Peripheral Tissue Ischemia Research Articles

Chasing the Perplexing Purple Butterfly through Biopsychosocial Model-based Precision Medicine: the Enigma of Fibromyalgia Unraveled Biopsychosocial perspectives in fibromyalgia care

A purple butterfly symbolizes the heightened sensitivity to even a gentle touch in fibromyalgia (FM), which is a common syndrome with persistent widespread pain and tenderness. The biopsychosocial model is currently the main framework used to appreciate different factors contributing to chronic pain in FM. Widespread pain in fibromyalgia is effected by multiple biopsychosocial factors (cognitive ability, depression, somatization, psychological trauma, anxiety, and social deprivation/isolation), which interact and contribute to chronic persistent pain. Interaction of influences such as gender, neuroendocrine milieu, and the hypothalamo–pituitary–adrenal axis also affect FM susceptibility and its clinical expression. Multiple neuroanatomic and neurochemical systems with many autonomic, cognitive & affective processes manifest as multisymptom illness in FM. While the etiology of FM is elusive, the associated symptoms indicate the role of autonomic dysfunction in its pathophysiology. Fatigue and widespread pain characterizing FM may be consequent to peripheral tissue ischemia caused by sympathetically mediated vasoconstriction. In light of some common denominators among FM patients, which include genetic variation, sympathetic hyper-activation, maladaptive thoughts, ineffective coping strategies, and nonrestorative sleep, an individualized care approach can help subgroup and phenotype these patients for specific diagnosis and management. A multidisciplinary approach involving person-centered approaches to biopsychosocial concepts in FM, incorporating relaxation therapy, physical activity, and psychotherapy targeting negative emotions that amplify pain, maladaptive coping strategies, and environmental stressors, can help manage FM's course, outcomes, and treatment.

Topical nitroglycerin ointment as salvage therapy for peripheral tissue ischemia in newborns: a systematic review.

Background:Topical nitroglycerin (TNG) ointment has been used for almost 3 decades to treat neonatal peripheral tissue ischemia, but this product is now no longer being produced by its Canadian manufacturer. Our aim was to investigate the efficacy and safety of TNG products in newborns in neonatal intensive care units.Methods:In this systematic review we searched Embase, CINAHL, MEDLINE, PubMed and Web of Science from inception to April 2020 for studies on the use of TNG products (TNG ointment, TNG spray, glyceryl trinitrate [GTN] patch) for the treatment of neonatal tissue ischemia. We did not apply language or study design limitations. Animal studies and duplicate records were excluded. Two reviewers screened and extracted data. The Tool for Evaluating the Methodological Quality of Case Reports and Case Series was used to assess the risk of bias of individual studies.Results:We included 23 articles (20 case reports, 2 case series and 1 retrospective audit) describing the use of TNG ointment, TNG spray or GTN patch in the treatment of 39 tissue ischemia events in 37 newborns. Twenty-three (62.2%), 12 (32.4%), 1 (2.7%) and 1 (2.7%) infants received TNG ointment, GTN patch, both TNG ointment and GTN patch, and TNG spray, respectively. Nineteen (76.0%) and 7 (53.8%) injuries treated with TNG ointment and GTN patch showed complete recovery, respectively. Two (16.7%) infants treated with GTN patch experienced adverse events (i.e., methemoglobinemia) requiring treatment discontinuation.Interpretation:TNG ointment presents a safe therapeutic modality for salvage therapy of neonatal tissue ischemia. Engagement of stakeholders is essential to address its recent commercial inaccessibility in Canada.

Successful Management of Severe Peripheral Tissue Ischemia after Arterial Catheterization in Micro Preemies using Humidification & Topical Nitroglycerin

Successful Management of Severe Peripheral Tissue Ischemia after Arterial Catheterization in Micro Preemies using Humidification & Topical Nitroglycerin

Bromodomain Blockade for Intimal Hyperplasia — A Good BET?

Bromodomain Blockade for Intimal Hyperplasia — A Good BET?

Multimodal in vivoimaging reveals limited allograft survival, intrapulmonary cell trapping and minimal evidence for ischemia-directed BMSC homing

BackgroundDespite positive reports on the efficacy of stem cell therapy for the treatment of cardiovascular disease, the nature of stem cell homing to ischemic tissues remains elusive.ResultsWe used a mouse model of peripheral tissue ischemia to study the survival and homing capacity of dual reporter gene (eGFP/Luciferase) expressing bone marrow-derived stromal cells (BMSC). Cell homing and survival were studied in the presence and absence of ciclosporin A (CsA) immunosuppression using bioluminescence imaging (BLI) together with confocal endomicroscopy. Different injection strategies were applied: central venous (CV), intra-arterial (IA) and intramuscular (IM). BLI and confocal endomicroscopy evidenced complete rejection of the IM injected allogeneic BMSC transplant within 5 to 10 days. Immunosuppression with CsA could only marginally prolong graft survival. IM injected BMSC did not migrate to the site of the arterial ligation. CV injection of BMSC resulted in massive pulmonary infarction, leading to respiratory failure and death. Intrapulmonary cell trapping was evidenced by confocal endomicroscopy, BLI and fluorescence microscopy. IA injection of BMSC proved to be a feasible and safe strategy to bypass the lung circulation. During the follow-up period, neither BLI nor confocal endomicroscopy revealed any convincing ischemia-directed homing of BMSC.ConclusionsBLI and confocal endomicroscopy are complementary imaging techniques for studying the in vivo biology of dual reporter gene-expressing BMSC. Allogeneic BMSC survival is limited in an immunocompetent host and cannot be preserved by CsA immunosuppression alone. We did not find substantial evidence for ischemia-directed BMSC homing and caution against CV injection of BMSC, which can lead to massive pulmonary infarction.

Nitrite/nitric oxide regulation of therapeutic angiogenesis for diabetic ischemic vascular disease

Diabetes is associated with increased incidence of cardiovascular disease along with concomitant peripheral vascular disease contributing to development of PAD and non-healing ulcers of the extremities. Previous work has revealed that NO bioavailability is markedly diminished during diabetes and figures to be a key contributor to increased cardiovascular disease in this metabolic disorder. Our group has determined that the NO/nitrite endocrine system serves as a critical mediator of ischemic vascular remodeling of peripheral limbs and has further revealed the importance of this endocrine system for diabetic vascular disease. Data will be presented demonstrating how nitrite/NO metabolism mediates protection against peripheral tissue ischemia and necrosis during diabetes by stimulating therapeutic angiogenesis in both young and aged diabetic animal models. Nitrite/NO therapeutic angiogenesis during diabetes significantly depends on VEGF induction and activity while also significantly decreasing vascular and ischemic tissue oxidative stress. Importantly, oral sodium nitrite administration to diabetic patients with peripheral tissue ulcers is well tolerated indicating the therapeutic potential of this approach for therapeutic angiogenesis for diabetic peripheral vascular disease.

Dipyridamole reverses peripheral ischemia and induces angiogenesis in the Db/Db diabetic mouse hind-limb model by decreasing oxidative stress

Dipyridamole anti-platelet therapy has previously been suggested to ameliorate chronic tissue ischemia in healthy animals. However, it is not known if dipyridamole therapy represents a viable approach to alleviating chronic peripheral tissue ischemia associated with type 2 diabetes. Here we examine the hypothesis that dipyridamole treatment restores reperfusion of chronic hind-limb ischemia in the murine B6.BKS-Lepr db/db diabetic model. Dipyridamole therapy quickly rectified ischemic hind-limb blood flow to near preligation levels within 3 days of the start of therapy. Restoration of ischemic tissue blood flow was associated with increased vascular density and endothelial cell proliferation observed only in ischemic limbs. Dipyridamole significantly increased total nitric oxide metabolite levels in tissue, which were not associated with changes in endothelial NO synthase expression or phosphorylation. Interestingly, dipyridamole therapy significantly decreased ischemic tissue superoxide and protein carbonyl levels, identifying a dominant antioxidant mechanistic response. Dipyridamole therapy also moderately reduced diabetic hyperglycemia and attenuated development of dyslipidemia over time. Together, these data reveal that dipyridamole therapy is an effective modality for the treatment of chronic tissue ischemia during diabetes and highlights the importance of dipyridamole antioxidant activity in restoring tissue NO bioavailability during diabetes.

Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning

Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K(+)-dependent ATP (K(ATP)) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 +/- 14.3 vs. 38.3 +/- 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 +/- 6% and 3 +/- 5% in control and PerC, respectively (P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a K(ATP) channel-dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes.

Adenosine A1 receptor antagonist improves intradialytic hypotension

Intradialytic hypotension is a most frequent complication of hemodialysis and may contribute to cardiovascular events and high mortality. There is a hypothesis that an increase in adenosine generation during hemodialysis may cause vasodilation and a decrease in cardiac output, which results in systemic hypotension. We studied whether this can be blocked by an adenosine A1 receptor antagonist. We investigated the effects of an A1 antagonist, FK352, injection in 30 chronic hemodialysis patients with frequent intradialytic hypotension by a prospective, multicenter, double-blind placebo-controlled study for 4 weeks after 4 weeks of the observation period. Intradialytic hypotension was defined as systolic blood pressure (SBP) less than 110 mmHg, with SBP drop of more than 30 mmHg from the predialysis level. The efficacy of FK352 was primarily assessed by the reduction rate of dialysis hypotension between the FK352 and placebo groups. Incidence of emergency treatments caused by hypotension was evaluated. FK352 (50 mg, intravenous) or an equivalent placebo was injected into the dialysis circuit 1 h after starting dialysis. Blood pressure and heart rate were monitored every 30 min during dialysis. FK352 significantly improved intradialytic hypotension (P=0.046), in that the reduction rates of intradialytic hypotension in the FK352 and placebo groups were -12.8% (Q1 (first quantile), Q3 (third quantile): -27.5, -1.7), and +8.3% (Q1, Q3: -16.6, +16.7), respectively. The frequency of discontinuation of dialysis was significantly reduced by FK352. No apparent side effects were observed from treatment with FK352. In conclusion, the A1 antagonist FK352 may offer a novel therapeutic option for chronic dialysis patients associated with intradialytic hypotension.

Resolution of peripheral tissue ischemia secondary to arterial vasospasm following treatment with a topical nitroglycerin device in two newborns: case reports

Resolution of peripheral tissue ischemia secondary to arterial vasospasm following treatment with a topical nitroglycerin device in two newborns: case reports

Pharmacology Review

Extravasation or inadvertent infiltration of fluids into subcutaneous tissue from peripheral intravenous (IV) devices is a common adverse event in newborns. (1)(2) Although fluids occasionally extravasate from central venous lines, the complication is much more common from peripheral catheters, which are used widely in sick neonates. (3) This article focuses on extravasations from peripheral IV devices. Injury to the skin, even in a very immature neonate, results in an inflammatory response and heals by scar formation. (4) Although the scars from many of these injuries appear to improve with time, (5) tissue necrosis from extravasation injury could result in partial or complete skin loss, infection, and nerve and tendon damage, with the potential risk of permanent cosmetic and functional impairment. (6)(7)(8) The incidence of extravasations from Teflon® catheters has been reported to vary from 23% to 63%. (1) A recent survey of regional neonatal intensive care units in the United Kingdom recorded the prevalence of extravasation injury resulting in skin necrosis as 38 per 1,000 neonates, with 70% of these injuries occurring in infants of 26 weeks’ gestation or less. (2) The incidence of extravasation is related closely to the type of device used, insertion site, duration of therapy, infusate administered, patient activity, and gestational age. (1)(3)(9)(10) The fragility of the skin, particularly in the first 2 weeks after birth, and the lack of subcutaneous tissue in preterm neonates makes them uniquely susceptible to injury and skin loss. Extravasation may occur from the tip of the cannula or needle piercing the vessel wall. Alternatively, distal obstruction of the vein due to thrombosis or venoconstriction from irritation of the vessel wall may lead to increased back pressure and leakage from the entry point of the needle or …

Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates

Four neonates had resolution of peripheral tissue ischemia after the application of 2% nitroglycerin ointment. A dosage of 4 mm nitroglycerin ointment per kilogram of body weight was applied to two patients with ischemia caused by vasospasm from indwelling radial artery catheterization and to two patients with ischemia resulting from dopamine extravasation. No adverse effects were noted except mild episodes of decreased blood pressure in two of the patients.