In our study, we found that even normal-range arterial lactate concentration is a prognostic marker for 28-day mortality (Fig. 1) and organ dysfunction in septic shock patients (Table 2). We found that patients having quartile 2 normal-range lactate concentrations (lactate between 1.4 and 2.3 mmol/L) had significantly greater mortality and organ dysfunction compared with quartile 1 patients who had baseline lactate 1.4 mmol/L or less in both VASST and SPH septic shock cohorts. Indeed, a Q2 normal-range lactate concentration was prognostic of adverse outcomes as severe as found with Q3 elevated lactate concentrations (2.3–4.4 mmol/L). These results suggest that the Surviving Sepsis Campaign International Guidelines may be very conservative in the recommendation that resuscitation is needed if blood lactate concentration is greater than 4 mmol/L in septic shock patients (4). Our results suggest that aggressive resuscitation may be beneficial even in the setting of a Q2 normal-range lactate concentration.
Regardless of the mechanism of hyperlactatemia, numerous studies show that blood lactate is a relevant prognostic marker of morbidity and mortality in various critically ill settings including patients with sepsis in the emergency department, high-risk surgery, burn, trauma, acute respiratory distress syndrome, and septic shock (10, 17–24). Increased arterial lactate also correlates well with central venous oxygen saturation (ScvO2), an important target of early goal-directed therapy (4, 5). Recently, lactate has also been found to be a reasonably good target of early goal-directed therapy in severe sepsis or septic shock, which is relevant because determination of arterial lactate is less invasive than ScvO2 (8, 25). Dynamic indices of blood lactate (i.e., repeated measurement of arterial lactate over time) are also a good predictor of outcome in general critically ill patients including septic patients (20, 26, 27).
However, the key issue that has not been fully resolved is what threshold value signifies an elevated lactate concentration that may require clinical attention. In general, a normal arterial lactate concentration is less than 2.0 to 2.5 mmol/L (8–10, 28–30). A number of studies recommend threshold values requiring clinical intervention ranging from 2.0 to 4.5 mmol/L (6, 23, 25, 28, 31). One prospective study in severe sepsis used a threshold lactate of greater than 2.0 mmol/L combined with a low gastric intramucosal pH (<7.32). Mortality was 60% in those patients exceeding this combined threshold compared with 20% in patients with both variables normal (P < 0.01). From ROC analysis, they also found that the AUC of blood lactate and gastric intramucosal pH was greater than the AUC for the APACHE II score (28). A randomized controlled trial by the LACTATE study group chose a threshold lactate concentration of 3.0 mmol/L or greater and compared early lactate-guided therapy (aimed to decrease lactate by ≥20% per 2 h for the initial 8 h in the ICU) with conventional therapy. They found that early lactate-guided therapy significantly reduced hospital mortality (25). Another study in septic shock patients found that the best threshold value for initial blood lactate, using ROC curve analysis, was 4.5 mmol/L (sensitivity 62%, specificity 68%) (31). In contrast to these studies with relatively high lactate thresholds, one recent retrospective study has suggested that even normal-range lactate may be prognostic of adverse outcomes. Nichol et al. (7) analyzed blood lactate concentrations in critically ill patients and found that hospital mortality was significantly increased when patients had lactate concentrations more than 0.75 mmol/L (P < 0.05). Surviving patients had median blood lactate concentrations of 1.2 mmol/L compared with nonsurvivors who had a median lactate concentration of 1.3 mmol/L (P < 0.0001) (7). In accord with this latter study with a low lactate threshold, we found that increased baseline blood lactate from Q1 to Q2 (both Q1 and Q2 are within the normal range) had a significantly increased hazard ratio of 28-day mortality of 1.78, which was not different from the hazard ratio for Q3 versus Q1 of 1.65 (Table 3). Thus, the overall message of our study is consistent with at least one recent previous report that demonstrated that even lactate concentrations within the normal range are associated with increased mortality (7). Although elevated lactate concentration has previously been found to correlate with adverse outcome, the key surprising finding of the current study is that the threshold of 1.4 mmol/L or less is very low, well within the normal range of lactate concentrations. Thus, clinicians who would have previously considered a lactate level of 1.4 mmol/L to be normal should be alert to the possibility that this may be associated with adverse outcome.
According to the ROC curve analysis, we found that lactate of 1.4 provides a good sensitivity (86%) for prediction of mortality, but cannot be used in isolation because of a very low specificity (27%). The clinician must use other perfusion markers such as ScvO2 and urine output to enhance the prediction value. Comparisons of lactate to the APACHE II score suggest that neither approach is particularly discriminatory, even though there is an overall relationship at the population level.
We also adjusted our analyses for presence of preexisting liver disease because lactate is mainly metabolized in the liver where hepatocytes convert lactate to glucose and glycogen via the Cori cycle. Thus, lactate clearance may be diminished and lead to blood lactate elevation in patients with preexisting liver disease (32, 33). We found that even after adjustment for presence of liver disease, minimally elevated lactate was associated with increased mortality rate (see Figure, Supplemental Digital Content 1, at http://links.lww.com/SHK/A131). In VASST, we found that liver disease was an independent predictor of increased 28-day mortality with a hazard ratio 1.18 (95% CI, 1.052–1.312; P = 0.004) (Table 3).
Another clinically important, relevant finding of our study was that lactate quartile was predictive of response to vasopressin compared with noradrenaline infusion. Normal-range lactate concentration was predictive of a beneficial response to vasopressin compared with noradrenaline treatment alone (Fig. 3). However, this result derives from a single cohort (VASST) and therefore is hypothesis generating only. Accordingly, we suggest that arterial lactate could be a simple biomarker of response to vasopressin in septic shock patients. This finding is aligned with some of the results of VASST, which suggested that patients who had less severe shock (as defined by dose of open-label noradrenaline infusion at the time of randomization) had an enhanced response to vasopressin (12). The mechanism is unknown, and further studies are required. One possibility is these patients have more reversible disease (i.e., less organ dysfunction) and so respond better to vasopressin. One advantage of staging severity of shock by arterial lactate as opposed to dose of noradrenaline is that the dose of noradrenaline is determined in part by clinician choice, whereas arterial lactate reflects patient pathophysiology.
The strengths of this study are, first, that our derivation cohort is a large prospective multicenter cohort of patients with well-defined septic shock and, second, that we confirmed replication in an independent single-center cohort. Another strength is that vasopressin and noradrenaline were given as well-controlled, randomized, blinded infusions in a multicenter controlled trial with a tight prospective protocol (12), thereby increasing the validity of our finding that lactate quartile was predictive of response to vasopressin compared with noradrenaline infusion. An additional strength is that our adjusted and unadjusted analyses were consistent.
However, there are some limitations to our study. First, we analyzed the data retrospectively in both cohorts. Although both cohorts were patients with septic shock, only VASST had a vasoactive drug protocol. This may have led to management variation between cohorts and only allowed us to assess response to vasoactive drugs in VASST. Confirmation that low lactate predicts a beneficial response to vasopressin needs further confirmation. Second, the use of quartiles in our statistical analysis does not allow us to determine the critical threshold level of lactate associated with increased mortality. Third, our adjustments for the presence of liver disease were likely not sensitive enough to adjust for patients with “new” hepatic impairment from septic shock. Last, the critical value of increased lactate in our study may not be directly applied to critically ill patients not due to septic shock because we analyzed only patients who had septic shock.
As a prognostic indicator of adverse outcomes in septic shock, lactate concentrations within the normal range (quartile 2, lactate 1.4–2.3 mmol/L) are as important as higher lactate concentrations above the normal range (quartile 3, lactate 2.3–4.4 mmol/L). Furthermore, low lactate concentrations may be predictive of a beneficial response to vasopressin versus noradrenaline infusion. These results suggest that it may be useful to revise the cutoff value of blood lactate-guiding therapy in septic shock patients [Surviving Sepsis Campaign Guideline lactate >4.0 mmol/L (4)].
1. Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR: Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol 79: 479–486, 1995.
2. Bateman RM, Sharpe MD, Ellis CG: Bench-to-bedside review: microvascular dysfunction in sepsis—hemodynamics, oxygen transport, and nitric oxide. Crit Care 7: 359–373, 2003.
3. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall’Ava-Santucci J, Brunet F, Villemant D, Carli A, Raichvarg D: Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 75: 533–541, 1987.
4. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36: 296–327, 2008.
5. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M: Early Goal-Directed Therapy Collaborative Group: early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345: 1368–1377, 2001.
6. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD: Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med 37: 1670–1677, 2009.
7. Nichol AD, Egi M, Pettila V, Bellomo R, French C, Hart G, Davies A, Stachowski E, Reade MC, Bailey M, et al.: Relative hyperlactatemia and hospital mortality in critically ill patients: a retrospective multi-centre study. Crit Care 14: R25, 2010.
8. 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 303: 739–746, 2010.
9. Jansen TC, van Bommel J, Mulder PG, Lima AP, van der Hoven B, Rommes JH, Snellen FT, Bakker J: Prognostic value of blood lactate levels: does the clinical diagnosis at admission matter? J Trauma 66: 377–385, 2009.
10. Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, Weiss JW: Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 45: 524–528, 2005.
11. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 13: 818–829, 1985.
12. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al.: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358: 877–887, 2008.
13. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20: 864–874, 1992.
14. Sibbald WJ, Vincent JL: Roundtable Conference on Clinical Trials for the Treatment of Sepsis. Brussels, March 12–14, 1994. Chest 107: 522–527, 1995.
15. Sutherland AM, Walley KR, Manocha S, Russell JA: The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med 165: 75–82, 2005.
16. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, Wright PE: A trial of antioxidants N
-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 112: 164–172, 1997.
17. Meregalli A, Oliveira RP, Friedman G: Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk, surgical patients. Crit Care 8: R60–R65, 2004.
18. Guyette F, Suffoletto B, Castillo JL, Quintero J, Callaway C, Puyana JC: Prehospital serum lactate as a predictor of outcomes in trauma patients: a retrospective observational study. J Trauma 70: 782–786, 2011.
19. Bakker J, Coffernils M, Leon M, Gris P, Vincent JL: Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock. Chest 99: 956–962, 1991.
20. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL: Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg 171: 221–226, 1996.
21. Jeng JC, Jablonski K, Bridgeman A, Jordan MH: Serum lactate, not base deficit, rapidly predicts survival after major burns. Burns 28: 161–166, 2002.
22. Valta P, Uusaro A, Nunes S, Ruokonen E, Takala J: Acute respiratory distress syndrome: frequency, clinical course, and costs of care. Crit Care Med 27: 2367–2374, 1999.
23. Phua J, Koay ES, Lee KH: Lactate, procalcitonin, and amino-terminal pro–B-type natriuretic peptide versus cytokine measurements and clinical severity scores for prognostication in septic shock. Shock 29: 328–333, 2008.
24. Watanabe I, Mayumi T, Arishima T, Takahashi H, Shikano T, Nakao A, Nagino M, Nimura Y, Takezawa J: Hyperlactemia can predict the prognosis of liver resection. Shock 28: 35–38, 2007.
25. Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J: LACTATE study group: early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 182: 752–761, 2010.
26. Nichol A, Bailey M, Egi M, Pettila V, French C, Hart GK, Stachowski E, Reade MC, Cooper DJ, Bellomo R: Dynamic lactate indices as predictors of outcome in critically ill patients. Crit Care 15: R242, 2011.
27. Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 32: 1637–1642, 2004.
28. Friedman G, Berlot G, Kahn RJ, Vincent JL: Combined measurements of blood lactate concentrations and gastric intramucosal pH in patients with severe sepsis. Crit Care Med 23: 1184–1193, 1995.
29. Okorie ON, Dellinger P: Lactate: biomarker and potential therapeutic target. Crit Care Clin 27: 299–326, 2011.
30. Levy B: Lactate and shock state: the metabolic view. Curr Opin Crit Care 12: 315–321, 2006.
31. Tamion F, Le Cam-Duchez V, Menard JF, Girault C, Coquerel A, Bonmarchand G: Erythropoietin and renin as biological markers in critically ill patients. Crit Care 8: R328–R335, 2004.
32. Mizock BA: Hyperlactatemia in acute liver failure: decreased clearance versus increased production. Crit Care Med 29: 2225–2226, 2001.
33. Bihari D, Gimson AE, Lindridge J, Williams R: Lactic acidosis in fulminant hepatic failure. Some aspects of pathogenesis and prognosis. J Hepatol 1: 405–416, 1985.