Lactate is GOOD for the patient and not BAD
It would appear that despite intense scientific inquiry most clinicians still believe that the Earth is flat and that an increased serum lactate is the result of impaired tissue oxygen delivery and anaerobic metabolism. This concept is perpetuated by The Surviving Sepsis Campaign who state “we suggest targeting resuscitation to normalize lactate in patients with elevated lactate levels AS A MARKER OF HYPOPERFUSION.” These concepts are WRONG.
The understanding of Lactate is shrouded with misconceptions and myths. These are briefly reviewed below.
- Humans are not yeast and rarely produce lactate anaerobically. It is widely regarded (and likely incorrect) that in the setting of sepsis, an increased lactate is a marker of impaired microcirculatory flow and anaerobic metabolism. There is however convincing clinical and experimental data that the increased lactate is as a result of increased B2 adrenergic activation (as part of the stress response) with greater production of pyruvate than can enter the Krebs cycle. Hence lactate accumulates aerobically (analogous situation to increased lactate production during exercise). B2 adrenergic stimulation increases glycogenolysis with increased production of glucose, which is then metabolized to pyruvate at a rate that exceeds its metabolic conversion in the Krebs cycle. This results in stress hyperglycemia and stress hyperlactemia. Both are evolutionary preserved responses which are designed to enhance survival during stress (and provide the vital organs with a source of fuel). Blocking these survival responses increases the risk of death during stress. It is likely that thiamine deficiency and decreased activity of pyruvate dehydrogenase (due to cytokines) further increase the likelihood of developing stress hyperlactemia. It has been demonstrated that the GLOBAL anaerobic threshold of adults is about 4mls/kg/min (JAMA 1993; 270;1724) and this threshold does not change with sepsis. In adults this translates into a hemoglobin of 4g/dl and a cardiac index of just over 1 L/minM2. This degree of impaired oxygen delivery is quite uncommon in critical illness and usually a pre-terminal event. From the above it is clear that the level of lactate is a measure of the degree of activation of the stress response (and serum catecholamine levels) and a prognostic marker. LACTATE IS GOOD FOR THE PATIENT AND NOT BAD.
- As a consequence of Myth No 1, it is widely believed that clinicians should increase oxygen delivery (DO2) in response to a high lactate. WRONG. The notion of increasing oxygen delivery to achieve some “magical target” DO2 or to achieve a certain central venous/mixed venous oxygen saturation or lactate concentration (or lactate clearance) has universally failed to improve patient outcomes. Gattonni et al demonstrated this over 20 years ago (NEJM 1995;333:1025). It is striking that in the b-blocker in sepsis study, treatment with a B1 antagonist (esmolol) decreased CI and DO2 was this associated with a more rapid clearance of lactate (JAMA 2013;310:1683). The only intervention that I am aware of that can actually decrease blood lactate level (and improve patient outcome) is the administration of thiamine (Crit Care Med 2016;44;360). Attempting to “titrate” therapy to a lactate level is as absurd as titrating treatment to a White Blood Cell count (WBC). However, in patients with localized lactate production (e.g ischemic bowel, ischemic limb etc) fixing the plumbing will reduce lactate levels and improve patient outcome.
- Probably one of the most remarkable of the Myths is the notion that the act of measuring lactate in and of itself improves patient outcomes. This concept is promoted by the Surviving Sepsis Campaign and is a core requirement of the SEP-1 Federal mandate. This concept is as absurd as suggesting that measuring a WBC improves the outcome of sepsis. While it is true that some studies have shown a lower mortality in patients in whom the lactate is measured within 3 hours (as opposed to later or never); this is not because measuring lactate improves outcome. It is simply a marker of better care. Measuring a blood lactate within 3 hours is a marker of more timely recognition of sepsis, receipt of antibiotics and earlier treatment.
- Lactate causes an acidosis. The conversion of pyruvate to lactate consumes rather than produces a hydrogen ion. Therefore lactate production retards, not causing an acidosis (Am J Physiol 2004;287: R502). The presence of an acidosis in many (not all) patients with an increased lactate is once again an association and not causal. The cause of the acidosis in these patients is not exactly clear; the hydrolysis of ATP has been one explanation that has been proposed.
- “Medical Fables” suggest that Ringers Lactate is contraindicated in patients with liver disease as this will cause a severe lactic acidosis. This is not correct; lactate is given as the base and not the acid and cannot cause an acidosis, rather, the opposite is true. The lactate is metabolized in the liver either by gluconeogenesis or oxidation with both reactions consuming a hydrogen ion. This has been demonstrated in both experimental models and clinical studies (even in presence of severe liver disease). In a murine model of acetaminophen toxicity LR has been demonstrated to improve liver recovery.(BMC Gasstroenerol 2011;11;125) In a hemorrhagic shock model LR as compared to NS was associated with less hepatic, renal and pulmonary injury (shock 2012;39268). Furthermore, LR has been reported to be safe in patients undergoing hepatectomy. Most specifically Goldstein evaluated the ability of dogs to handle a rapid infusion of Ringers lactate solution in the presence of severe hepatic injury. (Can J Surg 1972; 15:318). In this study they failed to demonstrate that exogenous lactate caused a prolonged or progressive elevation of arterial lactate in animals with a severe disturbance of hepatic function.
Paul Marik
Intensivist, Researcher, Myth-Buster, Status Quo Destabilizer
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Great explanations as always. I am sending the link to a lot of collegues, hoping that they read this stuff and correct their wrongdoings. As I am trying to correct mine. I mean ” his lactate was increasing, so i gave him 1 liter fluids”. I cannot hear that anymore. Small steps, small steps
Fantastic article, as always, Prof. Marik…. Allow me to add to the confusion of acidosis and lactate! In our zeal ( individual or state mandated) to optimize numbers and achieve “EUBOXIA”, we sometimes fail to distinguish between causation and association. I think, Lactate has been a victim of this misunderstanding for ever…. If you imagine Critical illness to be a condition of extreme cellular stress eating into the cell’s energy reserve, then you can imagine tons of ATP being hydrolyzed. Now, what we have forgotten is the truth, that ATP hydrolysis releases a proton every time. ( The inorganic phosphate and the phosphate groups on ATP and ADP are weakly acidic, and have pK values in the physiological range. The activities of the different forms will vary depending on the pH of the reaction medium, and this will alter the value for the free energy of hydrolysis of ATP • HATP3- ATP4- + H +; pK1′ = 6.95 • HADP2- ADP3- + H +; pK2′ = 6.88 • H2PO4- HPO42- + H +; pK3′ = 7.20 The effect of these pK values is that a H+ is released on ATP hydrolysis, with a stoichiometry which approaches 1 above pK3′. In… Read more »
In regards to the continuously painful Point 4 (oh, when will the myth-buster stop perpetrating new myths), I think you will find this NEJM letter elucidative; the 2nd author is a brilliant doc.
NEJM Letter
Thanks Scott: You may be correct, however, this is not as clear as many assume. I bit of a disagreement is a great way to generate discussion and for folks to think about the issue.. It certainly has generated some interest.
Changing your point 4 to:
While the anion lactate may cause acidosis, there is no indication that this acidosis is in any way deleterious. In fact, the body performs many functions in critical illness better in an acidotic milieu. It is very likely that when a patient has hemodynamic decompensation and lactic acidosis, that the latter is a marker rather than the cause. Marathoners become profoundly acidotic as a result of elevated lactate, which leads to superior rather than deteriorating performance.
would make you unassailable.
Scott,
I’m surprised you don’t have more comments about Dr. Marik’s point #3 on the SEP-1 Federal mandate, In my sepsis lecture to our incoming interns, I borrow concepts/history and reference your Emerg Med Clin North AM 2017 article: https://www.ncbi.nlm.nih.gov/pubmed/27908335
-Jason
measuring lactate per se has no beneficial effects if you were going to admit the pt to the same level of care regardless of the value. if a lactate of 6 got a borderline patient to a monitored setting rather than a floor, then it has value–i think most preventable septic deaths are from blood pressure swings in patients who are not being carefully watched. Otherwise, lactate has no great value. Lactate clearance is likely another marker rather than something we accomplish through fluids, etc.
Scott: This is complicated and since I don’t pretend to be a biochemist I struggle with this. However two lines of reasoning question the lactate acidosis theme. .Firstly, if lactate was the source of Hydrogen ions there would be a good relationship between lactate concentration and pH, BE, bicarbonate, etc; such a relationship simply does not exist. Secondly, it is now widely believed that excessive B2 stimulation underlies the increased production of lactate. In a prospective study, Lewis administered B2 agonists to a cohort of asthmatic patients who were not hypoxic or hemodynamically unstable. (Chest 2014;145:53). In this study the lactate increased significantly from 2.05 to 2.94 mmol/L whereas the bicarbonate was unchanged.
Relationship between base excess and lactate in an in vitro experiment
https://www.researchgate.net/profile/Thomas_Morgan4/publication/7179650_Hyperlactaemia_without_acidosis_-_an_investigation_using_an_in_vitro_model/links/02e7e529d12c7d5441000000.pdf
Unable to read that link :/
Paul. I am happy to sit down with you and explain the P-chem of acid base or I have the 6 part series here on the site, but honestly Dr. Bellomo or Dr. Kellum can do a far better job than I can.
I don’t even know what to do with this: “…would be a good relationship between lactate concentration and pH, BE, bicarbonate”
there is a mathematically precise, consistent relationship between all of these, demonstrated in vitro and in vivo. To understand the relationship requires a ton of variables. If you want to read the proofs, Kellum’s reworking of Stewart’s textbook has all of them. Saying I gave lactate but the pH stayed the same so lactate doesn’t cause acidosis is to ignore the 100’s of other interactions that separate those two things.
The chest study you quote above has a lactate increase of 0.94 and a bicarb decrease of 0.7, which would be proof of the opposite point for which it was quoted even if we want to ignore all of the aforementioned other variables that could leave bicarb unchanged with a rising lactate.
Thanks for that wonderful article! Hope those myths are getting busted soon.
Regarding Lactate and metabolic acidosis: Could it be that the body‘s strong affection to be neutral leads to a downregulation of other anions, e.g. bicarbonate, or efflux of H+ to the extracellular space? and hence causing a acidosis?
Best regards,
SwissEMdoc
Thank you for this article. But I have some comments:
-I don’t agree with your 2nd mythbust: optimizing cardiac output has been shown to improve patients outcome (http://journals.lww.com/ccmjournal/Fulltext/2017/09000/Incorporating_Dynamic_Assessment_of_Fluid.15.aspx). Most of the studies in this meta-analysis includes patients scheduled for planned high risk surgery. But you cannot deny it!
-I don’t agree with your 5th mythbust: in all experimental studies using lactic acid infusion, animals become acidotic. Peter A Steward explained this very well in 1983: lactate is a strong anion!
Remi: Thanks for your comments. Yes you are correct. Pre-operative optimization of cardiac output improves the outcome of high risk surgical patients. I was particularly referring to driving up oxygen delivery in critically ill patients, particularly those with sepsis.
As regards the second point, multiple experimental and clinical studies have all demonstrated that Ringers Lactate increases pH as compared to other resuscitation fluids. .
Thank you for your answer. Sorry I was talking about the 4th point and not the 5th.
I totally agree that balanced cristalloid causes causes less acidemia than normal saline.
Sorry, but it is Gattinoni.
I think in the big picture, Lactate is the marker that body need help. It may be the maker of reduction of DO2, it can be a increasing of production of Pyruvate. Your Claims give to me more concept how and what we should do when we get result of lactate. I still agree with SSC for lactate is one of parameter to estimate the outcome of patient. But we need more information, not just only lactate. -> Lactate may be the meaning of ” I need help” when the body of patient cannot resolve the “Problem”. Nice article, great concept, Thank you for the acticle !
Love these reads based in solid basic science applied to the bedside. Is it possible the excess pyruvate leads to increased gluconeogenesis as another source for hyperglycemia in the stress response?
Yes. Hyperglycemia and hyper-lactemia are intimately linked via multiple pathways.
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So, for clinical practice and those who like protocols – are you saying that in the presence of a high lactate, we should be looking for a cause of physiological stress? And if that stress is perhaps not life threatening, we should not really take the lactate into account?
Example, had a elderly patient today with a lactate of 2.8, rising to 3.5 two hours later. CT confirmed Cholecystitis. hameodynamically stable, appears well. Everyone here in a panic about the rising lactate and fixing tissue hypoxia.
I guess my question is: If lactate is a good thing, should we ignore the high value and instead just ensure there is not a serious physiological stressor as the cause of it?
Mars: Good question. Lactate is a marker of illness severity and is due to metabolic failure and not tissue/cellular hypoxia. Please refer to my recent editorials in Critical Care Medicine. Increasing oxygen delivery does not lower lactate in patients with sepsis; this has been demonstrated multiple times over the last 3 decades. The only interventions which have been shown to decrease lactate in sepsis are thiamine alone or as part of the Hydrocortisone -Vitamin C- Thiamine (HAT) metabolic resuscitation protocol. See also: https://www.preprints.org/manuscript/201810.0285/v1