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Lactate in sepsis: a sign of feast or famine?

Lactate in sepsis: a sign of feast or famine?. Association of Clinical Biochemists Southwest and Wessex Region SMA Hubble September 2007. _______________________________________ _______________________________________ _______________________________________

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Lactate in sepsis: a sign of feast or famine?

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  1. Lactate in sepsis: a sign of feast or famine? Association of Clinical Biochemists Southwest and Wessex Region SMA Hubble September 2007

  2. _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________ _______________________________________

  3. Septic Shock A 70 year lady (Mrs B) is admitted to Intensive Care with severe pneumonia. She is pyrexial, tachypnoeic, tachycardic and hypotensive. These are her blood results: pH 7.21 paO2 7.1kPa pCO2 5.8 kPa HCO3 12 mmol/l BE -12 Lactate 8 mmol/l 70-80% Mortality

  4. Outline • What are the causes of raised lactate in sepsis? • Is there any evidence of oxygen debt in resuscitated sepsis? • Multi-organ failure…-Is it microvascular or mitochondrial dysfunction? • What’s all this about PARP? • Can a lactic acidosis be protective?

  5. “The difficulty lies, not in new ideas, but in escaping the old ones…” John Maynard Keynes 1933

  6. History and backround of lactate measurement. • Initial experiments with animal models of circulatory shock. • Lactate as a poor prognostic marker in other shock states. • Oxygen delivery DO2 vs Consumption VO2 graphs. • Below a critical oxygen delivery point, lactate values rose. • Lactate as a sign of oxygen debt in humans.

  7. Oxygen consumption Arterial O2 – Venous O2 VO2 mls/min Critical DO2 Oxygen debt Lactate Oxygen delivery CO x arterial O2 content DO2 mls/min 300mls/min

  8. History and backround of lactate measurement. • Shoemaker 1980’s • “Super-normal” goal oriented approach in high risk surgical patients with high lactate Shoemaker, Boyd 1993, Wilson 1999. • Why “Super-normal” DO2 ?...

  9. A nice theory… Oxygen consumption VO2 mls/min Critical DO2 Oxygen debt Lactate Oxygen delivery DO2 mls/min 300mls/min

  10. The reality… • Increasing oxygen delivery in septic patients does not improve outcome. • Too much inotropy kills patients. • Increasing oxygen delivery in sepsis does not lower arterial lactate levels.

  11. Septic shock is not the same as circulatory shock. • Failure of supra-normal goal therapy in septic patients…Why? • Difficulties demonstrating oxygen debt in sepsis. • Poor VO2 rather than DO2 may be the problem

  12. Lactate metabolism CellCytoplasm Glucose ADP Glycolysis 2 ATP Lactate Pyruvate Oxygen O2 + NADH Oxidative phosphorylation 36 ATP NAD+CO2+H2O Mitochondria

  13. “A Tale of two lactates..”B. MizockShock lactate and Stress lactate

  14. New ideas…

  15. Evidence forOxygen debt in sepsis • Global Oxygen debt • Delayed or inadequate circulatory resuscitation • Increased cellular metabolism. • Increased critical oxygen delivery point (cDO2) Rashkin, Haupt, Gilbert • Regional oxygen debt • Perfusion heterogeneity. Lang, Cryer, Powell • Microvascular disturbances, OPL techniques. DeBakker, Ince • Covert oxygen debt in vulnerable tissues despite normal DO2 Gutierez, Thio, Vallet. “Shock lactate”

  16. Evidence against oxygen debt in sepsis • No relationship between SvO2 and lactate Kraft P et al. Chest 1993, Bakker J et al. Chest 1991 • Failure of goal directed therapy in non surgical populations Hayes 1994, Gattinoni 1995 • Lack of evidence of tissue hypoxia in sepsis • [31P] MRS Intracellular ATP Astiz, Jepsom, Pasque. • [18F] Fluromisonidazole studies Hotchkiss et al. • gut mucosal and muscle pO2 Vandermeer and Sair 2001

  17. Mechanisms of non-hypoxic lactate production in sepsis • Accelerated glycolysis • Catacholamine mediated • Via B2 adrenoreceptors of Na/K -ATP-ase mediated stimulation of glycolysis Liddell 1979, Bungaard 2003, Levy 2007 • Increased cellular glucose uptake Zeller et al 1991 • Decreased PDH activity Vary et al 1986 “Stress Lactate”

  18. What’s the use of stress lactate? • Evidence of lactate as a mobile metabolite for oxiation or recycling allowing ATP provision • Signalling molecule involved in cellular redox state and oxidative defence • In sepsis, switch away from fatty acid oxidation to glycolysis via lactate reconversion to pyruvate • Lactate is a myocardial fuel in shock states • ICI-118551 plus DCA worsened mycardial function and bioenergetic status

  19. Lactate accumulation due to mitochondrial dysfunction • Evidence of mitochondrial dysfunction • Mechanisms • Nitric oxide and peroxynitrite mediated inhibition • Poly ADP-ribose …the “PARS” hypothesis. • Chicken or Egg?

  20. Cytopathic Hypoxia Pyruvate Lactate Oxygen Perioxinitrite DNA breakage NO Oxygen PARP activation NADH

  21. Tissue lactate production and clearance • Muscle • Inflammatory cells • Hepatosplanchnic region • Lung • Brain, myocardium and kidney

  22. Clinical implications of elevated lactate • Prospective data collection • 240 consecutive admissions to Derriford ITU (Jan –June 2003) • Lactate at admission and lactate at 24 hours. • APACHE II risk of Death score (ROD) • ITU and Hospital mortality • Wilcoxon rank sum test to look for significant difference in lactate values between survivors and non-survivors • Area under ROC curves to test the discrimination of lactate and/or APACHE ROD between survivors and non survivors

  23. Results • Overall intensive care mortality 29% and hospital mortalities 35%. • Lactate on admission and lactate at 24 hours significantly associated with ICU mortality p=0.0002 • Which is the best discriminating test ? • Lactate on admission, lactate at 24 hours, APACHE ROD score, or a combination?

  24. Results

  25. Shock and Stress lactate Mrs B’s[Lactate] mmol/l Time (hrs)

  26. Future research • Gold standard techniques for the investigation of mitochondrial, cellular and tissue energy status. • Resuscitation of the microvascular circulation. • Phase 1 trials of PARP inhibitors. • Lactate into APACHE data-set.

  27. Lactate in Sepsis: “The good, the bad and the ugly”.. • Shock lactate may be “Good” because it is often treatable and helps guide resuscitation. • Stress Lactate is probably “Bad” because although it may just reflect hypermetabolism it is more likely a sign of microvascular or mitochondrial distress. • Usually there is a mixedpicture…but if lactate is still high at 24 hours, the prognosis is “Ugly”.

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