…and his missing lactate
I am, as I am sure many of you are, a big fan of using lactate to guide my resuscitative efforts in my critically ill septic patients. You would pour fluids into your large bore catheters, infuse pressors through your ultrasound guided central lines and revel in how quickly you cleared the patient’s elevated lactate levels.
10%? I cleared my patient’s lactate by 50% in the first 2 hours!” You shout.
I am a god among men! I have brought upstairs medicine downstairs!”
Then comes the patient who you seem to do everything right for. Follow the protocol laid out by Manny Rivers and Alan Jones and still their lactate does not budge. And that ego you have built on the rise and fall of lactate comes crashing down.
What kind of doctor must I be, if I can’t even clear a simple lactate???”
There have been a number of studies published over the last months which have called into question the utility of lactate and lactate clearance in the diagnosis and resuscitation of the critically ill septic patient.
The first being from Dr. Marik and Dr. Bellomo published in March of this year in OA Critical Care (1) Though it is an excellent review on lactate physiology and brings up some interesting theories why we do or do not clear our lactate burden, it fails to provide a convincing argument in changing how we use lactate in everyday practice. From the Jones study (2) we know that people who clear their lactate levels do better than those who do not. Whether this is a prognostic factor or simply an evaluation of our resuscitation efforts is unclear.
In their final paragraph Dr. Marik and Dr. Bellomo cite two trials as evidence as to why lactate should not be used as a guide for resuscitation (4,5). Both are articles from the NEJM published in the 1990s. Interestingly they both represent attempts at goal directed therapy in the ICU. In the first article, the goals of cardiac index and oxygen delivery are utilized to guide care (4). If, after proper fluid resuscitation, these goals were not met, dobutamine was added. The second trial (5) randomized patients to one of 3 groups. In each respective group they used cardiac index, oxygen delivery or standard care to guide their resuscitation. If you look at the methods of this study it is very similar to the EGDT protocol in Dr. Rivers landmark trial (6). Obviously both trials were negative. As are all the trials of goal directed therapy before Dr. Rivers utilized its concepts in the ED. This is more a comment on the importance of early, aggressive care and maybe, the lack of utility of dobutamine. The leap to using this as evidence that we should not use lactate to guide our care is weak at best.
Another article published in the June 2013 issue of Chest by Puskarich et al (7) provides a much more convincing argument that lactate adds very little to your resuscitative efforts. This data is actually a preplanned analysis from the well known Jones cohort, whose primary results were published in JAMA in 2010 (8). In the original manuscript the authors compared Scvo2 to lactate as end points to guide your resuscitation. The initial study found that lactate was non-inferior, or in other words equally effective (or ineffective) in guiding the resuscitation of the patient in septic shock.In this most recent paper they looked at only the subgroup of patients, whose initial lactate was greater than 2.0. Basically they examined the patients where lactate performed well and excluded all the potential false negatives. This accounted for only 69% of the original cohort. The authors measured lactate in a variety of different ways and found that the strongest predictor of mortality was relative lactate clearance. But even after excluding all the patients for whom lactate was falsely negative and dredging the data the best AOC they could achieve was 0.67. Interestingly the rate at which patients cleared their lactate had close to no correlation with clinical outcomes and AOC of 0.58
These findings call into question the two most common ways we use lactate in the emergency room. First, can we use lactate to screen for “occult” sepsis? Second, does the trending of lactate add anything to or resuscitative efforts over clinical evaluation and gestalt? Lactate and lactate clearance have for some time been theorized as a marker for predicting poor outcomes in multiple patient populations. Many studies have found that higher levels of lactate in the blood are associated with increased mortality rates (3,10,11,12,13,14). Is this association accurate enough to be of use in clinical practice and does trending it change outcomes in a positive fashion?
In a study published by Shapiro et al in 2005 (3), the authors found increasing lactate levels in septic patients correlated nicely with increasing mortality. Whether that correlation can be used clinically is another question. The AOC of lactate to predict mortality was 0.67. Interestingly, almost identical to the performance of lactate in all its variations in the author's more recent study previously discussed (7). In fact even at serum lactate levels as low as 2.5 mmol/L the sensitivity of lactate at predicting poor outcomes was 59%. Virtually no better than flipping a coin. And as you would expect at such low levels the specificity was an abysmal 71%. If you were to use the level suggested by the ”surviving sepsis campaign”, 4.0 mmol/L (9), the sensitivity would fall as low as 36%. Even at levels as low as 2.5 mmol/L you will miss a large quantity of very sick patients if you use it as your single screening tool to diagnose “occult sepsis”.
Now that we have established that lactate does not function well as a tool to tell us which septic patients we should worry about, lets examine how well it helps us manage our resuscitations. This is by far the more difficult question to answer. First we have to examine how we use lactate clearance in our resuscitation scheme. It has been proposed by Jones et al (2) that lactate clearance could replace Scvo2 in the EGDT protocol. In this form it is drawn along with the initial labs but not does not play an active role in the protocol until after CVP and mean arterial pressure are both normalized. At this point a second lactate, drawn 2 hours after the first, is compared to the initial value. If the lactate has cleared by greater than 10% you have accomplished your goals, everyone yells “Hurrah!!” and the patient is saved. If the lactate has not cleared by 10% you buckle down and add dobutamine and/or blood transfusions depending on the patient’s hemoglobin level. So where did this 10% clearance come from and how well does it predict adequate hemodynamic resuscitation?
10% lactate clearance was initially derived in a paper by Nguyen et al (10) published in 2004. In this paper they examined a cohort of 111 patients in septic shock and trended their lactate levels. After multiple regression analysis (for which they did not provide their results) they proclaimed that a lactate clearance of 10% offers the optimal test characteristics at predicting mortality. What were these optimal values? A 10% lactate clearance offers a sensitivity of 44.7% and a specificity of 84.4% with an overall accuracy of 67.7%. As you can see lactate clearance is virtually unusable in prognosticating which patients may be at risk.
Even with these poor test characteristics, does lactate clearance aid in the resuscitative effort of a septic patient? In 2010, Jones et al published a paper in JAMA attempting to prove just that. The Jones study (2) demonstrated that when lactate clearance was used to guide resuscitation efforts in the place of Scvo2, there was a non-statistically significant absolute risk reduction in mortality of 6%. The real question is not whether lactate is superior to Scvo2, but how much the monitoring of either one influences the resuscitation? As mentioned earlier, lactate clearance or Scvo2 does not play an active role until after CVP and mean arterial blood pressure have been normalized. Theoretically, you could manage a resuscitation this far without the knowledge of either value. Lactate and/or Scvo2 only play a role in determining who receives dobutamine and PRBCs. In the overall cohort only 5% received PRBCs and 4% received dobutamine within the first 6 hours of their resuscitation (the allocated ED time). At best lactate clearance can play a very small role in the success or failure of an active resuscitation. Given its poor diagnostic accuracy, that is most probably a good thing.
It is important for all diagnostic tools we use to not only be reliable and accurate, but perform better than a clinician’s own clinical gestalt. Though there is a strong correlation with elevated lactate levels and poor outcomes, it is clearly not accurate enough to guide clinical decisions. Whether lactate clearance and the lack thereof is a prognostic value of patient outcome or a dependent variable, which we can intervene on, is still to be determined. It is clear that either way it should not be the single tool we use to evaluate and resuscitate our septic patients.
- Marik PE, Bellomo R, Demla V. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3.
- Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010 Feb;303(8):739-46.
- Nathan I. Shapiro, Michael D. Howell, Daniel Talmor, Larry A. Nathanson, Alan Lisbon, Richard E. Wolfe, J. Woodrow Weiss Serum Lactate as a Predictor of Mortality in Emergency Department Patients with Infection . Annals of Emergency Medicine May 2005 Vol. 45, Issue 5, Pages 524-528
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- Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377
- Puskarich MA, Trzeciak S, Shapiro NI; et al. . Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock,. Chest. 2013; 143(6): 1548—1553.
- Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; ; Emergency Medicine Shock Research Network (EMShockNet) Investigators, . Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial,. JAMA. 2010; 303(8): 739—746
- Delinger et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med. 2013;41(2): 580 637
- Nguyen HB, Rivers EP, Knoblich BP; et al. . Early lactate clearance is associated with improved outcome in severe sepsis and septic shock,. Crit Care Med. 2004; 32(8): 1637—1642
- Regnier MA, Raux M, Le MY, Asencio Y, Gaillard J, Devilliers C. Prognostic significance of blood lactate and lactate clearance in trauma patients. Anesthesiology 2012 Dec;117(6):1276-88.
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- McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH, Ritter G. Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg 2001 Nov;182(5):481-5.
- Simone Vanni, Gabriele Viviani, Michele Baioni, Giuseppe Pepe, Prognostic Value of Plasma Lactate Levels Among Patients With Acute Pulmonary Embolism: The Thrombo-Embolism Lactate Outcome Study. Annals of Emergency Medicine Vol. 61, Issue 3, Pages 330-338
University of Maryland
Resuscitation Fellowship Graduate