Schrodinger’s Lactate by Jake Good
Schrodinger’s Law is a law of physics that states that subatomic particles can exist in two states simultaneously until acted upon by an external force. Take, for example, the analogy of the plates:
These plates exist in both a broken and un-broken state, simultaneously. Which state the plates end up in depends on what we observe when the cabinet opens (the external force). Schrodinger’s law applies to subatomic particles, plates, cats and even lactate in sepsis!
The ambiguity surrounding lactate in sepsis has led many to doubt its clinical utility. Sepsis-3 authors note that hyperlactatemia is a marker of illness severity, has been correlated with higher mortality, and includes lactate levels in their clinical criteria for septic shock (Singer et. al., 2016). The 2018 Surviving Sepsis Campaign Bundle cites lactate as being a poor indicator of overall tissue perfusion but also shows correlation with higher mortality rates.
The confusion in regard to lactate’s clinical utility is dichotomous: Evidence continues to show its poor relationship to perfusion but continues to be utilized in diagnostic criteria of septic shock. It is this state of ambiguity that leads me to believe lactate exists in Schrodinger’s realm!
How does Lactate become elevated?
In a normal, healthy adult, glucose is converted to pyruvate through the process of glycolysis. It is then converted to Acetyl-CoA via pyruvate dehydrogenase (PDH) where it ends up in the abyss of the Krebs Cycle we love so much. When our bodies become stressed via infection or catecholamine surge, we begin to produce more lactate.
Think of it in this fashion: As our bodies become stressed, we overload the pyruvate to Acetyl-CoA pathway. This is like a bathtub that is overflowing with water. We have a finite amount of water in the tub (pyruvate) and a small drain to facilitate movement of that water out (the PDH). When we overload this tub, the water that spills out to the top of the tub is converted to lactate when it hits the bathroom floor.
Following thus far?
The body converts this overflowing pyruvate to lactate because lactate is a better intermediate fuel than fatty acids in high stress states (Chatham, 2002). When our body begins to produce lactate, it is important to recall that water is still draining from the bottom of the tub and some pyruvate is still entering the krebs cycle.
The notion that lactate production is increased due to a shift from aerobic metabolism to anaerobic metabolism has been called into question. In the Grocott et. al Everest study, climbers at 8400 meters showed to have a PaO2 of 24.6mmHg while maintaining a lactate of 2.2mmol/L. Similarly, Richardson et. al., published a study looking at skeletal muscle oxygen levels and corresponding lactate during exercise. They found that despite increasing lactate efflux (lactate conversion to glucose), the oxygen concentration remained unchanged.
The bottom line: Lactate is independent of oxygen concentration. Lactate becomes elevated as the stress on our body demands more than the supply of glucose. The body responds by filling our tub with as much pyruvate as possible to facilitate conversion via Dr. Glaucomflecken’s favorite Krebs cycle (shameless celeb plug). However, the path to the Kreb’s cycle is only a small drain at the bottom of the tub and as the pyruvate water overflows, we get conversion to lactate as an intermediate fuel source.
So what causes the acidosis??
This is an overwhelming and complex topic engrained deep into biochemistry. So, without getting too “into the weeds”, the answer is simple: breakdown of ATP yields three products:
It is the release of the hydrogen ion that results in the acidosis, not the lactate! As our bodies become more stressed, we exhaust our ATP fuel source. As a result, we release more of this hydrogen into our system. Our rising lactate has no net contribution to our pH or acid status — Remember, pH is a “percent of hydrogen”, not a “percent of lactate”. The rising lactate is nothing more than an innocent bystander. (Steven Curry, MD & Robergs, PhD, 2020).
But is lactate JUST an innocent bystander?
We now understand that lactate is not responsible for the acidosis in our septic patients, hydrolysis of ATP is. However, lactate does serve a role beyond just by-standing innocently: Lactate is re-converted back to pyruvate in the liver, then to glucose. This is known as the Cori Cycle.
The process by which lactate is converted back to pyruvate in the liver is mediated by the enzyme— lactate dehydrogenase (LDH). In order to fuel this reaction, LDH actually consumes two hydrogen ions out of our system (Robergs et. al., 2004). So if LDH consumes two hydrogen ions (our acid), lactate conversion to pyruvate actually slows down the acidosis!
Looking deeper into the physiology of lactate as a fuel source, lactate is a compensatory mechanism to stress. Levy et. al., evaluated myocardial output and energetics of rat hearts when lactate was deprived from myocardial tissue in states of stress. They found a severely depressed myocardial state when lactate was removed as a fuel source. In humans, lactate infusion in post-CABG patients actually improved cardiac performance and cardiac output (Nalos et. al., 2014).
What are the clinical implications of Schrodinger’s Lactate??
Lactate is not always a marker of tissue perfusion — We now understand that the acidosis in sepsis is due in large part to the hydrolysis of ATP. However, during this stressed state of sepsis, our pyruvate “tub” overflows into lactate production as an intermediate fuel source.
Lactate is no longer the gold standard of end organ perfusion. When our “tub” overflows BOTH lactate and ATP from the krebs cycle are being produced. It is not as binary as simply being anaerobic versus aerobic metabolism. However, lactate does offer some clinical utility as it is a marker for overall stress response and may guide therapeutic decision making. Lactate is also an intermediate fuel source and actually slows the acidosis process down.
Lactate can be a helpful clinical tool as well as a misleading tool, hence why I consider it Schrodinger’s Lactate. Interpretation depends on using good clinical judgement sprinkled in with a few principles of Biochemistry that I hope to have made bit clearer to you in this blog post!
Chatham, J. C. (2002). Lactate - the forgotten fuel! The Journal of Physiology, 542(2), 333–333. https://doi.org/10.1113/jphysiol.2002.020974 In high stress states, lactate was consumed more than fatty acids in regards to cardiac fuel.
Grocott, M. P. W., Martin, D. S., Levett, D. Z. H., McMorrow, R., Windsor, J., & Montgomery, H. E. (2009). Arterial Blood Gases and Oxygen Content in Climbers on Mount Everest. New England Journal of Medicine, 360(2), 140–149. https://doi.org/10.1056/nejmoa0801581 Sampled PaO2 values of Everest climbers at 8400 m. It showed a PaO2 of extreme hypoxemia at 24.6, however a lactate remained at 2.2.
Levy, B., Mansart, A., Montemont, C., Gibot, S., Mallie, J.-P., Regnault, V., Lecompte, T., & Lacolley, P. (2007). Myocardial lactate deprivation is associated with decreased cardiovascular performance, decreased myocardial energetics, and early death in endotoxic shock. Intensive Care Medicine, 33(3), 495–502. https://doi.org/10.1007/s00134-006-0523-9
Myocardial lactate deprivation led to decrease cardiac function and cardiac output.
Nalos, M., Leverve, X., Huang, S., Weisbrodt, L., Parkin, R., Seppelt, I., Ting, I., & Mclean, A. (2014). Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Critical Care (London, England), 18(2), R48. https://doi.org/10.1186/cc13793
In humans, lactate infusion improves cardiac performance in the post-CABG patient.
Richardson, R. S., Noyszewski, E. A., Leigh, J. S., & Wagner, P. D. (1998). Lactate efflux from exercising human skeletal muscle: role of intracellular P O 2. Journal of Applied Physiology, 85(2), 627–634. https://doi.org/10.1152/jappl.19188.8.131.527
Study from exercise physiology showing that oxygen levels remained unchanged despite an increase in lactate efflux and no net change in arterial lactate concentration.
Robergs, R. A., Ghiasvand, F., & Parker, D. (2004). Biochemistry of exercise-induced metabolic acidosis. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 287(3), R502–R516. https://doi.org/10.1152/ajpregu.00114.2004 Lactate consumed hydrogen as LDH converts back to pyruvate.
Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J.-D., Coopersmith, C. M., Hotchkiss, R. S., Levy, M. M., Marshall, J. C., Martin, G. S., Opal, S. M., Rubenfeld, G. D., van der Poll, T., Vincent, J.-L., & Angus, D. C. (2016). The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315(8), 801. https://doi.org/10.1001/jama.2016.0287 Sepsis 3 and lactate clinical criteria.
Steven Curry, MD, & Robergs, PhD, R. (2020, July 24). Tox and Hound - Fellow Friday - Whence the Protons of Lactic Acidosis? EMCrit Project. https://emcrit.org/toxhound/ff-lactic-acidosis/ Majority of acidosis from “lactic acidosis” is derived from ATP hydrolysis and release of hydrogen ions.
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