Lactate in sepsis: a sign of feast or famine?

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Lactate in sepsis: a sign of feast or famine?. Association of Clinical Biochemists Southwest and Wessex Region SMA Hubble September 2007. _______________________________________ _______________________________________ _______________________________________
Lactate in sepsis: a sign of feast or famine?Association of Clinical BiochemistsSouthwest and Wessex RegionSMA Hubble September 2007_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Septic ShockA 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/l70-80% MortalityOutline
  • 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?
  • “The difficulty lies, not in new ideas, but in escaping the old ones…”John Maynard Keynes 1933History 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.
  • Oxygen consumptionArterial O2 – Venous O2VO2 mls/minCritical DO2Oxygen debtLactateOxygen deliveryCO x arterial O2 contentDO2 mls/min300mls/minHistory 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 ?...
  • A nice theory…Oxygen consumptionVO2 mls/minCritical DO2Oxygen debtLactateOxygen deliveryDO2 mls/min300mls/minThe 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.
  • 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
  • Lactate metabolismCellCytoplasmGlucoseADPGlycolysis2 ATPLactatePyruvateOxygenO2 + NADHOxidative phosphorylation36 ATP NAD+CO2+H2OMitochondria“A Tale of two lactates..”B. MizockShock lactate and Stress lactateNew ideas…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”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
  • 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”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
  • 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?
  • Cytopathic HypoxiaPyruvateLactateOxygenPerioxinitriteDNA breakageNOOxygenPARP activationNADHTissue lactate production and clearance
  • Muscle
  • Inflammatory cells
  • Hepatosplanchnic region
  • Lung
  • Brain, myocardium and kidney
  • 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
  • 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?
  • ResultsShock and Stress lactateMrs B’s[Lactate] mmol/lTime (hrs)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.
  • 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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