Lactate in sepsis: a Lactate in sepsis: a sign of feast or sign of feast or

famine?famine?

Association of Clinical BiochemistsAssociation of Clinical Biochemists

Southwest and Wessex RegionSouthwest and Wessex Region

SMA Hubble SMA Hubble

September 2007September 2007

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Septic ShockSeptic Shock

A 70 year lady (Mrs B) is admitted to A 70 year lady (Mrs B) is admitted to Intensive Care with severe pneumonia. She is Intensive Care with severe pneumonia. She is pyrexial, tachypnoeic, tachycardic and pyrexial, tachypnoeic, tachycardic and hypotensive. These are her blood results:hypotensive. These are her blood results:

pH 7.21pH 7.21

paO2 7.1kPapaO2 7.1kPa

pCO2 5.8 kPapCO2 5.8 kPa

HCO3 12 mmol/lHCO3 12 mmol/l

BE -12BE -12

Lactate 8 mmol/lLactate 8 mmol/l70-80% Mortality

OutlineOutline

What are the causes of raised lactate What are the causes of raised lactate in sepsis?in sepsis?

Is there any evidence of oxygen debt Is there any evidence of oxygen debt in resuscitated sepsis?in resuscitated sepsis?

Multi-organ failure…-Is it Multi-organ failure…-Is it microvascularmicrovascular or or mitochondrialmitochondrial dysfunction?dysfunction?

What’s all this about PARP?What’s all this about PARP? Can a lactic acidosis be protective?Can a lactic acidosis be protective?

““The difficulty lies, not in The difficulty lies, not in new ideas, but in escaping new ideas, but in escaping

the old ones…”the old ones…”

John Maynard Keynes 1933John Maynard Keynes 1933

History and backround of History and backround of lactate measurement.lactate measurement.

Initial experiments with animal models Initial experiments with animal models of circulatory shock. of circulatory shock.

Lactate as a poor prognostic marker in Lactate as a poor prognostic marker in other shock states.other shock states.

Oxygen delivery DOOxygen delivery DO2 2 vs Consumption vs Consumption VOVO22 graphs. graphs.

Below a critical oxygen delivery point, Below a critical oxygen delivery point, lactate values rose.lactate values rose.

Lactate as a sign of oxygen debt in Lactate as a sign of oxygen debt in humans.humans.

Oxygen consumption

Arterial O2 –

Venous O2 VO2 mls/min

Oxygen delivery

CO x arterial O2

content DO2 mls/min

300mls/min

Lactate

Critical DO2

History and backround of History and backround of lactate measurement.lactate measurement.

Shoemaker 1980’sShoemaker 1980’s ““Super-normal” goal oriented Super-normal” goal oriented

approach in high risk surgical approach in high risk surgical patients with high lactate patients with high lactate Shoemaker, Boyd 1993, Wilson 1999.Shoemaker, Boyd 1993, Wilson 1999.

Why “Super-normal” DO2 ?...Why “Super-normal” DO2 ?...

A nice theory…A nice theory…Oxygen

consumption VO2 mls/min

Oxygen

delivery DO2 mls/min

300mls/min

Lactate

Critical DO2

The reality…The reality…

Increasing oxygen delivery in septic Increasing oxygen delivery in septic patients does not improve outcome.patients does not improve outcome.

Too much inotropy kills patients.Too much inotropy kills patients. Increasing oxygen delivery in sepsis Increasing oxygen delivery in sepsis

does not lower arterial lactate levels.does not lower arterial lactate levels.

Septic shock is not the Septic shock is not the same as circulatory shock.same as circulatory shock.

Failure of supra-normal goal therapy Failure of supra-normal goal therapy in septic patients…Why?in septic patients…Why?

Difficulties demonstrating oxygen Difficulties demonstrating oxygen debt in sepsis.debt in sepsis.

Poor VOPoor VO22 rather than DO rather than DO22 may be may be the problemthe problem

Lactate metabolismLactate metabolism

Glucose

Pyruvate

Lactate

Oxidative phosphoryla

tion

2 ATP

36 ATP NAD+CO2+H2

O

O2 + NADH

Glycolysis

ADP

Cell Cytoplasm

Mitochondria

Oxygen

““A Tale of two lactates..”A Tale of two lactates..”B. MizockB. Mizock

ShockShock lactate and lactate and StressStress lactatelactate

New ideas…New ideas…

Evidence Evidence forfor Oxygen debt in Oxygen debt in sepsissepsis

Global Oxygen debtGlobal Oxygen debt Delayed or inadequate circulatory resuscitationDelayed or inadequate circulatory resuscitation Increased cellular metabolism.Increased cellular metabolism. Increased critical oxygen delivery point (cDOIncreased critical oxygen delivery point (cDO22) )

Rashkin, Haupt, GilbertRashkin, Haupt, Gilbert Regional oxygen debtRegional oxygen debt

Perfusion heterogeneity. Perfusion heterogeneity. Lang, Cryer, PowellLang, Cryer, Powell Microvascular disturbances, OPL techniques. Microvascular disturbances, OPL techniques. DeDe

BakkerBakker, , InceInce Covert oxygen debt in vulnerable tissues despite Covert oxygen debt in vulnerable tissues despite

normal DOnormal DO2 2 Gutierez, Thio, Vallet.Gutierez, Thio, Vallet.

““Shock lactate”Shock lactate”

Evidence Evidence againstagainst oxygen oxygen debt in sepsisdebt in sepsis

No relationship between SvO2 and lactateNo relationship between SvO2 and lactateKraft P et al. Chest 1993, Bakker J et al. Chest 1991Kraft P et al. Chest 1993, Bakker J et al. Chest 1991

Failure of goal directed therapy in non Failure of goal directed therapy in non surgical populations surgical populations Hayes 1994, Gattinoni 1995Hayes 1994, Gattinoni 1995

Lack of evidence of tissue hypoxia in Lack of evidence of tissue hypoxia in sepsissepsis [31P] MRS Intracellular ATP [31P] MRS Intracellular ATP Astiz, Jepsom, Pasque.Astiz, Jepsom, Pasque. [18F] Fluromisonidazole studies [18F] Fluromisonidazole studies Hotchkiss et al.Hotchkiss et al. gut mucosal and muscle pO2 gut mucosal and muscle pO2 Vandermeer and Sair Vandermeer and Sair

20012001

Mechanisms of Mechanisms of non-hypoxicnon-hypoxic lactate production in sepsislactate production in sepsis

Accelerated glycolysisAccelerated glycolysis Catacholamine mediated Catacholamine mediated

Via B2 adrenoreceptors of Na/K -ATP-ase Via B2 adrenoreceptors of Na/K -ATP-ase mediated stimulation of glycolysis mediated stimulation of glycolysis Liddell 1979, Liddell 1979, Bungaard 2003, Levy 2007 Bungaard 2003, Levy 2007

Increased cellular glucose uptake Increased cellular glucose uptake Zeller et al Zeller et al 19911991

Decreased PDH activity Decreased PDH activity Vary et al 1986Vary et al 1986

““Stress Lactate”Stress Lactate”

What’s the use of stress What’s the use of stress lactate?lactate?

Evidence of lactate as a mobile metabolite Evidence of lactate as a mobile metabolite for oxiation or recycling allowing ATP for oxiation or recycling allowing ATP provisionprovision

Signalling molecule involved in cellular Signalling molecule involved in cellular redox state and oxidative defenceredox state and oxidative defence

In sepsis, switch away from fatty acid In sepsis, switch away from fatty acid oxidation to glycolysis via lactate oxidation to glycolysis via lactate reconversion to pyruvatereconversion to pyruvate

Lactate is a myocardial fuel in shock statesLactate is a myocardial fuel in shock states ICI-118551 plus DCA worsened mycardial ICI-118551 plus DCA worsened mycardial

function and bioenergetic statusfunction and bioenergetic status

Lactate accumulation due Lactate accumulation due to mitochondrial to mitochondrial

dysfunctiondysfunction Evidence of mitochondrial Evidence of mitochondrial

dysfunctiondysfunction MechanismsMechanisms

Nitric oxide and peroxynitrite mediated Nitric oxide and peroxynitrite mediated inhibitioninhibition

Poly ADP-ribose …the “PARS” Poly ADP-ribose …the “PARS” hypothesis.hypothesis.

Chicken or Egg?Chicken or Egg?

Cytopathic HypoxiaCytopathic Hypoxia

Pyruvate

Lactate

NO

PerioxinitriteDNA breakage

PARP activation

NADH

Oxygen

Oxygen

Tissue lactate production Tissue lactate production and clearanceand clearance

MuscleMuscle Inflammatory cellsInflammatory cells Hepatosplanchnic regionHepatosplanchnic region LungLung Brain, myocardium and kidneyBrain, myocardium and kidney

Clinical implications of Clinical implications of elevated lactateelevated lactate

Prospective data collectionProspective data collection 240 consecutive admissions to Derriford ITU 240 consecutive admissions to Derriford ITU

(Jan –June 2003)(Jan –June 2003) Lactate at admission and lactate at 24 Lactate at admission and lactate at 24

hours.hours. APACHE II risk of Death score (ROD)APACHE II risk of Death score (ROD) ITU and Hospital mortalityITU and Hospital mortality Wilcoxon rank sum test to look for Wilcoxon rank sum test to look for

significant difference in lactate values significant difference in lactate values between survivors and non-survivorsbetween survivors and non-survivors

Area under ROC curves to test the Area under ROC curves to test the discrimination of lactate and/or APACHE discrimination of lactate and/or APACHE ROD between survivors and non survivorsROD between survivors and non survivors

ResultsResults

Overall intensive care mortality 29% Overall intensive care mortality 29% and hospital mortalities 35%.and hospital mortalities 35%.

Lactate on admission and lactate at 24 Lactate on admission and lactate at 24 hours significantly associated with ICU hours significantly associated with ICU mortality p=0.0002mortality p=0.0002

Which is the best discriminating test ?Which is the best discriminating test ? Lactate on admission, lactate at 24 hours, Lactate on admission, lactate at 24 hours,

APACHE ROD score, or a combination?APACHE ROD score, or a combination?

ResultsResults

Discharge Discharge Mortality Mortality rates %rates %

Admission Admission lactatelactate

24hr 24hr lactatelactate

50%50% 22 1.51.5

75%75% 55 3.63.6

80%80% 1111 n/an/a

Shock and Stress lactateShock and Stress lactate

Shock lactate

Stress lactate

Tissue hypoxia

yes no

Increased glycolysis

no yes

DO2 responsive

yes no

source Muscle, hepato-splanchnic

phagocytes

Time (hrs)

Mrs B’s

[Lactate] mmol/l

Future researchFuture research

Gold standard techniques for the Gold standard techniques for the investigation of mitochondrial, investigation of mitochondrial, cellular and tissue energy status.cellular and tissue energy status.

Resuscitation of the microvascular Resuscitation of the microvascular circulation.circulation.

Phase 1 trials of PARP inhibitors.Phase 1 trials of PARP inhibitors. Lactate into APACHE data-set.Lactate into APACHE data-set.

Lactate in Sepsis: “The Lactate in Sepsis: “The good, the bad and the good, the bad and the

ugly”..ugly”.. Shock lactateShock lactate may be may be “Good”“Good” because it is because it is

often treatable and helps guide often treatable and helps guide resuscitation.resuscitation.

Stress LactateStress Lactate is probably is probably “Bad”“Bad” because because although it may just reflect although it may just reflect hypermetabolism it is more likely a sign of hypermetabolism it is more likely a sign of microvascular or mitochondrial distress.microvascular or mitochondrial distress.

Usually there is a Usually there is a mixedmixed picturepicture…but if …but if lactate is still high at 24 hours, the lactate is still high at 24 hours, the prognosis is prognosis is “Ugly”.“Ugly”.