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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is considerable evidence to implicate aggressive species of oxygen in the pathogenesis of organ dysfunction consequent to sepsis and septic shock. The inflammatory process appears to participate ubiquitously in this setting. A characteristic of inflammation is the involvement of activated neutrophils and their generation of aggressive oxygen species. Such species may both directly injure cells proximal to the oxidant generating cells, and may inactivate any proteolytic mechanisms normally protective against proteolytic injury caused by neutrophil elastase and other proteolytic enzymes released during inflammation. The offending agent in sepsis is most commonly envisioned as bacterial lipopolysaccharide, or endotoxin. Infusion of endotoxin into animals can reproduce much of the pathophysiology of sepsis and septic shock. In addition, administration of endotoxin to cultured cells, particularly endothelial cells, can cause responses consistent with a sequence of events that occurs in intact animals and humans. In both experimental models, it appears that aggressive oxygen species are important actors in the scenario eventuating in cell or organ injury. Of importance, the toxic consequences of these free radicals probably occurs in relatively protected spaces, including microenvironments created by close adherence between inflammatory cells and endothelial cells and the cell interior. For those reasons, the potential for antioxidants as therapy should include consideration of the volume of distribution of such substances. It is probably important that antioxidants access excluded spaces including cell interiors in order to have their maximum effect in this setting. We have studied ina preliminary way the effects of n-acetyl-cysteine, a highly permeable free radical scavenger and anti-oxidant, in patients with established ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen radicals--an important mediator of sepsis and septic shock. 179 73

For health, well perfused tissues, oxygen uptake is determined primarily by metabolic need rather than by oxygen supply. Tissue hypoxia supervenes when tissue oxygen tension (PO2) falls below a critical point, and the point where this occurs can be predicted from the systemic oxygen delivery or extraction ratio. A growing body of evidence suggest that tissue oxygen extraction may be impaired in adult respiratory distress syndrome (ARDS) and sepsis. In these syndromes the minimum oxygen delivery needed to maintain a normal oxygen uptake appears to be increased, as tissues become hypoxic despite high levels of delivery. However, controversy surrounds every phase of this observation, from its experimental basis, to potential causes, to its implications for patient care. In this review, we discuss the physiology of oxygen transport, the determinants of tissue oxygenation in normal and pathological states, and the therapeutic implications of oxygen transport.
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PMID:Oxygen delivery to tissues. 180 74

The primary function of the cardio-respiratory system is to meet the oxygen demands of the various organs and tissues and to remove metabolic wastes. The cellular O2 supply in the critically ill patient afflicted with severe infection, sepsis or ARDS is impaired not only by reduced O2 transport to the tissue due to myocardial depression caused by inadequate preloading and depressed contractility, but also by inadequate blood flow at the regional and microcirculatory levels. To obtain adequate tissue oxygenation despite derangements of the microcirculation, it is useful to aim for a hyperdynamic circulatory state that provides a supramaximal O2 transport. The best way to achieve this goal is first to optimize cardiac filling pressures, i.e. to the upper range of normal, and then to improve cardiac output using inotropic support. Only when the arterial pressure remains too low despite these measures is the use of vasopressors indicated.
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PMID:[Oxygen transport and tissue oxygenation in critically ill patients--value of volumes and vasoactive substances]. 181 5

Twenty years have now elapsed since Ashbaugh and Petty first described the syndrome of acute respiratory failure associated with a wide spectrum of clinical conditions. During the past two decades, significant advances have emerged in our understanding of the clinical conditions associated with the syndrome and the pathophysiological changes affecting the alveolar-capillary membrane responsible for the characteristic non-cardiogenic pulmonary edema. Recent data have reaffirmed the notion that mortality rates in ARDS remain in excess of 60 percent, essentially unchanged since the first description of the syndrome, despite all the advances in critical care medicine in the intervening years. The incidence of ARDS has been difficult to establish because of lack of agreement on precise definition criteria. The lack of agreed definition criteria has hampered evaluation of the natural history of the syndrome, its epidemiology and mortality rates, and the efficacy or otherwise of a variety of therapeutic interventions. This review will highlight a recent, clinically appropriate, expanded definition of ARDS. New understandings of the roles of sepsis and multi-system organ failure in mortality associated with ARDS will be discussed. Several mediators, both locally in the lung and in the systemic circulation, have been implicated in the pathophysiology of ARDS. This review will discuss the evidence for and against neutrophils, platelets, cytokines derived from mononuclear cells and macrophages, complement, prostaglandins/leukotrienes, oxygen-derived radicals, and a variety of proteases. Current treatment strategies for ARDS are designed to increase tissue oxygen delivery by increasing arterial oxygen tension and cardiac output while simultaneously attenuating the pulmonary and systemic injury by appropriate pharmacologic and surgical interventions. Recent data advocating pharmacological augmentation of cardiac index and oxygen delivery will be highlighted. The persistently high mortality rates of 60-70 percent in patients with established ARDS have provoked recurring interest in new techniques of providing mechanical ventilation. Most studies have shown, however, that mortality in ARDS patients is attributable mainly to sepsis and multi-system organ failure rather than primarily to respiratory failure. Established and speculative intervention to reduce sepsis and multi-system organ failure associated with ARDS will be featured in the review.
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PMID:Acute respiratory distress syndrome--two decades later. 181 55

Protein C, a potent vitamin K-dependent protein activated by an endothelial cell cofactor, thrombomodulin, has anticoagulant and profibrinolytic activity. Free protein S, a cofactor for protein C, potentiates protein C activity at the endothelial cell surface. Pulmonary thromboemboli are a consistent finding in adult respiratory distress syndrome (ARDS). To determine if protein S or protein C were affected by widespread endothelial cell damage in ARDS, we measured bound and free protein S levels and protein C antigenic and functional levels in 18 patients with acute lung injury, 6 critically ill patients without lung history, and 22 normal subjects. Free (PS:F) and bound (PS:Ag) protein S and protein C antigen (PC:Ag) levels were measured using an enzyme-linked immunoassay and protein C function (PC:Fn) by measuring its anticoagulant activity. We found a significant decrease in bound and free protein S levels of both patient groups in comparison to normal and a shift toward the inactive, bound protein S form. In addition, a significant decrease in free protein S compared to bound protein S in both patient groups was observed. While both PC:Ag and PC:Fn were significantly reduced compared to normal, the PC:Fn was significantly and severely decreased out of proportion to the PC:Ag in both patient groups. There was no difference between those with and without lung injury for both protein S and protein C. Analyzed according to etiology of lung injury, there was no difference in the bound and free protein S, nor in PC:Ag and PC:Fn levels between patients with sepsis and trauma. However, there were significant decreases in both protein S and protein C levels compared with normal subjects. Levels of both PS and PC levels in patients who survived did not differ from those who died. In summary, our data show that both protein S and C are markedly deranged in acutely ill patients who suffered from either sepsis or trauma, and these changes are independent of lung injury. The marked reductions in functional activity of PS and PC may be contributing factors to the thromboembolic complications often observed in these patients.
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PMID:Protein S and C alterations in acutely ill patients. 182 9

The role of neutrophil oxidative burst activation (OBA) in the development of fulminant post-trauma adult respiratory distress syndrome (ARDS) was studied in 30 patients. Neutrophil (PMN) chemiluminescence (LE) was used as the index of OBA. Serially, for 8 days post-trauma, patient neutrophils (Pc) were studied in their own serum (Ps) normal serum (Ns), or Gey's solution (G). Ps was checked against normal neutrophils (Nc) for inhibition. LE was initiated by the addition of preopsonized zymosan to 1 x 10(6) PMN, the LE response monitored by luminometer, and the peak of the integral of LE recorded. Seven developed ARDS within the first 4 days; 12 patients developed sepsis (TS) but no ARDS, and 11 patients had uncomplicated trauma (TR). All ARDS showed increased LE (P less than 0.0001), at 48-96 hr. Patients without ARDS showed no significant increase in LE, although their mean injury severity (ISS) was the same. The ARDS LE response was mediated by activation of Pc [74%] with only a small but significant additional effect (6%) by ARDS serum (Ps): LE = 0.672 (Pc) + 0.24 [ARDS(Ps)] + 1343; N = 146, r2 0.733, P less than 0.0001. However, sera (Ps or Ns) was required, as incubation in G inhibited LE; [cells + s] greater than [cells + G], P less than 0.0001. LE is a biologic marker of ARDS, and the delay between injury and the LE indicated that initiation of ARDS may have therapeutic importance. Neutrophil activation in ARDS requires sera, but the ARDS effect appears mainly due to cells with only a small ARDS-specific serum-mediated role. The physiologic response to ARDS was evaluated by serial 8-hr studies of blood gases and pH; the respiratory index (RI) to pulmonary shunt (QS/QT) relationship, compliance (COMPL), and net fluid balance (DFLUID) PMN and platelet (PLAT) counts were also measured. Compared with TR and TS, the ARDS patients at 48-96 hr, showed increased RI, QS/QT, and DFluid requiring increased FiO2 and PEEP as COMPL and PLAT fell and LE rose. These changes were all simultaneously significant (P less than 0.05 to P less than 0.0001) by Bonferroni t-statistic applied to ANOVA. The clinical importance of these physiologic and biochemical responses was emphasized by the significantly (P less than 0.005) increased mortality in the ARDS patients. These data suggest that PMN LE and simple measures of respiratory function are early biologic markers of the development of fulminant post-traumatic ARDS and can be used to predict ARDS severity.
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PMID:Neutrophil oxidative burst activation and the pattern of respiratory physiologic abnormalities in the fulminant post-traumatic adult respiratory distress syndrome. 184 56

Tumor necrosis factor (TNF) was measured antigenically and functionally in serum and bronchoalveolar lavage fluid (BAL) of patients with ARDS and those at high risk for ARDS. Of 22 patients with ARDS, 14 had sepsis or serious infection as the major clinical predisposition, and 10 of 20 high-risk patients had sepsis or serious infection. Mean levels of TNF in serum of patients with ARDS and high risk showed a trend toward elevation but were not significantly higher than mean serum levels in normal subjects. Mean levels of TNF in BAL of ARDS patients (242 +/- 126 pg/ml) were significantly higher than in normal subjects (9 +/- 5 pg/ml), p less than 0.05. Antigenic levels of TNF were undetectable in approximately half the patients with ARDS or the high-risk state. Levels of TNF in BAL appeared to be highest in the first day of ARDS. There appeared to be no relationship between levels of TNF in serum or BAL and subsequent mortality. However, serum levels of TNF were significantly higher in septic patients than in nonseptic patients, whereas this difference was not apparent in BAL. These results show that functional and antigenic elevations of TNF are present in BAL and perhaps in serum of patients with ARDS or with the high-risk state.
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PMID:Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. 185 48

The variable clinical presentation and natural history of acute pancreatitis are illustrated by case reports, namely a case with a falsely positive diagnosis of biliary pancreatitis, a case with acute interstitial pancreatitis of biliary origin, a patient with early and severe late systemic complications and with sterile necrotizing pancreatitis necessitating operative debridements twice, a patient with acute pancreatogenic ascites and ARDS requiring drainage and respiratory supportive care, a patient with biliary pancreatitis and operation for necrotizing cholecystitis, with a further, late intervention for pancreatic abscess, and a patient with internal drainage for a pseudocyst, complicated by acute biliary pancreatitis due to cholesterolosis of the gallbladder. Modern clinico-pathological classification of acute pancreatitis and modern definitions of pancreatic sepsis are important for determining prognosis and adequate treatment.
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PMID:[Variable course in acute pancreatitis exemplified by case reports]. 186 65

Endotoxemia, complement activation, and the generation of C5a occur in the course of sepsis, trauma, and the adult respiratory distress syndrome, clinical situations in which TNF and IL-1 are thought to play an important role. In the present studies, we examined the effect of picogram concentrations of endotoxin (LPS) on the synthesis of IL-1 beta and TNF alpha by human PBMC exposed to recombinant human C5a (rhuC5a). rhuC5a induced the synthesis of IL-1 beta by PBMC made in response to otherwise substimulatory levels of LPS. In the presence of rhuC5a, LPS concentrations from 10 pg to 1000 pg/ml substantially amplified IL-1 beta synthesis by PBMC compared to LPS alone. Since rhuC5a can induce transcription of IL-1 beta with minimal translation to cytokine protein, these studies support the concept that fM concentrations of LPS can combine with rhuC5a to provide the "second signal" for optimal translation of IL-1 beta mRNA.
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PMID:Picogram concentrations of endotoxin stimulate synthesis of IL-1 beta and TNF alpha by human peripheral blood mononuclear cells exposed to recombinant human C5a. 187 91

Adequate matching of the tissue O2 supply to the cellular O2 demands depends on the integrity of all components of the O2 transport system. The quality of O2 uptake by the lungs as well as O2 transport to the tissues can be assessed nowadays in the clinical setting. However, even if O2 uptake by the lungs and O2 transport to the tissues are normal cellular O2 supply may nevertheless be inadequate, if gas and substrate exchange are impaired on the tissue level. This may occur when nutritive blood flow is disturbed, as in patients with sepsis and ARDS. The hemodynamic monitoring parameters that are available in the clinical setting (i.e. systemic blood pressure, heart rate, cardiac filling pressures and art. blood gases) are only poor reflectors of the adequacy of tissue oxygenation. This review attempts to evaluate the extent to which the commonly measured hemodynamic variables relate to O2 transport and tissue oxygenation.
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PMID:[The clinical assessment of tissue oxygenation. The significance of hemodynamic and oxygen transport-related parameters]. 188 25


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