TNF Binding Protein Prevents Hyperlactatemia and Inactivation of PDH Complex in Skeletal Muscle during Sepsis

Vary, Thomas C.; Hazen, Stacy A.; Maish, George O.; Cooney, Robert N.

doi:10.1006/jsre.1998.5324

Cited by 32 publications

(19 citation statements)

References 30 publications

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“…associated with increased lactate, and that, by blocking the sepsis-associated inhibition of PDH activity, lactate levels can be lowered (10). We also found an inverse correlation between PDH activity and lactate, suggesting that PDH activity may be a clinically relevant parameter.…”

Section: Brief Communicationsupporting

confidence: 50%

“…To elucidate a possible mechanism, Alamdari and colleagues showed an increase in the inactive form of PDH preceded by marked increases in inflammatory markers (including TNF and IL-6) in sepsis. Vary and colleagues provided further support for this relationship by demonstrating that infusions of a protein that binds TNF resulted in higher active PDH levels than in control subjects with sepsis not given the TNF inhibitor (10). Looking more globally at mitochondrial dysfunction, Karamercan and colleagues (11) found that traumatic stress resulted in reduced mitochondrial oxygen consumption (a surrogate of mitochondrial function) in all tissues, including PBMCs.…”

Section: Discussionmentioning

confidence: 98%

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Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Nuzzo¹,

Berg

Andersen

et al. 2015

Annals ATS

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Rationale: Rodent studies have shown that pyruvate dehydrogenase (PDH) levels are low in sepsis. This may cause cells to shift to anaerobic metabolism, resulting in increased lactate production. Alterations in PDH during sepsis have never been studied in humans.Objectives: The objective of this pilot study was to measure PDH activity and quantity in patients with severe sepsis. Methods:We conducted a pilot case-control study at a single urban tertiary care center. We compared PDH activity and quantity between patients with severe sepsis admitted to the intensive care unit and healthy control subjects. PDH activity and quantity were measured in isolated peripheral blood mononuclear cells. We measured PDH activity and quantity in control subjects at baseline and in patients with sepsis at 0 (baseline), 24, 48, and 72 hours. Measurements and Main Results:We enrolled 56 patients with sepsis and 20 control subjects with at least one blood sample being drawn from each patient. PDH activity and quantity in the sepsis group were significantly lower than the control group (P , 0.001). In multivariable linear regression adjusting for age, race, sex, and assay plate, the difference remained significant. Patients with sepsis who died had significantly lower PDH activity compared with those who survived (P = 0.03).Conclusions: PDH activity and quantity is decreased in peripheral blood mononuclear cells of humans with severe sepsis when compared with healthy control subjects, and may be associated with mortality. Whether decreased PDH activity plays a role in lactate metabolism or whether pharmacologic modification of PDH activity may improve outcomes remains unknown.

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Section: Brief Communicationsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 98%

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Nuzzo¹,

Berg

Andersen

et al. 2015

Annals ATS

View full text Add to dashboard Cite

show abstract

“…This may reflect a decreased peripheral metabolism of pyruvate as seen when the activity of the enzyme pyruvate dehydrogenase is impaired by tumour necrosis factor, for example in septic patients [38], also indicating that this increased lactate should not necessarily be taken as an indication of oxygen debt either in the skeletal muscle nor in the gut lumen, but rather altered lactate homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Rectal lactate levels in endoluminal microdialysate during routine coronary surgery*

et al. 2007

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SummaryThe aim of this prospective study was to determine the feasibility of intestinal endoluminal microdialysis as a new method for clinical monitoring of the adequacy of splanchnic perfusion in the large bowel. A microdialysis catheter for continuous lactate, glycerol, glucose and pyruvate measurements attached to a tonometric catheter was placed into the lumen of the recto-sigmoid junction prior to surgery in 13 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB). Lactate was also measured in blood and muscle. CPB was associated with a 10-fold increase in luminal lactate from 0.16 (0.01) to 1.67 (0.38) mmol.l )1 (p < 0.001). Muscular lactate increased from baseline levels 1.20 (0.21) to 1.77 (0.36) mmol.l )1 during CPB (p = 0.01), but the muscular lactate-pyruvate ratio remained unchanged. Arterial lactate increased only slightly from 0.9 (0.05) to 1.1 (0.06) mmol.l )1 (p = 0.027) during CPB. Increased lactate concentrations in the large bowel during CPB are suggestive of local lactate production consistent with impaired oxygen delivery. Intestinal endoluminal microdialysis is a potential clinically applicable method for monitoring intestinal metabolism. Combined with tonometry, microdialysis provides the opportunity to monitor both circulation and metabolism in the rectal mucosa. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of developing intestinal mucosal ischaemia, leading to disturbed mucosal integrity and increased intestinal permeability [1]. The latter may result in leakage of endotoxins into the circulation contributing to systemic inflammation observed during CPB [2]. The most likely cause of increased intestinal vascular permeability is imbalance between splanchnic oxygen supply and demand [3].There are currently few reliable methods available for monitoring adequacy of splanchnic perfusion during CPB. If available, these data could lead to strategies being developed to reduce intestinal ischaemia and the resulting increased mucosal permeability. Gastric tonometry is the only clinically available method that allows monitoring of gastro-intestinal perfusion. Even though in cardiac [4,5] and high-risk surgical patients [6] peri-operative tonometry-derived variables are predictive

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“…The cycle is a central pathway providing energy and maintaining the mitochondrial redox state. In sepsis, inhibition of pyruvate dehydrogenase limits pyruvate conversion to acetyl-coenzyme A, the main substrate of the cycle [58]. Furthermore, Weinberg and colleagues have shown that citric acid cycle intermediates may protect proximal tubules against injury and may promote recovery from sustained mitochondrial energetic deficit.…”

Section: Citratementioning

confidence: 99%

Clinical review: Anticoagulation for continuous renal replacement therapy - heparin or citrate?

2010

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Heparin is the most commonly prescribed anticoagulant for continuous renal replacement therapy. There is, however, increasing evidence questioning its safety, particularly in the critically ill. Heparin mainly confers its anticoagulant effect by binding to antithrombin. Heparin binds to numerous other proteins and cells as well, however, compromising its efficacy and safety. Owing to antithrombin consumption and degradation, and to the binding of heparin to acute phase proteins, and to apoptotic and necrotic cells, critical illness confers heparin resistance. The nonspecific binding of heparin further leads to an unpredictable interference with inflammation pathways, microcirculation and phagocytotic clearance of dead cells, with possible deleterious consequences for patients with sepsis and systemic inflammation. Regional anticoagulation with citrate does not increase the patient's risk of bleeding. The benefits of citrate further include a longer or similar circuit life, and possibly better patient and kidney survival. This needs to be confirmed in larger randomized controlled multicenter trials. The use of citrate might be associated with less inflammation and has useful bio-energetic implications. Citrate can, however, with inadequate use cause metabolic derangements. Full advantages of citrate can only be realized if its risks are well controlled. These observations suggest a greater role for citrate.

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TNF Binding Protein Prevents Hyperlactatemia and Inactivation of PDH Complex in Skeletal Muscle during Sepsis

Cited by 32 publications

References 30 publications

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Pyruvate Dehydrogenase Activity is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis: A Prospective Observational Trial

Rectal lactate levels in endoluminal microdialysate during routine coronary surgery*

Clinical review: Anticoagulation for continuous renal replacement therapy - heparin or citrate?

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