Response to letter of Abraham et al Ovadia-Blechman, Zehava; Gritzman, Ashley; Shuvi, Maya ...
Clinical biomechanics (Bristol),
11/2018, Letnik:
59
Journal Article
Zusammenfassung Veränderungen in der Mikrozirkulation der Haut sind ein häufig beobachtetes Begleitphänomen vieler Erkrankungen, weit über das Spektrum dermatologischer Krankheiten hinausreichend. ...Nicht alle dieser Veränderungen haben einen Krankheitswert, viele treten temporär auf, ohne schwerwiegende Folgen zu verursachen. Dies trifft für viele inflammatorische Erkrankungen wie die Psoriasis vulgaris oder das atopische Ekzem zu. Daneben gibt es aber auch Erkrankungen, bei denen funktionell und morphologisch erkennbare Mikroangiopathien zu schwerwiegenden Krankheitsfolgen führen. Eine der wichtigsten Erkrankungen in diesem Zusammenhang ist die systemische Sklerose, eine autoimmune Systemerkrankung mit multiplen Organmanifestationen. Hier sind die Untersuchungen der kutanen Mikrozirkulation sowohl in der Erstdiagnose als auch in der Prognose‐ und Verlaufsbeurteilung von weitreichender Bedeutung. Auch bei Erkrankungen der peripheren Hämodynamik wie der peripheren arteriellen Verschlusskrankheit (pAVK) und der chronisch venösen Insuffizienz (CVI) spielt das Verständnis von Mikrozirkulationsstörungen eine wichtige Rolle für die Therapie und die Erfolgskontrolle therapeutischer Interventionen.
OBJECTIVES:Sepsis induces microvascular alterations that may play an important role in the development of organ dysfunction. However, the relationship of these alterations to systemic variables and ...outcome is still not well defined. We investigated which factors may influence microcirculatory alterations in patients with severe sepsis and whether these are independently associated with mortality.
DESIGN:Analysis of prospectively collected data from previously published studies by our group.
SETTING:A 36-bed, medicosurgical university hospital Department of Intensive Care.
PATIENTS:A total of 252 patients with severe sepsis in whom the sublingual microcirculation was visualized using orthogonal polarization spectral or sidestream darkfield imaging techniques.
MEASUREMENTS AND MAIN RESULTS:Microcirculatory measurements were obtained either early, within 24h of the onset of severe sepsis (n = 204), or later, after 48h (n = 48). When multiple measurements were obtained, only the first was considered. Although global hemodynamic variables were relatively preserved (mean arterial pressure 70 65–77 mm Hg, cardiac index 3.3 2.7–4.0 L/min.m, and SvO2 68.3 62.8–74.7%), microvascular variables were markedly altered (proportion of perfused small vessels 65 50–74%, microvascular flow index 2.15 1.80–2.60, and heterogeneity of proportion of perfused small vessels 35 20–50%). Among microcirculatory variables, proportion of perfused small vessels was the strongest predictor of outcome (receiver operating characteristic curve area 0.818 0.766–0.871, p < 0.001). Survival rates decreased markedly with severity of alterations in the proportion of perfused small vessels (70% and 75% in the two upper proportion of perfused small vessel quartiles compared with 3% and 44% in the two lower quartiles, p < 0.0001). Multivariable analysis identified proportion of perfused small vessels and sequential organ failure assessment score as independent predictors of outcome. Microcirculatory alterations were less severe in the later than in the earlier (proportion of perfused small vessels, 74 57–82% vs. 63 48–71%, p = 0.004) phase of sepsis. In multivariable analysis focused on the early period of sepsis, proportion of perfused small vessels and lactate were independent predictors of outcome.
CONCLUSIONS:Microcirculatory alterations are stronger predictors of outcome than global hemodynamic variables.
The endothelial glycocalyx (eGC) covers the luminal surface of the vascular endothelium and plays an important protective role in systemic inflammatory states and particularly in sepsis. Its ...breakdown leads to capillary leak and organ dysfunction. Moreover, sepsis-induced alterations of sublingual microcirculation are associated with a worse clinical outcome. The present study was performed to investigate the associations between eGC dimensions and established parameters of microcirculation dysfunction in sepsis.
This observational, prospective, cross-sectional study included 40 participants, of which 30 critically ill septic patients were recruited from intensive care units of a university hospital and 10 healthy volunteers served as controls. The established microcirculation parameters were obtained sublingually and analyzed according to the current recommendations. In addition, the perfused boundary region (PBR), an inverse parameter of the eGC dimensions, was measured sublingually, using novel data acquisition and analysis software (GlycoCheck™). Moreover, we exposed living endothelial cells to 5% serum from a subgroup of study participants, and the delta eGC breakdown, measured with atomic force microscopy (AFM), was correlated with the paired PBR values.
In septic patients, sublingual microcirculation was impaired, as indicated by a reduced microvascular flow index (MFI) and a reduced proportion of perfused vessels (PPV) compared to those in healthy controls (MFI, 2.93 vs 2.74, p = 0.002; PPV, 98.53 vs 92.58, p = 0.0004). PBR values were significantly higher in septic patients compared to those in healthy controls, indicating damage of the eGC (2.04 vs 2.34, p < 0.0001). The in vitro AFM data correlated exceptionally well with paired PBR values obtained at the bedside (rs = - 0.94, p = 0.02). Both PBR values and microcirculation parameters correlated well with the markers of critical illness. Interestingly, no association was observed between the PBR values and established microcirculation parameters.
Our findings suggest that eGC damage can occur independently of microcirculatory impairment as measured by classical consensus parameters. Further studies in critically ill patients are needed to unravel the relationship of glycocalyx damage and microvascular impairment, as well as their prognostic and therapeutic importance in sepsis.
Retrospectively registered: Clinicaltrials.gov, NCT03960307.
Angiogenesis is an essential part of normal skin healing, re‐establishing blood flow in developing granulation tissue. Non‐healing skin wounds are associated with impaired angiogenesis and although ...the role of re‐establishing macroscopic blood flow to limbs to prevent wound chronicity is well investigated, less is known about vascular alterations at the microcirculatory level. We hypothesised that significant phenotypic changes would be evident in blood vessels surrounding chronic skin wounds. Wound edge tissue, proximal to wound (2 cm from wound edge) and non‐involved skin (>10 cm from wound edge) was harvested under informed consent from 20 patients undergoing elective amputation due to critical limb ischemia. To assess blood vessel structure and viability, tissue was prepared for histological analysis and labelled with antibodies specific for PECAM‐1 (CD31), CD146, endoglin, ALK‐1, ALK‐5, and p16Ink4a as a marker of cellular senescence. Density of microvasculature was significantly increased in wound edge dermis, which was concomitant with increased labelling for endoglin and CD146. The number of CD31 positive vessel density was unchanged in wound edge tissue relative to non‐involved tissue. Co‐labelling of endoglin with the transforming growth factor receptor ALK‐1, and to a lesser extent ALK‐5, demonstrated activation of endothelial cells which correlated with PCNA labelling indicative of proliferation. Analysis of p16Ink4a staining showed a complete lack of immunoreactivity in the vasculature and dermis, although staining was evident in sub‐populations of keratinocytes. We conclude that the endoglin‐ALK‐1‐endothelial proliferation axis is active in the vasculature at the edge of chronic skin wounds and is not associated with p16Ink4a mediated senescence. This information could be further used to guide treatment of chronic skin wounds and optimise debridement protocols.
Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable ...despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2–24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.
Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic ...events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with ‘normal or near normal’ coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.
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