Lactic Acid/Lactate in Sepsis & the Critically Ill: The Ultimate Guide

This post will be a compendium of all things and questions we ask ourselves regarding lactate/lactic acid in sepsis and other critically ill patients. We have become a culture where, as soon as a person even hints at being sick, we check a stat lactate/lactic acid. If we understand our enemy, we won’t be frightened by it. We are going to learn about lactic acid in sepsis and other pathologies. The objective is to maintain the respect of patients with an elevated lactate, but to understand where it comes from. Also, I would like to decouple the thought process where elevated lactate levels need IV fluids.

If you are interested in learning more about Resuscitation and Fluid Responsiveness, click here. I’d like to provide the disclaimer that this is not peer-reviewed. This is my opinion on lactic acid and sepsis. I have provided citations so you could double check my work. I am currently working on this and will continue to do so to provide you all with a living review of this incredibly important topic.

Disclaimer/What I am doing with this post?

None of this is medical advice. This is a work in progress. The citations are there for you to double check me and they will improve. The grammar will improve. Thanks for your patience and assistance in putting this all together. I wish I would have had a resource like this when I was training which motivated me to create it for you all. Last updated on 02/09/22.

If you find this blog post useful, and you want to cite it in your own work, please give me credit when credit is due.
Cite this post as: Eddy J. Gutierrez, “Lactic Acid/Lactate in Sepsis & the Critically Ill: The Ultimate Guide”, eddyjoemd blog, February 9, 2022. Available at:

Don’t fall into the sepsis + elevated lactic acid = fluids trap.

Ultimately, I do not want you to get trapped into what Rory Spiegel et al. calls the “lacto-bolo reflex”. They define that as “A well-known pathological reflex observed in the majority of house staff and a large portion of attending physicians.” Lactate or lactic acid is elevated, the patient gets a bolus of fluids. Don’t do that.

Why do we care about the pH/acidemia in our ICU patients?

We have learned that severe acidemia (pH<7.2) is associated with 57% mortality based on a study published by Jung and his team in 2011. They also found that the longer it took the patient to recover from their acidosis, the higher their mortality. Please don’t confuse this with the patients needing more fluids. I’ll get to more of that in a moment.

Why do we check lactate/lactic acid levels in patients with sepsis?

Elevated lactate levels are associated with increased mortality, but not causative per Mikkelsen et al. Yes, this is inarguable. Heck, their paper is even titled “Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock”. They looked at 830 ED patients in this cohort study with 28-day mortality as the primary outcome. The broke down lactate levels into three groups: low (<2), intermediate (2–3.9), or high (>4). Remember, these patients all had sepsis.

Even in patients without shock, the intermediate lactate levels (OR=2.05, p<0.024) and high serum lactate levels (OR=4.87, p<0.001) were associated with increased mortality. In patients with shock, patients with intermediate lactate levels (OR=3.27, p<0.022) and high serum lactate levels (OR=4.87, p<0.001) has higher odds of mortality. But this could be expected as they were in septic shock.

Although it is clear that an elevated lactate is associated with higher mortality, this does not mean it is causative. This also doesn’t mean that you have to drown the patients with fluids.

What does Lactate Clearance mean?

First of all, I personally struggle with what one means by lactate clearance. Do they mean that the kidneys and liver are making it go away faster than it is being produced? Do they mean that the body is producing less of it? Or is it a combination of the two? Either way the outcomes are not good if the patient does not “clear” their lactate.

Kattan and Hernandez best explained the conundrum of lactate clearance by stating that “the term clearance should be abandoned since the evolution of lactate levels over time reflects the balance between increased production, redistribution, and metabolism in shock states, and not only real clearance in kinetic terms”. I agree with these fine gentlemen.

Does Lactate “Clearance” mean improved outcomes?

A paper published my Nguyen et al that is NOT FREE looked at early lactate clearance in severe sepsis and septic shock. They defined lactate clearance as “lactate at ED presentation (hour 0) minus lactate at hour 6, divided by lactate at ED presentation, then multiplied by 100”.

They found that the higher the amount of “clearance”, the better the patients did in the first 6 hours. So if the lactate goes down, it’s much better than it going up or staying the same. Also, the faster the “clearance”, the better. As an aside, they found that the higher the lactate levels were on presentation, the worse the outcomes for the patient.

There are pitfalls, however, with using lactate clearance. Hernandez et al. published a paper explaining exactly that. Thankfully, it’s free to download. In that paper, they published a flowchart on the clinical use of increased lactate levels. I personally do not use dPCO2 (difference between central venous and arterial PCO2) in my practice and, unless there is a change in the data, never will. If you want to learn about SvO2 and ScVO2, CLICK HERE.

Is it really hypoxemia that elevates lactic acid?

When did the interest initially begin?

In 1961, Dr. Huckabee published a paper in the American Journal of Medicine stated “The biochemical cause of the accumulation of lactic acid appeared to be widespread tissue hypoxia, but the causes of such hypoxia remained obscure.” This was after looking at 9 ill patients.

Lactic acid as a prognostic factor: its birth

In 1970, Dr Max Harry Weil published a study on 142 who were in hemorrhagic shock. He and his team trended the lactate levels on the patient and were able to determine the probability of survival based on the numerical lactate level.

Recent “tissue hypoxia” data

It’s difficult to get upset at the whole “tissue hypoxia” myth that I am about to dispel when even as recently as 2014, the New England Journal of Medicine was publishing review articles by Dr Jeffrey Kraut who is an expert on the matter. This goes to show that we need to stay up to date with our information as we are learning so much.

Recent backtracking by the Surviving Sepsis Campaign in 2016 occurred where they stated that “Serum lactate is not a direct measure of tissue perfusion”.

Does an elevated lactic acid in sepsis or lactic acidosis really mean tissue hypoperfusion? I break down this data HERE.

Are lactate and lactic acid interchangeable terms?

For the sake of our vernacular, we use them interchangeably in our clinical practice. We are humans who are communicating. Ultimately, for the sake of scientific accuracy, they are not the same.

Lactate is a strong anion.
Lactic acidosis is the result of an accumulation of lactate and protons (H+).

Normal Lactate: <2mmol/L (0.5-1.8 mmol/L)
Hyperlactatemia: 2-4mmol/L
Lactic Acidosis: Lactate > 5mmol/L with metabolic acidosis

Where does Lactate come from?

Physiological conditions:
muscle (25%)
skin (25%)
brain (20%)
intestine (10%) 
red blood cells (20%)

Non-physiologic conditions:
a deficit in oxygen delivery (tissue hypoxia) 
impaired oxygen extraction
peripheral shunting
increased adrenergic stimulation

Is having a normal lactate the endpoint of Resuscitation?

UPDATED on 1/2/22: We get the warm and fuzzies when we have a critically ill patient who comes in with an elevated lactate and we watch as the lactate drops precipitously at the CMS mandatory 6 hour mark. But does that really mean the job is done when it comes to resuscitation? Is that an appropriate endpoint? Mok et al. consider that the normalization of lactate and blood pressure are not enough to declare the termination of resuscitation based on these two parameters. Instead, they mention that we should target capillary refill testing (which is described below) and elimination of mottling as well.

Lactic Acidosis: Causes/Differential Diagnosis

Click here to see a previous post of mine where I cover this topic more in detail.
If you want a list on things that can cause an elevated lactate/lactic acid that’s not just sepsis, here you go. This is not all encompassing. Notice that there are many things that cause an elevated lactic acid that is not sepsis.

  • cardiogenic shock
  • hypovolemic shock
  • severe trauma
  • sepsis
  • severe hypoxemia
  • carbon monoxide poisoning
  • severe anemia
  • vigorous exercise
  • seizures
  • shivering
  • cancer
  • liver disease
  • pheochromocytoma
  • metformin
  • cocaine
  • thiamine deficiency
  • propofol in cases of PRIS
  • beta-2 agonists like albuterol
  • cyanide
  • salicylates
  • propylene glycol
  • toxic alcohols such as methanol and ethylene glycol
  • source: Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371:2309–19.

Lactic acidosis and Lactate Levels cannot be corrected by Giving More Oxygen

Since many people are taught and trained that lactic acidosis occurs due to an oxygen deficiency causing anaerobic metabolism, then why not just more oxygen? This seems to be a logical thought process on the surface. It was put to the test by Ronco, et al in 1993. Their paper published in JAMA looked at what we could call a very small sample size by todays metrics. They documented several key findings:

1. “Critical O2 delivery was identified and is considerably lower than previously estimated. Increasing O2 delivery to supra-normal levels in critically ill patients in the hope of increasing O2 consumption may be inappropriate”.

2. Sepsis was not associated with an increased critical O2 delivery or impaired O2 extraction.

“Increased arterial lactate concentration was not associated with an increased critical O2 delivery or impaired tissue O2 extraction in our critically ill patients”

3. The increased concentration of arterial lactate at baseline was not associated with global tissue hypoxia, suggesting that lactate may not be a specific marker of tissue hypoxia in critically ill patients.

All in all, the authors concluded that the increase in lactate is not due to global tissue hypoxia.

Why does Epinephrine cause an elevated lactate?

Well, be aware that it’s not just epinephrine that does it. Norepinephrine, dopamine, dobutamine, and others all stimulate the beta-2 adrenoreceptors. This stimulation increased cAMP production. The cAMP turns on the Na+/K+ATPase pump. This Na+/K+ATPase pump chews up the ATP and produces ADP as a byproduct. This ADP reactivates glycolysis. Glycolysis, as we have discussed, generates pyruvate. Pyruvate generates lactate if there isn’t enough pyruvate dehydrogenase, thiamine deficiency, etc. Please let me know if this does not make sense.
Citation: Levy B. Curr Opin Crit Care. 2006.

Don’t forget that we produce epinephrine, norepinephrine, and dopamine endogenously in our adrenal glands. These all stimulate the beta-2 receptors. This means that when a patient shows up to the emergency room, their lactate could be part of their sympathetic response and not volume depletion.

Does an increased lactate caused by endogenous catecholamine production also reflect increased mortality?

One would think that if it’s “tissue hypoperfusion” that causes the elevated lactate then sure, one can expect an elevated mortality. But what about the increased lactate production from overstimulation of the beta-receptors in the cytosol by endogenous catecholamines such as epinephrine? Earlier this year (2021), Jagen et al. published a retrospective paper where they looked into this question. Now, their methodologies are worth debating because they used heart rate as a surrogate for endogenous catecholamine stimulation, but they found that regardless of the lactate level being elevated due to the repercussions of hypotension or endogenous catecholamine production, patients still did poorly with an elevated lactate. This further cements the concept that an elevated lactate is bad news regardless if it’s from endogenous catecholamine production or some other source.

Why does Albuterol cause an elevated lactate?

To prove my point further that not everything that causes an elevated lactate is sepsis, patients who come in with asthma exacerbations and receive albuterol nebulizations could also have an elevated lactate. Team, don’t forget that albuterol is a long beta-2 adrenergic receptor agonist. Like epinephrine, this can also cause an elevated lactate. That does not mean to treat it with 30cc/kg of fluids. I have seen this happen numerous times before, unfortunately.
Citation: Lewis L, et al. Chest. 2014.

Why does thiamine deficiency cause an elevated lactate and an increased likelihood of lactic acidosis?

Thiamine is a co-factor needed for the function of pyruvate dehydrogenase (PDH). Without PDH, pyruvate cannot be converted into acetyl-Co-A. Acetyl-Co-A likes to head down into the Krebs cycle where it makes a lovely 38 ATP (depending on your source). Without PDH the pyruvate turns the corner and turns into lactate. Definitely not as much ATP. Therefore, without thiamine, if the patient is in septic shock or whatnot, there’s a higher chance they’ll create lactate rather than acetyl-Co-A.

I have covered other things thiamine here.

Where is Lactate Metabolized?

Approximately 60% in the liver and 30% in the kidneys. The other 10% is in the brain, heart, and skeletal muscles.

In the liver, it could either go via the pyruvate pathway or the Cori cycle. In the former, it is transformed into oxaloacetate or alanine. The Cori Cycle is the place where it is used directly by the periportal hepatocytes. These produce glycogen and glucose.

If your patient is in renal failure and liver failure, don’t expect the lactate to be metabolized with any expediency.

Does Lactic Acid even produce Lactic Acidosis?

You may have heard this before but you have no idea what to do with it. Fortunately, there are people much smarter than I am who blew my mind with their findings regarding lactic acid and metabolic acidosis. I will just link their works here out of respect. Steven C. Curry, MD and Robert A Robergs, Ph.D. flex their big brains quite a bit here.

Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis?
Tox & Hound. EMCrit Blog. Published on July 24, 2020. Accessed on September 23rd 2020. Available at [ ].

Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis, Part II
Tox & Hound. EMCrit Blog. Published on August 14, 2020. Accessed on September 23rd 2020. Available at [ ].

Don’t give fluids just because the lactate/lactic acid is elevated.

This is how it goes in practice:
Nurse: lactate is higher than reference range
Clinician: (without assessing the patient) Give a fluid bolus.

Wait, WHAT?!?!? Whyyyy? 😫

This is something I routinely see today. I routinely saw it at the Ivory Tower where I trained in fellowship. I routinely did it myself when I was a young whipper snapper of a resident and didn’t know any better. Now, I’m here to tell you that you can do better.

I don’t blame you for doing this, though. You’ve seen other clinicians do it. Doctors and nurses were likely trained this way. When the lactate is high, page the doctor and expect an order for a fluid bolus. It makes one feel all warm and fuzzy inside like “I did something”. Everyone pats themselves on the back. Well I’m here to tell you that from now on, every time you do that, you’re more likely to be wrong in your management that right.

Spiegel, et al. describes the “lacto-bolus reflex”, i.e. to give a bolus of fluid for every elevated lactate. The authors of this paper are just as fed up about it as I am. IV fluid boluses are not benign. Fortunately, this article is completely free. It describes why the whole idea of patients developing a lactic acidosis due to cells not getting oxygen hypoperfusion is silly to the point where many of us need to be re-educated which is the intention of this page. I will admit, I had to be re-educated myself. I was not born knowing this stuff. Now I’m trying to do it right after doing it wrong.

The article is easy to read. It’s down in the citations for those of you who choose to dive further into it. Ultimately, they conclude that, although lactate levels are helpful for prognosis (plenty of data on that), and lactate not going away is helpful to know whether you have control of your patient or not, it ultimately does not help in any way, shape, or form, to guide fluid resuscitation.

Elevated Lactate/lactic acid in sepsis does not mean give more fluids: Diminishing returns.

There is a law of diminishing returns when resuscitating patients with bolus after bolus of IV fluids.

Yes, lactate decreased with additional boluses by 1.3% per every 7.5mg/kg increase in fluids making the numbers look pretty, but does that mean we’re treating the source of the lactate or are we just diluting it? A study by Liu, et al. shows that mortality actually increases as we keep providing more fluids.

I’m not saying that patients who have an elevated lactic acid in sepsis and septic shock do not need fluids. On the contrary, they need judicious use of IV fluids. 30cc/kg initial resuscitation is okay with me in the vast majority of patients. I had to read many articles to finally fall in line with that. Of course, there are several patient populations where I’m against it. For example, severe pulmonary hypertension patients with right hearts living on a tight rope. I digress. But tagging along with my prior commentary discussing giving fluid boluses reflexively, this study shows that fluids don’t really “clear” lactate in the way we all hope and want them to.

The correlation of having an elevated lactate to mortality is there. The correlation with more fluids making lactate decrease isn’t. The pathophysiology behind where lactate comes from explains why not. And as we all should know, fluids are not benign. The more fluids we give patients the higher the mortality per the 9000 patients in this study.
Citation: Liu V, et al. Ann Am Thorac Soc. 2013.

How Does Lactate Turn Into Lactic Acid?

You have NO IDEA how much I banged my head against my desk looking for the answer to the question: how does lactate turn into lactic acid? Well, after many hours of searching for an answer, and you can think I’m a dummy for not find the answer sooner or knowing it like a useless fact off of the top of my head, I FOUND IT! It’s honestly some information that’s not readily available. Many articles play it off and don’t mention specifics assuming that “it just happens”. I am by no means a biochemist. I’m simply trying to understand all this. In my explanation, I purposefully will be oversimplifying things.

Here’s how it works:
In the cytosol, pyruvate turns into lactate (rather than move towards acetyl-CoA) for a number of reasons, again that I’m not going to get into, via lactate dehydrogenase. That lactate (via shuttles) gets to the cytosol of the liver and kidneys where it eventually makes its way into the Cori/Lactic Acid Cycle. The Cori cycle eventually spits out glucose. So far so good, right? Glucose via glycolysis seems to be metabolized into lactate, ATP, and water. Said ATP gets hydrolyzed into ADP and inorganic phosphate which releases that very necessary proton (H+). When conditions get revved up, i.e. septic shock, and an excess of lactate is being produced, then the cell cannot handle the metabolism of lactate and guess what’s also being overproduced? Said H+ which tags onto the lactate creating lactic acid.

The articles I’ve read tend to say that you start running into lactic acidosis territory when you have a lactate of 5 with a concurrent acidosis (pH less than 7.35). 
Citation: Fall P, Szerlip H. Lactic acidosis: from sour milk to septic shock. J Intensive Care Med 2005; 20: 255-71.

Venous vs. Arterial Lactate/Lactic Acid samples

Click HERE to see the data behind checking arterial or venous samples for lactic acid.

Fresh arterial stick vs. a fresh peripheral stick.

van Tienhoven, et al found in 2019 that if the arterial lactate is negative, or to be exact ≤2mmol/l, then venous is between 97-100% sensitive. Pretty good in my book.

What if the patient has an arterial line?

Mahmoodpoor A, et al. looked at 100 patients by checking lactate levels at the start of resuscitation and 6 hours after. The team found that the venous lactate tended to be higher than the radial artery lactate by 0.684mmol/L. This article is taken apart in far more detail HERE.

What do I do in my practice?

Is a difference of 0.5mmol/L really going to change my management? Meh. I am in favor of checking venous lactate values simply because they cause less pain to the patient if they do not have an arterial line in place. I do not know the validity of this, but I have heard that certain iStat machines do not have a valid lactate assay. Some shops have stopped using the iSTAT machines at the bedside for lactate levels.

Does Using a Tourniquet increase Lactate levels?

The short answer is no, it does not. There are three studies published between 1997 and 2016 which all state in some way, shape, or form that the use of a tourniquet nor the time the tourniquet was on the patient affected the sample.

Gallagher EJ, et al. Ann Emerg Med. 1997.
Lavery RF, et al. J Am Coll Surg. 2000.
Balakrishnan, et al. CJEM. 2016.

Why do we transport the lactate/lactic acid samples on ice?

Your hospital may have a policy that states that lactate samples need to be sent down to the lab in a plastic ziplock bag sitting on ice. The theory and rationale behind that includes that the lower temperature will keep the erythrocytes from hemolyzing and therefore falsely elevating the lactate levels. I hate to get all biochem here but this may help you understand why. Erythrocytes, red blood cells, do not have mitochondria. They also cannot use oxygen to produce ATP. The RBCs produce lactate through glycolysis.

Jones, et al looked at 80 healthy patients in the ED and found that there was no difference in lactate levels whether the staff: placed the sample on ice, left the sample at room temperature, or used a tourniquet for 5 minutes and then placed the sample on ice. Seymour, et al found in healthy subjects (5) that lactate stored at room temperature were higher within both 5 and 10 minutes. This was statistically significant but ultimately it was a mean 0.36mmol/L. Is that going to change your management? Even at 30 minutes the difference wasn’t, in my opinion, management altering. Save the ice.

Can we treat lactic acidosis with bicarbonate?

There are several schools of thought when it comes to providing bicarbonate to patients who have an elevated lactate. There are those who say it causes harm, those who are indifferent, and those who say it’s beneficial. It is a pendulum of sorts that is now swinging in the direction of it being beneficial.

The anti-bicarbonate school of thought.

Based on the data I have found, this seems to be a pre-2000 school of thought. Stacpoole, et al. went on to say that “bicarbonate worsens rather than alleviates the metabolic and hemodynamic consequences”. Mathieu, et al. concluded in their study that “administration of sodium bicarbonate did not improve hemodynamic variables in patients with lactic acidosis”. This led to the eventual proclamation by Forsythe, et al in 2000 to state that “we do not give or advise bicarbonate infusion regardless of the pH”.

Possible negatives of providing bicarbonate to treat lactic acidosis.

We need to take into account from a physiologic perspective that providing bicarbonate causes an intracellular acidification. This is due to the accumulation of carbon dioxide. Then, in patients with circulatory failure, this carbon dioxide is not removed from the tissues and is not excreted by the lungs. This is something we need to consider in patients who receive bicarb pushes during ACLS. We feel like we are doing something but is it beneficial? In addition, there is a pH dependent decrease in ionized calcium levels. This causes hypocalcemia and a litany of other effects related to this.
Citation: Kraut JA, et al. NEJM. 2014.

The pro-bicarbonate swing of the pendulum.

Kraut, et al published in 2001 a rationale as to why we should consider providing bicarbonate to our patients with a lactic acidosis. They argued that administering “bicarbonate might prolong survival sufficiently to allow treatment of the underlying cause of lactic acidosis. In another paper published in 2012, their recommendations on the treatment of lactic acidosis included starting base therapy when the pH ≤ 7.10 or when the pH≤7.2 if the patient had underlying hemodynamic compromise.

It was unfortunate when in 2016, the Surviving Sepsis Campaign suggested “against the use of sodium bicarbonate therapy to improve hemodynamics or reduce vasopressor requirements”. Ultimately, there were no randomized clinical trials looking at this to my knowledge. Correct me if I’m wrong. I understand their point, though.

The BICAR-ICU Trial: can providing bicarbonate help in lactic acidosis?

Jaber, et al. published the BICAR-ICU trial in Lancet in 2018. I would like to make this perfectly clear, this article has many nuisances to it. Many limitations and different components that need to be dissected carefully. Please attempt to obtain it and read it for yourself as it does not provide a black and white response to the question: can we treat lactic acidosis with bicarb?

They took 389 patients in multiple center in France who were very sick, with a lactic acidosis, and randomized them to get either nothing or 4.2% bicarb gtt. When I say sick, I mean that more than 50% were in septic shock, 47% had acute kidney injury, they had a pH of less than 7.2. Remember what I mentioned earlier about patents with a pH of less than 7.2? Reminder: 57% of them die.

If you’re in the United States like I am, you may be scratching your head as to what 4.2% sodium bicarbonate infusion is. I know I was. You know those amps of bicarb you whip out during a code and push? Those are 8.4% sodium bicarb. They are 50mEq in 50ml=1mEq/ml. Consider the version of this study to be 25mEq in 50ml, or half the concentration of that ampule. This would help out with the hypernatremia effect of using the higher concentration.

The maximum amount of fluid these patients got was just one liter of 4.2% sodium bicarbonate. What they found that the bicarbonate infusion was “associated with an improved outcomes and a reduced rate of mortality” in patients who had acute kidney injury. The 28 day mortality of patients with AKIN score or 2-3 decreased from 63% to 46%. That equates to a number needed to treat of just 5.9.

There were several other positive secondary outcomes such as the decreased need for renal replacement therapy, when it was needed, it was later in the hospital course, and those in the bicarbonate group got off of vasopressors faster. I encourage you to read this article for yourself.

Some complications were noted but none that were life threatening. You need to take these things into account when administering bicarbonate infusions. Things such as metabolic alkalosis, hypernatremia, and hypocalcemia. That’s a pretty easy checklist in my opinion.

If you’re considering providing bicarbonate to a patient with a respiratory acidosis, however, please think twice and check out this article.

Does dialysis clear lactate/lactic acidosis?

Yes, dialysis does clear lactate, but it’s not all sunshine and roses. Unfortunately, in patients who have severe acidosis, the quantity cleared of lactate is less than the amount produced by the critically ill patient. Kraut, et al states that continuous dialysis is better than intermittent dialysis for lactic acidosis. Also, there are fewer adverse effects in patients with hemodynamic instability. Dialysis also has the bonus feature that it eliminates substances that create lactic acidosis such as metformin in the appropriate patient populations.

Does the Lactate in Lactated Ringer’s cause a lactic acidosis?

“Lactate in fluids, such as Ringer’s lactate, causes a lactic acidosis”. Ugh. How I cringe every time I hear or read that. You should take into account your patients organ failures since lactate is metabolized approximately 60% in the liver, 30% in the kidneys, and 10% elsewhere (including the heart, muscles, etc depending on your source). I noted this earlier in this post.

There’s no perfect trial to go ahead and prove this concept, but I have linked this study by Nalos, et al where they provided patients with a sodium lactate solution versus Hartmann’s solution, aka Ringers Lactate. To provide some context, LR provides the patient with Sodium Lactate, 28mmol/L to be exact. The half-molar Sodium Lactate solution described in this article has 504mmol/L of Sodium Lactate. I struggled quite a bit to find that concentration but thankfully I found it in a Spanish (Spain) article.

In that paper, the Sodium Lactate did not create an acidosis in any of the patient groups, on the contrary, they trended more so towards an alkalosis, even a statistically significant alkalosis in the case of the “lactate” group. Overall, there was no increase in lactate whatsoever in the LR group which means that there’s no “lactic acidosis” created by LR. It does not make patients acidotic. If you have a functioning liver and kidneys, that lactate is metabolized into bicarbonate. Hope that all makes sense.

Others have also looked into this. In 1997, Didwania et al found no difference after giving 1L to 24 healthy subjects. When given to patients receiving a renal transplant, Hadimioglu, et al. found that the lactate increased approximately 1.5mmol/L over the saline group when given Ringers Lactate. I must emphasize that although the lactate went up, the pH increased as well where it was 7.36 in the saline group and 7.42 in the LR group.

Shin, et al compared Ringers Lactate to Plasma-lyte in hepatectomy patients. They found that while there is an increase in lactate of approximately 1.1mmol/L, there was no difference in pH. Zitek, et al. randomized patents in the ED to receive 30cc/kg of either Lactated Ringers or 0.9% sodium chloride. There was no difference in the lactate levels between the two groups but the saline group did have larger declines in their pH attributed to the hyperchloremia.

All in all, you can see an elevation of the lactate but that does not mean lactic acidosis. This lactate elevation actually translates to an improved acid-base status by increasing the pH.

Checking Lactic Acid in Sepsis: Does it help?

Centers for Medicare and Medicaid Services (CMS) wants those of us practicing medicine in the United States to recheck lactate levels in those who are septic. As mentioned, having an elevated lactate is a bad sign, but does rechecking it or trending it make a difference? The short answer is yes, but it is my opinion that it is not because of the lactate itself.

In 2019, Chen et al. published a study that retrospectively looked at 2642 patients who had sepsis and a lactate greater than or equal to 2 after ICU admission. They wanted to see if checking the lactate within 1 hour of ICU admission changed their outcomes. They compared those patients (early lactate group) to those who had their lactate checked >1 hour after ICU admission (late lactate group). The authors did not mention if the lactate was checked on the ward or in the ED prior to ICU admission.

The patients who had an earlier lactate check did better! But why?

It turns out that the early lactate had vasopressors started earlier (2.6h vs. 4.2hr; p<0.0001) and they also had initial antibiotics started earlier (1.6h vs. 2.2h; p=0.014). To me, this means that the lactate level being elevated sounded a bell in the brain of the clinician and they said “oh, let’s do something about this”.

Out of all the parameters of the Surviving Sepsis Guidelines tell us to do, the one with the best evidence is to give antibiotics early. Patient gets better care, patient lives. That’s what it seems like to me. This is reflected in a lower mortality rate in the early lactate group as well (22.2% vs. 27.5%; p=0.026). The NNT to save a life with early lactate/lactic acid is 18.9. Basically, checking lactate levels sounded an alarm in the ears of clinicians that forced them to have some sort of therapeutic intervention. In other words, do something.

I broke down this study in more detail in THIS POST.

Does lactate clearance predict mortality?

Mahmoodpoor, et al. performed a prospective study of 100 patients who were in septic shock. They obtained lactate concentrations in these patients and assessed lactate clearance as a predictor for mortality. The lactate levels were checked 6 hours after establishing a baseline.

The authors performed receiver-operator characteristic (ROC) analysis for the lactate clearance. They found that the cutoff for predicting ICU mortality was 3.2mg/dL from arterial blood and 4.0mg/dL from venous blood. The cutoff value for lactate clearance that predicted ICU mortality most reliably was 20% within 6 hours of active resuscitation.

Combining a lactate > 3.2 mmol/L AND a lactate clearance <20% culminated in 100% of the patients who met those parameters dying. The area under the curve (AUC) was 0.905±0.038. That’s an outstanding AUC for those of you who are rusty on statistics.

Can we use something other the lactate and lactic acid to guide resuscitation?

Capillary Refill Time

Nurses, you see those orders. q1, q2, q4h lactates to help guide resuscitation in septic shock. You have to drop what you’re doing and draw labs. Hopefully, if the patient is sick enough to need the labs, they have a central line. Hold off of titrating drips, hold off on the ever important charting you are required to do, let’s trend lactates. Along the way we contribute to iatrogenic anemia, spend a bunch of lab money, etc.

What if there was another option? Well, the ANDROMEDA-SHOCK trial by Hernandez, et al. proves that you can intelligently resuscitate patients without checking lactate levels. What they did was randomize >400pts to either have their resuscitation guided by lactate or this nifty little trick called Capillary Refill Time.

One of my favorite parts of the trial wasn’t even the CRT vs. lactate component but their algorithm to determine fluid responsiveness which is a major interest of mine. I am not a fan of arbitrarily giving a pt liter after liter of fluid to “clear lactate” or improve the blood pressure. That just does not work and my body of work has data to prove that. I digress. Sometimes you need to read the supplementary materials in these articles as their algorithm was hidden in there.

Standard of care by CMS (the body that pays the hospitals and therefore us in the US) has mandated checking lactates despite no good evidence that trending it does much. This study shows that checking CRT is AT LEAST as good as checking lactate levels. The mortality was not statistically significant (p=0.06) but I wonder what would’ve happened if they would’ve had an additional 200pts in the trial.

The CRT group had 34.9% mortality vs 43.4% in the lactate group. The CRT group also had fewer organ failures (p=0.045). Other fun facts include the fact that the lactate group received more fluids in the first 8h (p=0.01) but not overall. I don’t know what to make of this. There was no difference in all the other secondary outcomes.

I personally like the capillary refill testing because its non-invasive, saves blood, saves money, and you get faster results. It does have its drawbacks, though. The clinician has to go to the bedside and actually do it. The results could be subjective. It is also influences by the degree of pressure applied as well as the ambient light and temperature.

Does a Prolonged Capillary Refill Predict Mortality in Shock?

In a study of 175 patient with septic shock, Morocho et al. analyzed the capillary refill time of these patients. The team collected the capillary refill time on admission and at 6 hours. They conducted their statistical analysis and found that checking the CRT was helpful for predicting mortality. The AUC on admission was not impressive at 0.66. The AUC at 6 hours, however, is excellent at 0.819 if CRT is > 3.5 seconds. This proved to be superior to their same assessment of lactate.

Morocho JP, Martínez AF, Cevallos MM, Vasconez-Gonzalez J, Ortiz-Prado E, Barreto-Grimaldos A, Vélez-Páez JL. Prolonged Capillary Refilling as a Predictor of Mortality in Patients With Septic Shock. J Intensive Care Med. 2022 Mar;37(3):423-429. doi: 10.1177/08850666211003507. Epub 2021 Mar 26. PMID: 33769108.
Link to Article

Is there a machine that can help us with this? Skin Laser Doppler

Mongkolpun, et al. recently (2020) published a paper looking at alterations in skin blood flow at the fingertip using skin laser doppler. I have personally never seen these devices before and, when I was building my lecture on this topic, found it difficult to find detailed information on it. Seems a bit far into the future at this moment so I won’t belabor it. They found that using skin laser doppler, they were able to determine that the area under the curve (AUC) was 0.94 when they did some calculations using the numbers to predict ICU mortality. It was better than checking lactate/lactic acid levels (AUC 0.76) and CRT (AUC 0.75). See? There are potential things better than checking lactic acid in sepsis.

Renin instead of Lactic Acid in Sepsis?

Jeyaraju et al. looked at using renin instead of lactate to predict mortality. From a statistical analysis standpoint, this study is rather complex. I will leave you with the key point: “renin levels greater than 40 pg/mL, but not lactate levels greater than 2 mmol/L, were associated with in-hospital mortality”.

Wrapping this up. (The Conclusions)

I am welcoming constructive criticism and feedback on this post about lactic acid in sepsis and other pathologies. This is my first attempt at tackling such a large topic on a blog post. This is not intended to be written in a dense, boring, deeply scientific way. At the end of the day, we are all doing our best to take care of patients. Hope you all got something out of this. I certainly did creating it. A hat tip to all the authors!

Citations to Lactic Acid in Sepsis and other states

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Jung B, Rimmele T, Le Goff C, Chanques G, Corne P, Jonquet O, Muller L, Lefrant JY, Guervilly C, Papazian L, Allaouchiche B, Jaber S; AzuRea Group. Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and administration of buffer therapy. A prospective, multiple-center study. Crit Care. 2011;15(5):R238. doi: 10.1186/cc10487. Epub 2011 Oct 13. PMID: 21995879; PMCID: PMC3334789.
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E. Kattan and G. Hernandez, The role of peripheral perfusion markers and lactate in septic shock resuscitation, Journal of Intensive Medicine,
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Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18. PMID: 28101605.
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Chen H, Zhao C, Wei Y, Jin J. Early lactate measurement is associated with better outcomes in septic patients with an elevated serum lactate level. Crit Care. 2019 Nov 11;23(1):351. doi: 10.1186/s13054-019-2625-0. PMID: 31711512; PMCID: PMC6849274.
Link to Article

Mongkolpun W, Orbegozo D, Cordeiro CPR, Franco CJCS, Vincent JL, Creteur J. Alterations in Skin Blood Flow at the Fingertip Are Related to Mortality in Patients With Circulatory Shock. Crit Care Med. 2020 Apr;48(4):443-450. doi: 10.1097/CCM.0000000000004177. PMID: 32205589.
Link to Abstract

Jeyaraju M, McCurdy MT, Levine AR, Devarajan P, Mazzeffi MA, Mullins KE, Reif M, Yim DN, Parrino C, Lankford AS, Chow JH. Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients. Crit Care Med. 2022 Jan 1;50(1):50-60. doi: 10.1097/CCM.0000000000005143. PMID: 34166293.
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