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The immune and lymphatic systems, infection and sepsis
Published in Peate Ian, Dutton Helen, Acute Nursing Care, 2020
Michelle Treacy, Caroline Smales, Helen Dutton
As sepsis progresses towards septic shock, endothelial damage increases nitric oxide synthase production; this is a potent vasodilator released from the endothelium. Now widespread vasodilatation and persistently leaking blood vessels lead to a gross maldistribution of the circulating volume. This, together with the intravascular micro-thrombi formation, causes a further imbalance between oxygen demand and oxygen supply to the tissues. As inflammation and increased permeability persist, a marked reduction in blood flow continues. This presents as hypotension with a narrow pulse pressure and exacerbates the pro-coagulant state. The body tries to regulate this process by releasing counter-inflammatory agents such as interleukins 4 and 10 and transforming growth factor-β (TGF β), but for some patients, the inflammation and ensuing endothelial changes become overwhelming (Nagalingam 2018). It is worth noting that the capillary refill, which was initially brisk, reduces as peripheral perfusion worsens. In the early phase of sepsis, as the heart tries to compensate for the persistently low systemic vascular resistance, the cardiac output may be high. Unfortunately, as sepsis progresses to septic shock, the myocardium is exposed to the circulation of substances such as myocardial depressant factor, which is synthesised by ischaemic pancreatic tissue, directly impairing myocardial contractility (Daniels and Nutbeam 2017).
The cardiovascular system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Mary N Sheppard, C. Simon Herrington
Leukocytes are important contributors to tissue damage. Neutrophil polymorphs adhere to the activated and injured endothelium of small vessels, especially in the lungs, and after 12 hours there may be significant neutropenia. Activated leukocytes and hypoxic cells release cytokines, especially tumour necrosis factor α (TNF-α) and interleukin 4 (IL-4) into the blood. This causes increased endothelial output of nitric oxide. They also release proteolytic enzymes, which activate the kinin and complement systems, and the circulation is further embarrassed by vasodilatation and increased permeability. Metabolic acidosis directly depresses cardiac myocytes, and a myocardial depressant factor is released from the ischaemic pancreas.
The immune and lymphatic systems, infection and sepsis
Published in Ian Peate, Helen Dutton, Acute Nursing Care, 2014
Andrea Blay, Jacqui Finch, Helen Dutton
With ongoing vasodilatation and loss of circulating volume the patient may exhibit further cardiovascular changes, many of which will increase the EWS score significantly. There may be marked hypotension, tachycardia with a bounding pulse and an impaired capillary refill; the last may be rapid at first and then reduced as peripheral perfusion worsens. It should be noted that in the early phase of sepsis, as the heart tries to compensate for the persistently low systemic vascular resistance, the cardiac output may be high. Unfortunately for the deteriorating patient, this will not achieve an increase in tissue perfusion owing to the circulation of substances like Myocardial Depressant Factor, synthesised in shock by ischaemic pancreatic tissue and directly impairing myocardial contractility.
Ramatroban for chemoprophylaxis and treatment of COVID-19: David takes on Goliath
Published in Expert Opinion on Therapeutic Targets, 2022
Kate C. Chiang, John G. Rizk, Deanna J. Nelson, Lakshmanan Krishnamurti, Selvakumar Subbian, John D. Imig, Imran Khan, Srinivasa T. Reddy, Ajay Gupta
Ramatroban improves vascular responsiveness, while inhibiting endothelial surface expression of ICAM-1 and VCAM-1, inhibiting MCP-1 expression in response to TNF-α or platelet-activating factor, and inhibiting macrophage infiltration [10] (Table 1). In a rat model of endotoxic shock, ramatroban prevented hypotension, reduced plasma TNF-α levels by over 90%, and markedly reduced myeloperoxidase levels in lungs, ileum, and heart, suggesting end organ protection by mitigating TxA2-mediated platelet-polymorphonuclear leukocyte activation. Ramatroban improved survival by 45% in endotoxic shock rats [137] (Table 2). In rats with splanchnic artery ischemia-reperfusion injury, the plasma levels of TxB2 were increased about 7-fold [138]. Interestingly, ramatroban restored phagocytic function of peritoneal macrophages partially, inhibited plasma myocardial depressant factor activity about 50%, inhibited tissue infiltration by neutrophils, as measured by a decline in ilium myeloperoxidase activity >50%, reduced lung myeloperoxidase activity >80%; and prevented hypotension while improving survival [138] (Table 2). Notably, plasma myeloperoxidase is significantly increased in COVID-19 and is abundant in NETs, and regulates NET formation via synergy with neutrophil elastase [43,139]. Therefore, ramatroban is remarkably effective in both endotoxin- and ischemia-reperfusion injury-induced shock states, which share common pathogenetic mechanisms with severe COVID-19 [140]. Moreover, ramatroban prevented occlusive arterial thrombosis in response to vessel wall injury [141]. Infusion of ramatroban after coronary artery occlusion in dogs reduced myocardial infarct expansion by 65% and suppressed reperfusion arrhythmias [142].