Thread by @aryadoctoryet

Alright #medtwitter, #medstudenttwitter, & #CriticalCare, today’s #tweetorial is on the ever challenging and misinterpreted lactate!

So, what does lactate most appropriately represent?

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If you’re like me, you had lactate = anaerobic respiration = hypoxia drilled into your head.

First, is this real? And then, most importantly, is this clinically relevant?

To unravel this mystery-we need to know where lactate comes from!

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Lactate is made in the cytoplasm according to this reaction:

ncbi.nlm.nih.gov/pmc/articles/P…

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Remember in mitochondria, OXIDATIVE phosphorylation (to make ATP) takes place! Meaning, since oxidiziation is LOSING electrons, NADH goes to NAD+ and we get a bunch of ATP!

In hypoxia, the NADH to NAD+ ratio increases because the powerhouse of the cell can’t oxidize!

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This shifts our equation to the right, generating lactate!

So, hypoxia DOES generate lactate biochemically, but...does this happen clinically the same way?

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According to multiple studies, almost assuredly not!

In fact, according to this study, in patients w/ elevated lactate, there is evidence for hypoxia in only the MINORITY of cases!

ncbi.nlm.nih.gov/m/pubmed/30985…

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Similarly, if hypoxia was causing an elevated lactate, we would expect some “threshold” of hypoxia to start correlating with our elevation in lactate, but this correlation DOES NOT EXIST!

ncbi.nlm.nih.gov/m/pubmed/33710…

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So, where the $*@k is lactate coming from and what does it mean?

My favorite clue comes from what is known as the “Lactate Paradox.”

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The Lactate Paradox was named after an observation that healthy men exerting maximal effort at hypoxic high-altitudes had LOWER blood lactate levels than when at sea-level doing the same thing!

ncbi.nlm.nih.gov/m/pubmed/29617…

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So what WAS different in these two groups as it relates to lactate?

At high altitude, the energy expenditure of these men was lower due to reduced exercise power outputs!

So power and lactate seem to be related...

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An obvious power source is glycolysis, only, as we now understand, AEROBIC glycolysis!

How? Well, glycolysis results in pyruvate! Remember our equation from earlier?

Physiologically, the equation is in balance with the lactate: pyruvate ratio at 10:1.

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So, if we have processes that result in more glycolysis, we get more pyruvate, and subsequently more lactate! All with plenty of oxygen around!

So, why would our body increase glycolysis...?

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Because of stress!

We know b2 agonism, aka catecholaminergic agonism, increases glycolysis (to make ATP).

This b2 agonism ALSO activates Na/K pumps that consume the glycolysis ATP, making ADP, further increasing the need for glycolysis.

⬆️glycolysis = ⬆️pyruvate = ⬆️lactate.

Levy et al. postulated that shock/stress state -> epinephrine -> Na/K agonism -> glycolysis -> increase lactate. So, to test this, they used ouabain, a Na/K pump inhibitor!

What did they find?

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They found that by BLOCKING the Na/K pump activity, which is fundamental to sympathetic glycolysis, they could STOP lactate production!

Meaning, physiologic stress causes lactate elevations clinically INDEPENDENT of hypoxia!

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ncbi.nlm.nih.gov/m/pubmed/16810…

Why would increasing lactate in stress states be of use?

This is where the “lactate shuttle” hypothesis comes in. It’s complex, but ultimately, the idea is that lactate helps mobilize “slow” energy via the Cori cycle (AHH THE CYCLES RETURN!).

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Lactate in the liver becomes glucose utilizing energy from the beta oxidation of fatty acids (slow energy)!

This glucose is “fast” energy and can be used whenever/wherever and becomes ESPECIALLY important in stressed states!

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This is why you should stop your Lacto-Bolo Reflex! (@EMNerd_)

Lactate is NOT INHERENTLY hypoxia related so attempts at increasing tissue oxygenation if hypoxia is not the stressor are likely to result in HARM!

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jtd.amegroups.com/article/view/3…

So, to recap:

- lactate CAN be generated from hypoxic anaerobic metabolism, but this doesn’t appear to be valuable clinically

- lactate is more likely to represent increased physiological stress! Mechanistically, it’s why we see increases in lactate when we give albuterol!

- lactate is a valuable molecule helping our bodies mobilize “slow” energy from fat into “fast” energy as glucose, and this is especially important is acute stress states!

- an elevated lactate should alert you to physiologic stress, be broad in your approach! Don’t lacto-bolo!