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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The liver is believed to play a major role in the initiation of multiorgan failure, the most lethal complication in the clinical course of sepsis. Microbes and their virulence factors enter the hepatic circulation where they first activate sinusoidal endothelial cells and Kupffer cells to produce proinflammatory mediators, including TNF-alpha, IL-1, IL-6, reactive oxygen metabolites, and eicosanoids. These mediators cause not only microbial killing, but also structural and functional liver damage concerning mainly the parenchymal cells. Leukocytes are targeted to the liver sinusoids by chemoattractants and, like platelets, tether to the sinusoidal endothelial cells, which are in a procoagulant state of inflammatory activation. Clogging of the sinusoids by these cells leads to a decrease of blood flow through the sinusoids, which is further aggravated by endothelin-1 effectuating the constriction of hepatic stellate cells in the sinusoids. In contrast, both nitric oxide (NO) and carbon monoxide (CO) act as antagonists of endothelin-1 by mediating relaxation of sinusoidal vessels. By maintaining an adequate sinusoidal perfusion, both NO and CO are hepatoprotective during the early, hyperdynamic phase of sepsis characterized by an increased cardiac output and moderate peripheral vasodilation. However, during the late, hypodynamic phase of sepsis, massive overproduction of NO by the inducible NO synthase leads to circulatory collapse, which inevitably includes breakdown of the liver circulation.
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PMID:The hepatic microvascular responses to sepsis. 1112 15

The study is retrospective review of the demographic, clinical, angiographic, and operative data of the first 205 consecutive CABG operations performed by Caribbean Heart Care at the Eric Williams Medical Sciences Complex (EWMSC), Trinidad and Tobago, between November 1993 and December 1997. The aim of the study was to determine the in-hospital and intermediate-term follow-up results. The mean age of patients was 59 +/- 10 years and 78% were male. Sixty-four per cent were of East Indian descent, whereas 16% were of African descent. Forty-eight per cent of the patients were hypertensive, 46% were diabetic, 33% had hyperlipidaemia, 20% had a recent history of cigarette smoking and 16% were obese. Sixty-five per cent had a positive family history of ischaemic heart disease. The average time interval between angiography and surgery was 2.3 months. At the time of angiography, 63.5% of patients had Canadian Cardiac Society (CCS) class 3 or 4 angina. The mean ejection fraction was 61 +/- 15%. Wall motion abnormalities were seen in 67% of patients. Significant stenoses of the left anterior descending artery, right circumflex artery, circumflex and ramus coronary arteries were present in 91%, 78%, 54% and 5%, respectively. Many patients (67%) had severe diffuse disease on angiography. The mean intensive care stay was 2.2 +/- 0.8 days. In-hospital mortality was 3.9% (8/205). The most frequent post-operative complication was haemorrhage (2.6%). Acute renal failure occurred in 2.1%; pulmonary collapse, 1.6%; stroke, 1% and cardiac arrest, 1%. Both sternal wound infections and systemic sepsis occurred in 0.5%. Intermediate-term follow-up data were obtained for 92% (189/205). The duration of follow-up ranged from 1 to 5 years (mean 3.7 years). During the follow-up period, 7 patients (3.4%) died. Angina severity was reduced from a mean CCS score of 2.61 +/- 0.95 before CABG to 1.22 +/- 0.55 at the time of follow-up (p < 0.0001). Overall 4-year mortality compared favourably with data from international studies. Among survivors, quality of life improved as evidenced by the reduction in the mean angina score.
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PMID:Coronary artery bypass graft outcome: the Trinidad and Tobago experience. 1121 37

To the modern mind, the term 'sepsis' conjures up images of microbes. It is easy to forget that the word predates any understanding of the microbial origins of infectious disease. Derived from the Greek 'sepsios' (rotten), sepsis denotes decay: a phenomenon that humans once regarded as a mysterious though inevitable natural process. A living organism does not accept decay passively. Virtually all multicellular life forms are capable of resisting infection through the generation of a vigorous immune response. In mammals, the response is so stereotypic that it has come to define sepsis itself: it is often called the 'septic syndrome'. Our current understanding of the innate immune system is deeply rooted in the study of sepsis. The chain of events linking infection to tissue injury and cardiovascular collapse is not obvious, and affirmation of the concept required three major discoveries. First, the septic syndrome was found to be caused by toxic products of microbes. Secondly, these toxic substances were found to be toxic because of their propensity to activate cells of the innate immune system, prompting cytokine production. Thirdly, the activating events initiated by microbial toxins were traced to members of an ancient family of defensive molecules, versions of which operate in virtually all multicellular life forms. In mammals, proteins of this family are now known as Toll-like receptors. They represent a point of direct contact, and first contact, between a pathogen and the host immune system.
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PMID:Sepsis begins at the interface of pathogen and host. 1170 87

Profound hypothermia (core temperature of less than 28 degrees C) is a life threatening state and a medical emergency associated with a high mortality rate. The prognosis depends on underlying diseases, advanced or very early age, the duration prior to treatment, the degree of hemodynamic deterioration, and especially, the methods of treatment, including active external or internal rewarming. This is a case study of an 80-year-old female patient with severe accidental hypothermia (core temperature 27 degrees C). She was found in her home lying immobile on the cold floor after a fall. The patient was in a profound coma with cardiocirculatory collapse, and the medical staff treating her was inclined to pronounce her deceased. On her arrival at the hospital, she was resuscitated, put on a respirator and actively warmed. Very severe metabolic disorders were found, including a marked metabolic acidosis composed of diabetic ketoacidosis (she had suffered from insulin treated type 2 diabetes mellitus) and lactic acidosis with a very high anion gap (42) and a hyperosmotic state (blood glucose 1202 mg/dl). There were pathognomonic electrocardiographic abnormalities, J-wave of Osborn and prolonged repolarization. Slow atrial fibrillation with a ventricular response of 30 bpm followed by a nodal rhythm of 12 bpm and reversible cardiac arrest were recorded. The pulse and blood pressure were unobtainable. Despite the successful resuscitation and hemodynamic and cognitive improvement, rhabdomyolysis (CKP 6580 u/L), renal failure and hepatic damage developed. She was extubated and treated with intravenous fluids containing dopamine, bicarbonate, insulin and antibiotics. Her medical condition gradually improved, and she was discharged clear minded, functioning very well and independent. Renal and liver tests returned eventually to normal limits. Progressive bradycardia, hypotension and death due to ventricular fibrillation or asystole commonly occur during severe hypothermia. Respiratory and metabolic, sometimes lactic, acidosis, lethargy and coma, hypercoagulopathy, hyperosmolar state, acute pancreatitis and renal and hepatic failure are frequent complications of hypothermia. Underlying predisposing causes of hypothermia are diabetic ketoacidosis, cerebrovascular disease, mental retardation, hypothyroidism, pituitary and adrenal insufficiency, malnutrition, acute alcoholism, liver damage, hypoglycemia, sepsis, hypothalamic dysfunction, sepsis and polypharmacy, and especially, the use of sedative and narcotic drugs. Our case demonstrates once again that CPR once begun should continue until the successful rewarming because "no one is dead until warm and dead".
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PMID:[Severe accidental hypothermia in an elderly woman]. 1175 73

Our current understanding of the pathogenesis of sepsis suggests that bacteria as well as bacterial-derived products activate an uncontrolled network of host-derived mediators such as proinflammatory cytokines (ie, tumor necrosis factor [TNF] and interleukin [IL]-1beta), which can ultimately lead to cardiovascular collapse and death. Despite the potentially important role that TNF and IL-1beta may play in producing cardiac dysfunction in human septic shock, little is known with regard to the basic biochemical mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in understanding the early events that are downstream from bacterial-mediated signaling has been the identification of Toll-like receptors (TLRs). TLR-mediated signaling is known to activate the transcription factor nuclear factor-kappaB and to upregulate TNF expression. It has recently been shown that the heart expresses TLRs, raising the possibility that these receptors may be responsible for mediating the deleterious effects of bacterial pathogens on cardiac function. In this review, we will discuss the emerging role for TLRs in the pathogenesis of the cardiovascular collapse that occurs during sepsis.
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PMID:Cardiac inflammation and innate immunity in septic shock: is there a role for toll-like receptors? 1194 70

Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.
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PMID:Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice. 1211 31

Three cases of splenic rupture causing cardiovascular collapse in critically ill patients are discussed. The first patient had received cardiopulmonary resuscitation (CPR) in the days before the collapse, the second patient was recovering from severe sepsis and the third patient was recovering from severe sepsis, had received CPR and had undergone percutaneous endoscopic gastrostomy (PEG). The diagnosis was made at post mortem in two of the patients, the third patient, who bled following PEG, survived after prompt surgical intervention. Splenic rupture should be considered as part of the differential diagnosis of unexpected cardiovascular collapse in patients who have received CPR or who are recovering from sepsis.
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PMID:Occult splenic rupture with cardiovascular collapse: a report of three cases in critically ill patients. 1244 29

Dysregulated apoptotic cell death contributes to many pathological conditions, including sepsis, prompting the suggestion that caspase inhibition to block apoptosis could have useful therapeutic applications. Because the cytokine tumor necrosis factor (TNF, also known as TNF-alpha) is both pro-apoptotic and pro-inflammatory and is involved in septic shock, we tested whether caspase inhibition would alleviate TNF-induced toxicity in vivo. General caspase inhibition by the protease inhibitor zVAD-fmk exacerbated TNF toxicity by enhancing oxidative stress and mitochondrial damage, resulting in hyperacute hemodynamic collapse, kidney failure and death. Thus, survival of TNF toxicity depends on caspase-dependent processes. Our results demonstrated the pathophysiological relevance of caspase-independent, ROS-mediated pathways in response to lethal TNF-induced shock in mice. In addition, survival of TNF toxicity seemed to require a caspase-dependent protective feedback on excessive reactive oxygen species (ROS) formation and phospholipase A2 activation.
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PMID:Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. 1266 Jul 28

Peritonitis generally results from gastrointestinal perforation, with systemic sepsis developing over hours or days from an initially localized nidus of infection. The consecutive inflammatory response induces the widespread generation of oxidants and free radicals, which are potent inducers of breaks and nicks in double-stranded DNA. This genetic damage triggers the activation of the nuclear enzyme poly(ADP-ribose) polymerase 1, which, in turn, cleaves the respiratory coenzyme nicotinamide adenine dinucleotide into nicotinamide and ADP ribose. The consecutive decrease in cellular nicotinamide adenine dinucleotide inhibits glycolysis and mitochondrial respiration, leading to cellular energy collapse and necrotic cell death. In parallel, poly(ADP-ribose) polymerase 1 positively regulates inflammatory signal transduction pathways through a functional association with the transcription factor nuclear factor kappaB, resulting in a progressive amplification of local inflammation. Recent data indicate that these molecular mechanisms are instrumental in the development of cardiovascular collapse and multiple organ dysfunction in sepsis, supporting the view that pharmacologic inhibitors of poly(ADP-ribose) polymerase 1 may represent useful tools for the treatment of this condition.
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PMID:Role of poly(adenosine diphosphate-ribose) polymerase 1 in septic peritonitis. 1265 79

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T(3) syndrome of severe illness.
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PMID:Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. 1284 66


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