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N-Acetylcysteine's Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements.
Chertoff, J
Journal of intensive care medicine. 2018;(2):87-96
Abstract
OBJECTIVE To review the data surrounding the utility of N-acetylcysteine (NAC) in sepsis and identify areas needed for additional research. DATA SOURCES A review of articles describing the mechanisms of action and clinical use of NAC in sepsis. SUMMARY OF REVIEW Despite many advances in critical care medicine, still as many as 50% of patients with septic shock die. Treatments thus far have focused on resuscitation and restoration of macrocirculatory targets in the early phases of sepsis, with less focus on microcirculatory dysfunction. N-acetylcysteine, due to its anti-inflammatory and antioxidative properties, has been readily investigated in sepsis and has yielded largely incongruous and disappointing results. In addition to its known anti-inflammatory and antioxidative roles, one underappreciated property of NAC is its ability to vasodilate the microcirculation and improve locoregional blood flow. Some investigators have sought to capitalize on this mechanism with promising results, as evidenced by microcirculatory vasodilation, improvements in regional blood flow and oxygen delivery, and reductions in lactic acidosis, organ failure, and mortality. CONCLUSION In addition to its antioxidant and anti-inflammatory properties, N-acetylcysteine possesses vasodilatory properties that could benefit the microcirculation in sepsis. It is imperative that we investigate these properties to uncover NAC's full potential for benefit in sepsis.
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Evaluation of systemic microvascular reactivity in adults with congenital heart disease.
Marino, P, de Oliveira Lopes, G, Pereira Borges, J, Carolina Terra Cola, M, Arkader Kopiler, D, Tibirica, E
Congenital heart disease. 2018;(6):978-987
Abstract
OBJECTIVE Adults with congenital heart disease share some features with those with chronic heart failure. Although microvascular endothelial dysfunction has been described in chronic heart failure, evaluation of the microcirculation in adults with congenital heart disease is lacking. The present study aimed to investigate systemic microvascular reactivity in adults with congenital heart disease. INTERVENTIONS The patients initially underwent cardiopulmonary exercise testing. Then, the cutaneous microvascular reactivity was evaluated in these patients using a laser speckle contrast imaging system coupled with skin iontophoresis of endothelial-dependent (acetylcholine) or -independent (sodium nitroprusside) vasodilators and postocclusive reactive hyperemia (PORH) and compared with healthy controls matched for age and sex. RESULTS Thirty-one patients and 29 healthy controls were evaluated. The basal microvascular flow (P < .0001) and area under the curve in response to acetylcholine (P < .0001) were higher in the patients than in the healthy volunteers. The increase in cutaneous vascular conductance in response to sodium nitroprusside was reduced in the patients compared to the healthy volunteers (P = .0031). No difference in the microvascular response was observed during postocclusive reactive hyperemia. The basal microvascular flow of patients with peak oxygen consumption below 16.0 mL kg-1 min-1 was superior to that of patients with values greater than 16.0 mL kg-1 min-1 (P = .0046). CONCLUSIONS Adults with congenital heart disease present a higher baseline cutaneous microvascular blood flow than healthy controls and do not present systemic microvascular endothelial dysfunction. Nevertheless, endothelium-independent microvascular reactivity is blunted, suggesting an altered vascular smooth muscle response or vascular structural alterations. Finally, patients with a lower functional capacity presented a greater microvascular basal blood flow than subjects with a higher functional capacity.
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Microvascular Vasodilator Plasticity After Acute Exercise.
Robinson, AT, Fancher, IS, Mahmoud, AM, Phillips, SA
Exercise and sport sciences reviews. 2018;(1):48-55
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Abstract
Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced.
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The effects of different remote ischemic conditioning on ischemia-induced failure of microvascular circulation in humans.
Akkoca, M, Usanmaz, SE, Tokgöz, S, Köksoy, C, Demirel-Yilmaz, E
Clinical hemorheology and microcirculation. 2018;(1):83-93
Abstract
BACKGROUND Intermittent ischemia in remote tissues can be applied before ischemic injury, during ischemic injury or at the beginning of reperfusion of an index organ ischemia. The aim of this study was to investigate the effect of Remote Ischemic Conditioning (RIC) of the leg on changes in ischemia-induced the microvascular functions of the arm. MATERIAL AND METHODS Ischemic microvascular injury was induced by arm ischemia (20 min) and reperfusion in healthy, nonsmoker, male volunteers (ischemia group-ISC, n: 9). In another group of volunteers, to investigate the effects of remote organ ischemic conditioning 5 cycles of reperfusion followed by leg ischemia (each lasting 60 seconds) were applied either before (preRIC, n:11), or during (perRIC, n:12) or immediately after (postRIC, n:9) 20 minutes of arm ischemia. The microvascular flow of arm was assessed before and after ischemia using iontophoresis of the endothelium-derived nitric oxide (NO) releaser acetylcholine (ACh) and the endothelium-independent NO donor sodium nitroprusside (SNP). Changes in microvascular blood flow were measured using Laser Doppler imaging. The plasma level of biomarkers related to endothelial function such as nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulphide (H2S) were measured. RESULTS No difference was determined between the groups in terms of age, BMI or blood biochemicals reflecting cardiovascular status. ACh caused a rise in microvascular blood flow in a charge dependent manner. The ACh-induced flow increase was not significantly depressed by ischemia and not affected by any of the types of RIC in the study subjects. The increase in SNP-induced microvascular flow was significantly decreased in the ISC, perRIC and postRIC groups, but not in the preRIC group. Plasma levels of NO, ADMA, TAC and H2S were not changed by ischemia and RIC. CONCLUSION These results suggested that microvascular perfusion of human forearm skin was elevated by either endothelium or drug-derived NO. The effect of ischemia and RIC on NO-induced flow increase was affected differently by different applications in the healthy young individuals. These complicated results are taken into consideration in experimental and therapeutic interventions.
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Looking into the eye of patients with chronic obstructive pulmonary disease: an opportunity for better microvascular profiling of these complex patients.
Vaes, AW, Spruit, MA, Theunis, J, Goswami, N, Vanfleteren, LE, Franssen, FME, Wouters, EFM, De Boever, P
Acta ophthalmologica. 2018;(6):539-549
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Abstract
Chronic obstructive pulmonary disease (COPD) is a complex disease with many patients suffering from cardiovascular comorbidity. However, cardiovascular diseases remain often undiagnosed in COPD. Assessment of the retinal microvasculature can provide value in cardiovascular profiling of these patients. Retinal microvascular assessment carried out via a noninvasive eye exam represents an easy to use tool when examining patients with COPD. The purpose of this review was to provide an overview of studies assessing structural and functional changes in the retinal microvasculature of patients with COPD. Findings demonstrated that structural and functional microvascular changes were more common and severe in COPD patients as compared to non-COPD controls, although few retinal investigations have been performed in patients with COPD. As cardiovascular comorbidities are highly prevalent in COPD, we advocate more research to investigate the value of an eye exam for microvascular phenotyping of COPD patients.
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Attenuated cutaneous microvascular function in healthy young African Americans: Role of intradermal l-arginine supplementation.
Kim, K, Hurr, C, Patik, JC, Matthew Brothers, R
Microvascular research. 2018;:1-6
Abstract
It has been established that endothelial function in conduit vessels is reduced in young African Americans (AA) relative to Caucasian Americans (CA). However, less is known regarding endothelial function in microvasculature of young AA. We hypothesized that microvascular function in response to local heating of skin is attenuated in young AA relative to age-matched CA due largely to the lack of NO bioavailability, which is in turn improved by intradermal l-arginine supplementation and/or inhibition of arginase. Nine AA and nine CA adults participated in this study. Participants were instrumented with four microdialysis membranes in the cutaneous vasculature of one forearm and were randomly assigned to receive 1) lactated Ringer's solution as a control site; 2) 20 mM NG-nitro-l-arginine (l-NAME) to inhibit NO synthase activity; 3) 10 mM l-arginine to local supplement l-arginine; or 4) a combination of 5.0 mM (S)-(2‑boronoethyl)-l-cysteine-HCL (BEC) and 5.0 mM Nω-hydroxy-nor-l-arginine (nor-NOHA) at a rate of 2.0 μl/min to locally inhibit arginase activity. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux divided by mean arterial pressure. All CVC data were presented as a percentage of maximal CVC (%CVCmax) that was determined by maximal cutaneous vasodilation induced by 44 °C heating plus sodium nitroprusside administration. The response during the 42 °C local heating plateau was blunted in the AA at the control site (CA: 84 ± 12 vs. AA: 62 ± 6 vs. %CVCmax; P < 0.001). This response was improved in AA at the l-arginine site (Control: 62 ± 6 vs. l-arginine: 70 ± 18%CVCmax; P < 0.05) but not in the arginase inhibited site (Control: 62 ± 6 vs. Arginase inhibited: 62 ± 13%CVCmax; P = 0.91). In addition, the AA group had an attenuated NO contribution to the plateau phase during 42 °C local heating relative to the CA group (CA: 56 ± 14 vs. AA: 44 ± 6 Δ %CVCmax; P < 0.001). These findings suggest that 1) cutaneous microvascular function in response to local heating is blunted in young AA when compared to age-matched young CA; 2) this attenuated response is partly related to decrease in NO bioavailability in young AA; and 3) a local infusion of l-arginine, but not arginase inhibition, improves cutaneous microvascular responses to local heating in young AA relative to CA.
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Cutaneous reactive hyperaemia is unaltered by dietary nitrate supplementation in healthy humans.
Wong, BJ, Keen, JT, Levitt, EL
Clinical physiology and functional imaging. 2018;(5):772-778
Abstract
The purpose of this study was to determine whether nitrate supplementation augments cutaneous reactive hyperaemia. Seven participants were tested pre- and postnitrate supplementation (25 ml beetroot juice); participants consumed one shot per day for 3 days. Participants were instrumented with two microdialysis fibres: control (Ringer's solution) and NO synthase inhibition (20 mM L-NAME). Skin blood flow was measured via laser-Doppler flowmetry (LDF). A blood pressure cuff was placed on the experimental arm and inflated to 250 mmHg for 5 mins to occlude arterial inflow. The cuff was released, and the resultant reactive hyperaemia was measured. Blood pressure was continuously measured via plethysmography from a finger on the non-experimental arm. Cutaneous vascular conductance was calculated (LDF/MAP) and normalized to maximal vasodilatation (%CVCmax ). Only diastolic blood pressure was reduced following nitrate supplementation (71 ± 2 vs. 66 ± 1 mmHg; P<0·05). There was no effect of nitrate supplementation on peak reactive hyperaemia at control (Pre: 52 ± 3 vs. Post: 57 ± 2%CVCmax ) or L-NAME (Pre: 52 ± 2 vs. Post: 59 ± 4%CVCmax ) sites. There was no effect of nitrate supplementation on total reactive hyperaemia at either control (Pre: 4197 ± 943 vs. Post: 4523 ± 1040%CVCmax * sec) or L-NAME (Pre: 5108 ± 997 vs. Post: 5694 ± 1002%CVCmax * sec) sites. These data suggest cutaneous reactive hyperaemia is unaffected by dietary nitrate supplementation in healthy humans.
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Assessment of flow dynamics in retinal and choroidal microcirculation.
Wei, X, Balne, PK, Meissner, KE, Barathi, VA, Schmetterer, L, Agrawal, R
Survey of ophthalmology. 2018;(5):646-664
Abstract
Alterations in ocular blood flow have been implicated in mechanisms that lead to vision loss in patients with various ocular disorders such as diabetic retinopathy, glaucoma, and age-related macular degeneration. Assessment of retinal and choroidal blood flow is also a window to evaluate systemic diseases that affect microvasculature. Quantification and qualification of the blood flow in the retina and choroid help us understand pathophysiology, stratify disease risk, and monitor disease progression in these disorders. Multiple methods are used by researchers for assessment of blood flow, but a gold standard is lacking. We review commonly used methods, both invasive and noninvasive, for evaluation of blood flow, including intravital microscopy, laser Doppler velocimetry, laser Doppler flowmetry, laser interferometry, confocal scanning laser Doppler flowmetry, laser speckle flowgraphy, Doppler optical coherence tomography, blue-field entoptic simulation, retinal vessel caliber assessment, optical coherence tomography angiography, retinal function imaging, color Doppler imaging, and scanning laser ophthalmoscope angiogram. As technology evolves, better evaluation of blood flow in various ocular and systemic diseases will likely bring new perspectives into clinical practice and translate to better diagnosis and treatment.
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Microvascular Permeability after an Acute and Chronic Salt Load in Healthy Subjects: A Randomized Open-label Crossover Intervention Study.
Rorije, NMG, Olde Engberink, RHG, Chahid, Y, van Vlies, N, van Straalen, JP, van den Born, BH, Verberne, HJ, Vogt, L
Anesthesiology. 2018;(2):352-360
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Abstract
BACKGROUND Sodium-induced microcirculatory changes, endothelial surface layer alterations in particular, may play an important role in sodium-mediated blood pressure elevation. However, effects of acute and chronic sodium loading on the endothelial surface layer and microcirculation in humans have not been established. The objective of this study was to assess sodium-induced changes in blood pressure and body weight as primary outcomes and also in microvascular permeability, sublingual microcirculatory dimensions, and urinary glycosaminoglycan excretion in healthy subjects. METHODS Twelve normotensive males followed both a low-sodium diet (less than 50 mmol/day) and a high-sodium diet (more than 200 mmol/day) for eight days in randomized order, separated by a crossover period. After the low-sodium diet, hypertonic saline (5 mmol sodium/liter body water) was administered intravenously in 30 min. RESULTS Both sodium interventions did not change blood pressure. Body weight increased with 2.5 (95% CI, 1.7 to 3.2) kg (P < 0.001) after dietary sodium loading. Acute intravenous sodium loading resulted in increased transcapillary escape rate of I-labeled albumin (2.7 [0.1 to 5.3] % cpm · g · h; P = 0.04), whereas chronic dietary sodium loading did not affect transcapillary escape rate of I-labeled albumin (-0.03 [-3.3 to 3.2] % cpm · g · h; P = 1.00), despite similar increases of plasma sodium and osmolality. Acute intravenous sodium loading coincided with significantly increased plasma volume, as assessed by the distribution volume of albumin, and significantly decreased urinary excretion of heparan sulfate and chondroitin sulfate. These changes were not observed after dietary sodium loading. CONCLUSIONS Our results suggest that intravenous sodium loading has direct adverse effects on the endothelial surface layer, independent of blood pressure.
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Effects of insulin analogs as an add-on to metformin on cutaneous microcirculation in type 2 diabetic patients.
Fysekidis, M, Cosson, E, Takbou, K, Sutton, A, Charnaux, N, Banu, I, Vicaut, E, Valensi, P
Microvascular research. 2018;:6-14
Abstract
BACKGROUND A single insulin injection was shown to improve microcirculatory blood flow. Our aim was to examine the effects of 4weeks of insulin therapy by three randomly assigned insulin analog regimens (Detemir, Aspart, and their combination) on cutaneous blood flow (CBF) and microcirculatory endothelial function as an add-on to metformin in type 2 diabetic patients poorly controlled on oral antidiabetic treatment. METHODS Fourty-two type 2 diabetic patients with no history of cardiovascular disease in secondary failure to oral antidiabetic agents had CBF measurements before and after acetylcholine (Ach) iontophoretic administration. CBF measurements were performed at fasting and after a standardized breakfast during the post-prandial period. Before randomization (Visit 1, V1) during the tests, participants took only metformin. The same tests were repeated after 4weeks of insulin treatment (Visit 2, V2). RESULTS Thirty-four patients had good quality recordings for both visits. During V1, CBF and CBF response to Ach increased in the post-prandial period. After 4weeks of insulin treatment, metabolic parameters improved. Compared to V1, CBF at fasting did not increase at V2 but there was an improvement in endothelial function at fasting after Ach iontophoresis, without difference across insulin regimens. Oxidative stress markers were not modified, and E-selectin and vascular cell adhesion molecule 1 levels decreased after insulin treatment, without differences between insulin groups. CONCLUSIONS A strategy of improving glycemic control for 4weeks with insulin analogs improves microcirculatory endothelial reactivity and reduces endothelial biomarkers at fasting, whatever the insulin regimen used. Insulin therapy associated to metformin is able to improve fasting microvascular endothelial function even before complete metabolic control.