Brian Locke

Lactic Acidosis

In Sepsis

When does the body make lactate?

Glucose -> Glycolysis -> Pyruvate

Pyruvate can then go to two paths:

  1. Pyruvate -> Krebs Cycle (requires thiamine) -> Oxidative Phosphorylation
  2. Pyruvate -> Lactate -> Cori Cycle or conversion to bicarbonate

Path two is chosen when:

  1. There is no oxygen for oxidative phosphorylation (e.g. ischemic bowel). This is a marker of hypoperfusion. It is debated whether this contributes at all to lactate production in sepsis. This is the theory that early goal directed therapy is based on (and has subsequently failed to show benefit when compared to modern care that is targeted toward optimizing this).
  2. Metabolism is running so fast that glycolysis outpaces aerobic metabolism (e.g. you sprint). This is mediated by B2 adrenergic tone as part of the stress response (glucose increases for the same reason -> mobilize energy stores).

What is the evidence for this? beta-blockers lower lactate in sepsis, and albuterol/epinephrine raises lactate in asthma.

So, why is it called lactic acidosis?

The protons come from ATP hydrolysis. Most proper would be a hyperlactatemia and acidosis (or, sepsis associated lactatemia), but that's a mouthful. However, it's important to realize that the acidosis is correlated with the lactate, but that the lactate is actually working to buffer increased cellular metabolism (ATP hydrolosis).

Why does this matter? There is no harm from accumulation of lactate (e.g. in decreased clearance due to liver failure).

Why does the body make lactate?

Pyruvate + H --LDH--> Lactate -> Cori Cycle (call gluconeogenesis), or used by heart/brain as fuel (called cell-cell lactate shuttle), or conversion to bicarbonate

Thus, the creation of lactate is a buffer

Lactate + H = lactic acid. In LR, lactate (not lactic acid) is given.

pKa of lactic acid = 4. Thus, "lactic acid" doesn't really exist in the body (it is a strong ion). Lactate, paired with something else, does.

Why do we care about the lactate in sepsis?

It's a canary in the coal-mine (=miners would bring down birds that would die from toxic fumes before they did, thus indicating something was amiss. It's not the bird's death per se that matters, it's the bad thing that causes the bird to die).

Surviving Sepsis Campaign: within 3h - measure lactate, obtain blood cultures before abx, administer abx within an hour, give 30 ml/kg of crystalloid for hypotension or lactate over 4.

Based on observational data that folks who had lactate measured within 3 hours did better. Of course they did - they had other stuff done within 3 hours as well.

SEP-1 Federal Mandate: lactate measured within 3 hours in severe sepsis and septic shock. (effect of measuing the lactate? or a marker of better care? - there are almost no "tests" that reduce mortality - tests only influence outcomes based on the actions that result from that test).

New sepsis definition:

Lactate as a marker of physiologic stress and is correlated with severity of sepsis. Over 4-6.5 = bad for mortality. Yes, it's better to have it back to normal (lactate clearance in 6h is associated with good outcomes). But treatments that intervene to directly lower lactate (beta blockers, thiamine), or that seek to decrease lactate in the method not present (e.g. decreased perfusion - would expect blood transfusions to increase) have not been shown to help. It is a confounder to the real issue.

Why trend the lactate? If you're not sure the patient is under more or less physiologic stress based on your other clinical indicators.

Other resuscitation targets:

  • UOP, mentation (markers of organ function)
  • cap refill (measurement of output to area, not necessarily delivery of O2) [ ] JAMA paper
  • S[c]VO2 - though falsely high if impaired O2 use, microcirculatory shunting.

are often equally important to integrate (and SvO2 & lactate clearance are not goals in themselves)

How do you measure perfusion? Lactic acidosis can occur with any VO2/DO2 aka ScVO2 due to mal-distribution of blood flow.

Methods to help "clear the lactate"

Fluids

Consider: why does giving crystalloid fluids (which do not carry Oxygen) decrease lactate?

  • 1 possibility: the adrenergic activation is the major driver of the lactic acidosis, and it is lessened with volume expansion
  • another possibility: in increases the matching of delivery of blood to areas that were under perfused due to the body shunting blood to critical organs. (e.g. decreasing the perfusion mismatch in the body.. which ironically, might decrease the mixed venous oxygen saturation)
  • it may increase the cardiac output by more than it dilutes the hemoglobin (this would be the case if the heart is on the steep slope section of the frank-starling curve)

Vasopressors

  • interestingly, vasopressors ought to make lactic acidosis worse for the 2nd option, and better for the 1st and 3rd. Which occurs?

Answer: early vasopressors correct faster, as in the CENSER trial of early vasopressors vs fluids.

Instrumentalism

All our models are simplified. They are useful not as a reflection of reality, but if they help you remember to do things that are empirically supported. In support of this, consider that someone who actually studies this - much more details. E.g. EGDT based on the idea that it's a deliver of O2 problem.

What we know, we know from empirical studies.

Relatedly, the idea of the reification fallacy (defined as when an abstraction or construct is treated as if it were treated as if it were the thing itself. Also known as the fallacy of misplaced concreteness) pertains: we overly trust our model of lactate kinetics - but we should recognize that the simplified model of "fluids to restore perfusion" does not accurately represent what is going on. We are relying on the construct validity, which has to be demonstrated empirically. "All models are wrong, but some are useful".