Occlusion Of Microcirculation Research Articles

Neurologic Manifestations of COVID-19 in Children: Emerging Pathophysiologic Insights.

The COVID-19 pandemic has affected mortality and morbidity across all ages, including children. Neurologic manifestations of coronavirus disease 2019, ranging from headaches to cerebrovascular stroke, may involve the CNS or peripheral nervous system. Neurologic involvement is also noted in the multisystem inflammatory syndrome in children, a pediatric condition that occurs weeks after infection with severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19. Knowledge about mechanisms of neurologic disease and immunologic response to severe acute respiratory syndrome coronavirus 2 is scarce but rapidly growing. Here, we concisely review experimental and clinical data relevant to pathophysiologic hypotheses regarding neurologic manifestations of coronavirus disease 2019. We highlight important knowledge gaps in differences between adults and children in their response to coronavirus disease 2019.

An evaluation of dermal microcirculatory occlusion under repeated mechanical loads: Implication of lymphatic impairment in pressure ulcers

Pressure ulcers are caused by prolonged mechanical loads deforming the underlying soft tissues. However, the mechanical loads for microcirculatory occlusion are unknown. The present study was designed to characterize the simultaneous response of microvascular and lymphatic structures under repeated mechanical loading. The effects of two distinct loading/unloading cycles involving (a) incremental pressures 30, 60, and 90mmHg and (b) three repeated cycles of 30mmHg were evaluated on a cohort of able-bodied volunteers. Microvascular response involved the monitoring of transcutaneous gas tensions, while dermal lymphatic activity was estimated from near-infrared imaging. Responses were compared during each load and recovery cycle. Changes in microvascular response were dependent on the load magnitudes, with 30mmHg resulting in a reduction in oxygen tension only, while 90mmHg affected both oxygen and carbon dioxide values in most cases (54%). By contrast, lymphatics revealed near total occlusion at 30mmHg. Although there were intersubject differences, temporal trends consistently revealed partial or full impairment under load, with recovery during off-loading. The pressure required to cause microcirculatory occlusion differed between individuals, with lymphatic impairment occurring at a lower pressure to that of microvascular vessels. This highlights the need for personalized care strategies and regular off-loading of vulnerable tissues.

Extensive Myelonecrosis: A Clinicopathological Study from A Tertiary Care Center

Background: The pathophysiology of bone marrow necrosis (BMN) remains unclear; however, the occlusion of microcirculation, accompanied by hypoxemia, causes damage to the cells and plays an important role in development of BMN. Methods: This is a descriptive study; a retrospective review of all trephine biopsies done over period of 22 months January 2017 to October 2018 in Department of pathology showing BMN were included. Only cases identified which showed extensive myelonecrosis > 20% of the diameter of trephine biopsy specimen was included in the study and BMN had to be diagnosed during life were included. Thirty cases met these criteria over this period. Result: In the study period, BMN was diagnosed in 30 samples among 3000 trephine biopsies showed extensive necrosis accounting for 1.0%. Almost all patients on peripheral blood examination shows anemia (100%), around 50% patients present with pancytopenia, followed by anemia with thrombocytopenia. From bone marrow aspiration and trephine biopsy examination shows 30 cases MN,among them 16 patients were acute leukemia either newly diagnosed or post chemotherapy follow-up cases, 10 out of 12 patients had severe bone pain before intuition of chemotherapy, acute leukemia followed by necrotizing granulomatous inflammation metastatic carcinoma were other causes for MN and one case was sickle cell hemolytic anemia. Conclusion: BMN is associated with many diseases, and yet presents with no clear patho physiology. In addition, clinical and laboratory characteristics are non-specific and, in many cases, symptoms are related to the causal condition that is most commonly a hematological disease.

Blood Congestion Can Be Rescued by Hemodilution in a Random-Pattern Skin Flap.

There is no standard method to ensure survival of random-pattern skin flaps. The authors developed a rat anemia model to observe survival of random-pattern skin flaps after blood transfusion and hemodilution. Anemia was induced by withdrawal of 35 percent blood volume followed by compensation with the same amount of blood (blood transfusion model) or plasma equivalent (normovolemic hemodilution). Control rats were subjected to a sham procedure. Subsequently, a random-pattern skin flap (1.5 × 6 cm) was elevated on the back of each rat. Physiologic assessments of flap vascularity/viability were performed using laser Doppler spectrophotometry before and after flap elevation. The normovolemic hemodilution group showed anemia (hemoglobin, 9.5 ± 0.8 g/dl) but less flow occlusion and greater flap survival (72.8 ± 8.6 percent) compared with control (57.4 ± 9.6 percent; p < 0.01) and blood transfusion (62.1 ± 6.5 percent; p < 0.089) groups. In control and blood transfusion groups but not the normovolemic hemodilution group, blood flow was decreased and relative quantity of hemoglobin was increased toward the flap tip, indicating congestion. In control and blood transfusion groups, blood flow and tissue oxygen saturation dropped after flap elevation, but recovered by day 7; congestion gradually improved by day 7. The authors determined that congestion promoted necrosis and hemodilution reduced microcirculatory occlusion and increased blood flow and oxygenation in skin flaps. It was suggested that perioperative hemodilution is superior to blood transfusion in any flap operations unless there is a critical systemic need for blood transfusion.

Chronic Transfusion Therapy in Sickle Cell Disease - Effect on Macrovascular Function, Microvascular Function, and Tissue Oxygenation Decreases the Potential for Ischemia

BACKGROUND: Sickle cell disease is an inheritable hemoglobinopathy that causes increased red blood cell (RBC) stiffness due to hemoglobin polymerization at low oxygen tension. This leads to microcirculatory occlusion as well as chronic hemolysis and chronic inflammation, resulting in a diffuse vasculopathy of bothmacrovascular and microvascular beds. Chronic transfusion therapy is used for both primary and secondary prevention of ischemic stroke, amacrovascular complication; however, there is limited knowledge of its effect on microvascular function.OBJECTIVE: To determine the effects of chronic transfusion therapy on microvascular function and tissue oxygenation.DESIGN/METHODS: We utilized a forearm, arterial and venous occlusion model, commonly used for flow-mediated dilation of the brachial artery, to simultaneously assess post occlusive reactive hyperemia (PORH) in the microcirculation and post hyperemic change in tissue oxygenation. PORH was measured using laser Doppler flowmetry placed over the third finger, proximal to the nailbed. Regional tissue oxygenation (rSO2) was measured using near infrared spectroscopy (NIRS) placed on the dorsal surface of the hand. FMD was measured using a linear ultrasound probe. Transfused patients were measured before and after a single transfusion. Kruskal-Wallis was used to test between group differences. Multivariate linear regression was used to model predictors of vascular function.RESULTS: We enrolled 18 control (CTL) patients, 75 non-transfused (NTR) SCD patients, and 26 chronically transfused (TR) SCD patients. Consistent with our previously published data, FMD was improved but not normalized by chronic transfusion and it was predicted by ln[plasma hgb], age and sex. PORH was reduced in both SCD patient groups when compared to the control group while resting flow by laser Doppler was elevated in both SCD groups (figure 1). PORH was also inversely related to resting flow, suggesting that basal conditions in the microcirculation are significant predictors of their response to forearm occlusion. Percent change in rSO2 was not different between the three groups. Lower baseline rSO2 was inversely associated with percent rSO2 increase following hyperemia; and, the baseline rSO2 was significantly decreased in the non-transfused SCD patients but normalized in the transfused SCD patients (Figure 2). Resting hypoxia was best predicted by RBC deformability in the non-transfused patients, even after correction for hemoglobin level, whereas resting hemoglobin levels predicted hypoxia in the transfused and healthy patients.DISCUSSION: With the goal to better understand the mechanism by which transfusion therapy decreases the risk of stroke, we tested the response to arterial and venous occlusion, simultaneously, at three different functional levels of the vascular system: 1.Conduit artery, 2.Pre-capillary arteriolar and capillary, 3.Tissue oxygen exchange. We confirm our previous findings that conduit vessel dysfunction is highly dependent on free hemoglobin, which is consistent with the hemolysis paradigm as a mechanism for sickle cell vasculopathy. This study extends our model to the microcirculation. Resting microcirculatory flow is increased in both transfused and non-transfused SCD patients; and while the resting rSO2 is near normal in the transfused SCD patients it is significantly lower in the non-transfused subjects. This creates the potential for severe hypoxia in the setting of a limited ability to augment flow through the microcirculation during periods of high demand, as in PORH. If there is also decreased conduit vessel reactivity upstream this creates the scenario over which large areas of tissue may rapidly become ischemic. This is a novel system, with simultaneous measurements in multiple vascular beds, allowing us to evaluate supply-demand matching.CONCLUSIONS: Chronic transfusion therapy improves both brachial artery endothelial function and regional tissue oxygenation but it does not significantly improve microcirculatory function, which may be near its maximal flow at rest. Hemoglobin determines resting tissue saturation in healthy and transfused SCD patients, but high shear RBC deformability determines rSO2 in non-transfused SCD patients. [Display omitted] [Display omitted] DisclosuresWood:World Care Clinical: Consultancy; Vifor: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Biomed Informatics: Consultancy; World Care Clinical: Consultancy; Ionis Pharmaceuticals: Consultancy; Apopharma: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy.

Molecular Imaging of the Human Pulmonary Vascular Endothelium Using an Adrenomedullin Receptor Ligand.

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.

Toward a Stroke-Free Childhood in Sickle Cell Disease

Stroke in childhood is not common outside of congenital heart disease and a few other conditions including sickle cell disease (SCD). The background rates reported have been between 2.3 and 2.7 per 100 000 per year.1–3 Adults, on the contrary, have a background rate of ≈800 per 100 000.4 There are some special conditions that increase the risk including congenital heart disease, trauma, infections (basilar meningitis), cancer, and SCD.5 Stroke rates in SCD were estimated to be high at 500 to 1000 per 100 000.6 The Baltimore Washington Cooperative Young Stroke Study reported data from 1988 to 1991 at rate of 285 per 100 000 children for SCD.7 For children with SCD, this is a long way for a stroke-free childhood. SCD fundamental pathophysiology results from hemoglobin S forming polymer strands inside the red blood cell which causes distortion of the red blood cell, leading to microcirculatory occlusion and accelerated erythrocyte destruction with release of toxic-free hemoglobin into the vascular system.8 How SCD leads to cerebrovascular disease is only partly understood. Although there are many manifestations of vascular pathology in SCD, the one that plays the most prominent role is an intracranial cerebral large artery vasculopathy causing stenosis or occlusion. This unusual vascular disease process was confirmed 90 years ago9 as a cause of large brain infarctions in patients with SCD, typically children, and confirmed with arterial studies much later. In the mid-1980s, a confluence of factors, from disparate worlds, led to the work herein described. Aaslid et al introduced the transcranial Doppler (TCD) for detection of intracranial artery vasospasm in 1982 based on experience in Norway.10 Interest in this tool was at first manifested in neurosurgery but soon its potential as a noninvasive way to assess intracranial arteries became …

Bone marrow necrosis in sickle cell disease: A case report and review of the literature

The clinicopathologic entity of bone marrow necrosis (BMN) was first reported by Wade and Stevenson in 1941. BMN is defined as necrosis of the myeloid tissues and stroma without cortical bone involvement. The pathophysiology of BMN remains unclear; however, the occlusion of microcirculation, accompanied by hypoxemia, causes damage to the cells and plays an important role. Severe BMN is rarely diagnosed in living patients. Herein, we report a rare case of severe BMN in a patient with sickle cell disease (SCD) who presented with an unusually severe vaso-occlusive crisis complicated by acute chest syndrome (ACS), pancytopenia, and disseminated intravascular coagulation. Although the clinical features are highly suggestive of BMN, the diagnosis still required a bone marrow (BM) examination because early transfusion therapy can be lifesaving. The prognosis of severe BMN seems to reflect the poor outcomes of such underlying conditions; however, the prognosis of generalized BMN is not so poor when associated with SCD.

Microvascular Thrombosis: A Serious and Deadly Pathologic Process in Multiple Diseases

Much of our understanding of the pathogenesis of thrombosis has long been based on observations made on large blood vessels. Nevertheless, there has been a recent shift in our attention to the microvasculature and to how microcirculatory occlusion affects function of various organs in diseases. This article provides an overview of microthrombosis in small blood vessels, with discussion of the progressive stages of its development. The initial event is triggered by a variety of diseases, followed by a second phase when multiple contributory factors amplify the process with the final phase of microvascular occlusion and microvascular thrombosis. The outcome is either recovery or injury to the affected organ. If the process is generalized, it is often associated with catastrophic or fatal outcomes. Our current knowledge of the major role of contributory factors leads to a new paradigm. A therapeutic approach limited to a single target of the underlying pathogenic factor, such as the use of anticoagulants, is insufficient and too often unsuccessful. Simultaneous management of all the contributory factors should therefore be considered.

Fibrin Plugging as a Cause of Microcirculatory Occlusion During Photodynamic Therapy

An experimental system that allows the white light observation of rapid changes in vessels without disturbance by red laser light was used. Mice were injected with mono-L-aspartyl chlorin-e-6 (Npe-6) i.v. via the tail vein and were immediately exposed to laser light. White emboli were observed forming on the inside of the vessel walls within seconds after commencement of light exposure. Emboli adhered to vessel walls and caused vascular obstruction. Light microscopy of the exposed material using fibrin staining was performed. Electron microscopy on the same material was also carried out. The embolisation time was influenced by both drug dose and laser power. With low laser power, it took a long time to stop the blood flow. Fibrin staining revealed the white emboli to be composed of fibrin. Electron microscopy findings revealed damage to endothelial cells and platelet aggregation. This study suggests that two main mechanisms (direct cellular damage and vascular shut-down ) might actually be complementary and synergistic in the production of vascular lesions using photodynamic therapy.

Effect of Stored-Blood Transfusion on Oxygen Delivery in Patients With Sepsis

Red blood cell transfusion is commonly used to augment systemic oxygen delivery to supranormal levels in patients with sepsis. However, clinical studies have not consistently demonstrated that this therapeutic maneuver is accompanied by an increase in oxygen utilization at either the whole-body level or within individual organs. To determine the effect of red blood cell transfusion on gastrointestinal and whole-body oxygen uptake. Prospective, controlled, interventional study. Multidisciplinary intensive care unit of a tertiary care teaching hospital. Twenty-three critically ill patients with sepsis undergoing mechanical ventilation. Systemic oxygen uptake was measured by indirect calorimetry and calculated by the Fick method. Gastric intramucosal pH as measured by tonometry was used to assess changes in splanchnic oxygen availability. Measurements were made prior to transfusion of 3 U of packed red blood cells. These were then repeated immediately following transfusion, as well as 3 and 6 hours later. There was no increase in systemic oxygen uptake measured by indirect calorimetry in any of the patients studied for up to 6 hours posttransfusion (including those patients with an elevated arterial lactate concentration). However, the calculated systemic oxygen uptake increased in parallel with the oxygen delivery in all the patients. More importantly, we found an inverse association between the change in gastric intramucosal pH and the age of the transfused blood (r = -.71; P < .001). In those patients receiving blood that had been stored for more than 15 days, the gastric intramucosal pH consistently decreased following the red blood cell transfusion. We failed to demonstrate a beneficial effect of red blood cell transfusion on measured systemic oxygen uptake in patients with sepsis. Patients receiving old transfused red blood cells developed evidence of splanchnic ischemia. We postulate that the poorly deformable transfused red blood cells cause micro-circulatory occlusion in some organs, which may lead to tissue ischemia in some organs.

Circadian variation of white blood cell aggregation and free radical indices in men with ischaemic heart disease.

The fibrinolytic activity of blood has a circadian variation with increased thrombotic tendency in the morning. This may be a contributory factor to the circadian variation in the time of onset of thrombotic events. However, there has recently been increasing interest to the role of the white blood cells (WBC) and free radicals (FRs) in thrombosis. We have previously reported a circadian variation in WBC aggregation and FR status in normal volunteers. No one has yet studied possible circadian variations in these parameters in patients with stable ischaemic heart disease (IHD). Ten men with stable IHD had blood samples collected at four-hourly intervals from midday until midday the following day. The patients were ambulant until midnight at which time they went to bed and remained in bed until 0800 h. The following were measured on each sample: WBC aggregation, malondialdehyde (MDA) which is a product of lipid peroxidation by FRs; the FR scavengers, plasma thiol (PSH), red cell glutathione (GSH) and superoxide dismutase (SOD) which are all altered in the presence of increased FR activity. WBC aggregation and PSH had significant circadian variations, P < 0.015 and P < 0.001 respectively. The WBC aggregation peak was at 1200 h and trough at 1600 h, the PSH peak was at midnight and the trough at 0400 h. WBC behaviour and FR status influence the flow properties of blood. The largest rise in WBC aggregation occurred from 0800 h to 1200 h; such an increase in aggregation could predispose to microcirculatory occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

An approach to hypothermic renal preservation

Abstract A selective review of the literature concerning hypothermic renal storage suggests that two major interrelated factors control the success of the various procedures that have been advocated; these are the preservation of an intact vascular endothelium and the maintenance of adequate adenine nucleotide reserves. The damaging effect of warm ischemia is ascribed primarily to microcirculatory occlusion by rigid, ATP-depleted red cells, and secondarily to other effects of adenine nucleotide deficiency. It is suggested that continuous perfusion is a valuable technique when there has been significant warm ischemia, because it provides an effective method of restoring a patent microcirculation and is also useful when prolonged storage is required, since adenine nucleotide levels are better maintained than by the available alternatives. However, careful selection of perfusates is necessary to avoid additional perfusion injury to the endothelium. The criteria for effective preservation without continuous perfusion appear to be: little if any warm ischemic injury, effective removal of blood prior to storage, and the inclusion in the washout fluid of relatively impermeant solutes that will prevent cell swelling (particularly endothelial swelling) during preservation. An integrated approach involving both “washout” and perfusion techniques is suggested.