculatory alterations after cardiac arrest: A pilot study

Aims of the study Post-cardiac arrest resuscitated patients often develop a “sepsis-like” syndrome, which may be associated with organ dysfunction. Impaired microcirculatory blood flow is thought to play a key role in sepsis-induced organ failure; however, few data are available on the microcirculation after cardiac arrest. We investigated microvascular density and reactivity in the early phase following cardiac arrest. Methods We prospectively evaluated the sublingual microcirculation in 10 patients admitted to the intensive care unit (ICU) after cardiac arrest using a Sidestream Dark Field device. Thenar oxygen saturation (StO 2) was also measured using a tissue spectrometer and a vaso-occlusive test was performed by rapid inflation of a pneumatic cuff around the arm to evaluate the StO 2 reperfusion rate, reflecting microvascular reactivity. In all patients, measurements were performed within the first 12 h after admission (T1) and 24–48 h thereafter (T2). Results There was a significant increase in functional capillary density (FCD, 7.2 ± 1.9–10.0 ± 1.4 N/mm, p = 0.001), in the proportion of small perfused vessels (PSPV, 76 ± 13–92 ± 3%, p = 0.004) and in the mean microvascular flow index (MFI, 2.1 ± 0.5–2.8 ± 0.2, p = 0.003) at T2 compared to T1. FCD and PSPV were significantly correlated to body temperature, but not to cardiac output or mean arterial pressure. The StO 2 reperfusion rate did not change over the study period and showed considerable inter-individual variability. Conclusions The early post-resuscitation phase is characterised by significant abnormalities in microvascular density and flow, which return to normal within 48 h after cardiac arrest. These changes may be influenced by body temperature. Microvascular reactivity is impaired after cardiac arrest.

Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: A double-blind randomized placebo controlled trial

Microcirculatory alterations have been associated with morbidity and mortality in human sepsis. Such alterations occur despite pressure-guided resuscitation. Earlier data suggested that impaired microcirculatory blood flow could be corrected with intravenous nitroglycerin in these patients. We tested this concept after fulfillment of preset systemic hemodynamic resuscitation end points in the early phase of sepsis. Prospective, single center, randomized, placebo-controlled, double-blind clinical trial. Closed-format 22-bed mixed intensive care unit in a tertiary teaching hospital. Patients > or =18 yrs with sepsis, according to international criteria, and at least one early sign of organ dysfunction, as the principal reason for intensive care unit admission, were eligible for enrollment. Patients were randomly assigned to receive nitroglycerin (n = 35) or placebo (n = 35) after fulfillment of protocol-driven resuscitation end points. This trial is registered with ClinicalTrials.gov as NCT00493415. Primary outcome was sublingual microcirculatory blood flow of small vessels, as assessed by side-stream dark field imaging. After protocolized resuscitation, we observed recruitment of sublingual microcirculation in both groups, as indicated by a significant improvement in the microcirculatory flow index after 24 hrs, in comparison to baseline. However, no difference in the sublingual microvascular flow index was observed between groups. The median microvascular flow index in sublingual small-sized vessels was 2.71 (1.85-3) in the nitroglycerin group and 2.71 (1.27-3), p = .80, in the placebo group. In medium-sized vessels, the respective values were 3 (2.75-3) vs. 2.86 (2.19-3), p = .21, and in large-sized vessels, 3 (3-3) vs. 3 (2.89-3), p = .06. In-hospital mortality, as a secondary outcome, was 34.3% in the nitroglycerin group and 14.2% in the placebo group, p = .09. In the context of a strict resuscitation protocol, based upon fulfillment of systemic hemodynamic end points in patients with early-phase severe sepsis or septic shock, we conclude that intravenous nitroglycerin does not promote sublingual microcirculatory blood flow.

Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis

Sepsis mortality is closely linked to multi-organ failure, and impaired microcirculatory blood flow is thought to be pivotal in the pathogenesis of sepsis-induced organ failure. We hypothesized that changes in microcirculatory flow during resuscitation are associated with changes in organ failure over the first 24 h of sepsis therapy. Prospective observational study. Emergency Department and Intensive Care Unit. Septic patients with systolic blood pressure <90 mmHg despite intravenous fluids or lactate >or=4.0 mM/L treated with early goal-directed therapy (EGDT). We performed Sidestream Dark Field (SDF) videomicroscopy of the sublingual microcirculation <3 h from EGDT initiation and again within a 3-6 h time window after initial. We imaged five sites and determined the mean microcirculatory flow index (MFI) (0 no flow to 3 normal) blinded to all clinical data. We calculated the Sequential Organ Failure Assessment (SOFA) score at 0 and 24 h, and defined improved SOFA a priori as a decrease >or=2 points. Of 33 subjects; 48% improved SOFA over 0-24 h. Age, APACHE II, and global hemodynamics did not differ significantly between organ failure groups. Among SOFA improvers, 88% increased MFI during EGDT, compared to 47% for non-improvers (P = 0.03). Median change in MFI was 0.23 for SOFA improvers versus -0.05 for non-improvers (P = 0.04). Increased microcirculatory flow during resuscitation was associated with reduced organ failure at 24 h without substantial differences in global hemodynamics. These data support the hypothesis that targeting the microcirculation distinct from the macrocirculation could potentially improve organ failure in sepsis.

Gastrointestinal Perfusion in Septic Shock

Septic shock is characterised by vasodilation, myocardial depression and impaired microcirculatory blood flow, resulting in redistribution of regional blood flow. Animal and human studies have shown that gastrointestinal mucosal blood flow is impaired in septic shock. This is consistent with abnormalities found in many other microcirculatory vascular beds. Gastrointestinal mucosal microcirculatory perfusion deficits have been associated with gut injury and a decrease in gut barrier function, possibly causing augmentation of systemic inflammation and distant organ dysfunction. A range of techniques have been developed and used to quantify these gastrointestinal perfusion abnormalities. The following techniques have been used to study gastrointestinal perfusion in humans: tonometry, laser Doppler flowmetry, reflectance spectrophotometry, near-infrared spectroscopy, orthogonal polarisation spectral imaging, indocyanine green clearance, hepatic vein catheterisation and measurements of plasma D-lactate. Although these methods share the ability to predict outcome in septic shock patients, it is important to emphasise that the measurement results are not interchangeable. Different techniques measure different elements of gastrointestinal perfusion. Gastric tonometry is currently the most widely used technique because of its non-invasiveness and ease of use. Despite all the recent advances, the usefulness of gastrointestinal perfusion parameters in clinical decision-making is still limited. Treatment strategies specifically aimed at improving gastrointestinal perfuision have failed to actually correct mucosal perfusion abnormalities and hence not shown to improve important clinical endpoints. Current and future treatment strategies for septic shock should be tested for their effects on gastrointestinal perfusion; to further clarify its exact role in patient management, and to prevent therapies detrimental to gastrointestinal perfusion being implemented.

The influence of local and systemic preconditioning on oxygenation, metabolism and survival in critically ischaemic skin flaps in pigs

Stress proteins represent a group of highly conserved intracellular proteins that provide adaptation against cellular stress. The present study aims to elucidate the stress protein-mediated effects of local hyperthermia and systemic administration of monophosphoryl lipid A (MPL) on oxygenation, metabolism and survival in bilateral porcine random pattern buttock flaps. Preconditioning was achieved 24h prior to surgery by applying a heating blanket on the operative site (n = 5), by intravenous administration of MPL at a dosage of 35 microg/kg body weight (n = 5) or by combining the two (n = 5). The flaps were monitored with laser Doppler flowmetry, polarographic microprobes and microdialysis until 5h postoperatively. Semiquantitative immunohistochemistry was performed for heat shock protein 70 (HSP70), heat shock protein 32 (also termed haem oxygenase-1, HO-1), and inducible nitrc oxide synthase (iNOS). The administration of MPL increased the impaired microcirculatory blood flow in the proximal part of the flap and partial oxygen tension in the the distal part by approximately 100% each (both P<0.05), whereas both variables remained virtually unaffected by local heat preconditioning. Lactate/pyruvate (L/P) ratio and glycerol concentration (representing cell membrane disintegration) in the distal part of the flap gradually increased to values of approximately 500 mmol/l and approximately 350 micromol/l, respectively (both P<0.01), which was substantially attenuated by heat application (P<0.01 for L/P ratio and P<0.05 for glycerol) and combined preconditioning (P<0.01 for both variables), whereas the effect of MPL was less marked (not significant). Flap survival was increased from 56% (untreated animals) to 65% after MPL (not significant), 71% after heat application (P<0.05) and 78% after both methods of preconditioning (P<0.01). iNOS and HO-1 were upregulated after each method of preconditioning (P<0.05), whereas augmented HSP70 staining was only observed after heat application (P<0.05). We conclude that local hyperthermia is more effective in preventing flap necrosis than systemic MPL administration because of enhancing the cellular tolerance to hypoxic stress, which is possibly mediated by HSP70, whereas some benefit may be obtained with MPL due to iNOS and HO-1-mediated improvement in tissue oxygenation.

Blood Cell Deformation in Neonates Who Have Sepsis

After completing this article, readers should be able to: 1. Describe alterations of red blood cells due to bacterial toxins. 2. Describe physical alterations of neutrophils during activation. 3. Delineate the role of red and white blood cells in the impairment of microcirculation and organ damage in sepsis. 4. List drugs that may inhibit neutrophil activation and improve their deformability and their actions. Sepsis remains a major cause of morbidity and mortality in neonates, particularly among preterm infants. (1) Impaired microcirculatory blood flow plays a pivotal role in the development of clinical manifestations and organ dysfunctions in severe sepsis and septic shock. (2)(3)(4) If not corrected, microcirculatory dysfunction can progress to organ dysfunction and subsequently to organ failure and death. Restoration of microcirculatory dysfunction is, therefore, an important step in preventing long-term sequelae (including brain damage) and death of the patient. Both red and white blood cells must deform to pass through narrow channels whose diameters are less than those of the cells. (5) Impaired deformability of red and white blood cells may contribute to impaired microcirculatory blood flow in septicemia. The membranes of neonatal red blood cells (RBCs) deform more in response to a given force than adult cells and are, therefore, more flexible. (6)(7) On the other hand, neonatal RBCs are larger and require higher pressures to enter filter pores and micropipettes that have diameters below the resting cellular diameters. (8)(9) The larger volume and increased deformability of neonatal RBCs are responsible for another favorable property, the increased Fahraeus and Fahraeus-Lindqvist effect (ie, hematocrit and viscosity reduction when going from 500- to 50-mcm tubes). (10) These favorable flow properties of neonatal RBCs suggest that their increased cellular deformability is a prerequisite for adequate flow in arterioles and capillaries. We have shown that loss of …

Gastric and sublingual capnometry

Tissue hypoperfusion is a common pathophysiologic process leading to multiple organ dysfunction and death. Increases in tissue PCO2 can reflect an abnormal oxygen supply to the cells, so that monitoring tissue PCO2 by the use of gastric or sublingual capnometry may help identify circulatory abnormalities and guide their correction. This review provides an update on these technologies. Gastric tonometry aims at monitoring PCO2 in the stomach, an organ that becomes ischemic quite early when the circulatory status is jeopardized. Despite substantial initial enthusiasm, this technique has never been widely implemented due to methodological problems. The measurement of sublingual mucosal PCO2 (PslCO2) by sublingual capnometry is technically simple and noninvasive. Experimental studies have suggested that PslCO2 is a reliable marker of tissue perfusion. Clinical studies have demonstrated that high PslCO2 values are associated with impaired microcirculatory blood flow and a worse prognosis in critically ill patients. Gastric tonometry was proposed for regional PCO2 monitoring, but it is prone to a number of technical limitations. Sublingual capnometry could offer a valuable alternative for tissue PCO2 monitoring in clinical practice, representing a simple, noninvasive method to monitor tissue perfusion and titrate therapeutic interventions in critically ill patients.

Tissue capnometry: does the answer lie under the tongue?

Increases in tissue partial pressure of carbon dioxide (PCO(2)) can reflect an abnormal oxygen supply to the cells, so that monitoring tissue PCO(2) may help identify circulatory abnormalities and guide their correction. Gastric tonometry aims at monitoring regional PCO(2) in the stomach, an easily accessible organ that becomes ischemic quite early when the circulatory status is jeopardized. Despite substantial initial enthusiasm, this technique has never been widely implemented due to various technical problems and artifacts during measurement. Experimental studies have suggested that sublingual PCO(2 )(P(sl)CO(2)) is a reliable marker of tissue perfusion. Clinical studies have demonstrated that high P(sl)CO(2) values and, especially, high gradients between P(sl)CO(2) and arterial PCO(2) (DeltaP(sl-a)CO(2)) are associated with impaired microcirculatory blood flow and a worse prognosis in critically ill patients. Although some questions remain to be answered about sublingual capnometry and its utility, this technique could offer new hope for tissue PCO(2) monitoring in clinical practice.

Ischemia/reperfusion injury in rat mesenteric venules: Red blood cell velocity and leukocyte rolling

The authors determined the effects of 15 (n = 9) and 30 (n = 12) minutes of warm ischemia on the rat mesentery and compared the results with those of a sham-operated group (n = 10). Red blood cell velocity and number of rolling leukocytes were assessed before ischemia as well as 10, 20, 30, 60, 90, and 120 minutes after the start of reperfusion. Leukocyte rolling is considered to be an early step of the inflammatory process. Leukocytes roll along the vessel wall at a velocity that is clearly lower than that of the other blood cells. The preischemic values of red blood cell velocity and number of rolling leukocytes in the 15- and 30-minute ischemia groups did not differ from those of the sham group. In the sham group, no significant changes in red blood cell velocity and number of rolling leukocytes were observed over time. Compared with the sham group, the red blood cell velocity of the 15-minute ischemia group was significantly lower at 30, 60, 90, and 120 minutes after the start of reperfusion the number of rolling leukocytes did not differ significantly. For the 30-minute ischemia group, red blood cell velocity also was significantly lower at 20, 30, 60, 90, and 120 minutes after the start of reperfusion, and the number of rolling leukocytes was higher at 10, 20, and 30 minutes after the start of reperfusion. The results of this study indicate that short periods of total warm ischemia of the rat small bowel and subsequent reperfusion result in a significantly impaired microcirculatory blood flow in the mesentery. However, a prolonged period of ischemia is required to increase leukocyte-vessel wall interactions. In the future, this model will enable us to study the effect of pharmacological interventions during an early stage of the inflammatory response to ischemia/reperfusion in the gut.