Mortality at 28 days was 16.9% (31/183) in patients with initial lactate more than 2.5 mmol/L and 5.8% (15/260) in patients with initial lactate at most 2.5 mmol/L (absolute difference, 11.1% [95% CI, 5.0%–17.3%]; relative risk, 2.93 [95% CI, 1.63–5.28]; P < 0.001). Initial blood lactate levels more than 2.5 mmol/L were significantly associated with increased 28-day mortality (HR, 3.22; 95% CI, 1.74–5.98; P < 0.001) (Fig. 2).
Out of the 443 patients included in the primary analysis, 260 (58.7%) had more than one lactate measurement performed during the first 24 h of ED admission. Of those 260 patients, 33 (12.7%) died, whereas 227 (87.3%) were alive at day 28 (Table 3). Lactate clearance time, absolute lactate clearance, relative lactate clearance, and lactate clearance rate did not differ between survivals and nonsurvivals (Table 3). The AUC was highest for the initial lactate levels (0.664) followed by absolute lactate clearance (0.571), clearance rate (0.550), and relative lactate clearance (0.515).
In our retrospective single-center cohort study with 443 severe sepsis and septic shock patients admitted to the ICU, initial lactate levels more than 2.5 mmol/L exhibited the highest sensitivity, specificity, and negative predictive value for 28-day mortality. Patients with initial lactate levels above this cutoff had a mortality rate 3.2 times higher than patients with initial lactate lower or equal to 2.5 mmol/L.
Clinical studies have emphasized tissue hypoxia, characterized by supply-dependent oxygen consumption, as a leading cause of increased lactate levels in septic patients (22, 23). During the acute phase, hyperlactatemia is often considered a marker of tissue hypoperfusion (15). Although the current guidelines for severe sepsis and septic shock resuscitation recommend that patients with severe sepsis or septic shock with an initial blood lactate level of at least 4.0 mmol/L must be promptly resuscitated (15), recent studies have shown that less expressive elevations in lactate levels have also been associated with poor outcomes (9–13), regardless of the presence of hepatic dysfunction (12).
Several other studies are consistent with our findings of mild hyperlactatemia as a predictor of mortality in septic patients (9, 10, 13). A prospective single-center cohort study involving 1,287 patients admitted to the ED with suspected infection showed that initial venous lactate levels between 2.5 and 4.0 mmol/L were independently associated with an increased risk of 28-day in-hospital death (9). Another single-center cohort study including 830 patients with severe sepsis and septic shock admitted to the ED showed that initial venous lactate levels between 2.0 and 3.9 mmol/L, compared with initial lactate levels less than 2.0 mmol/L, were associated with increased mortality at day 28, regardless of the presence of shock (10).
Along with our results, available evidence suggests that the current guidelines might be too conservative when recommending that resuscitation should be only reserved for those septic patients with blood lactate concentrations at least 4.0 mmol/L (15). Considering the increased risk of unfavorable outcomes reported in septic patients presenting to the ED with intermediate hyperlactatemia (9–13), aggressive resuscitation may be advisable and might improve morbidity and mortality. Nevertheless, a mild hyperlactatemia must be placed in the appropriate clinical context to prove value as a prognostication in sepsis (24). Indeed, a recent randomized controlled trial involving 348 critically ill patients used a lower cutoff of blood lactate concentration (≥3.0 mmol/L) to trigger resuscitation (25). In this study, patients undergoing lactate-guided therapy exhibited a lower risk of in-hospital mortality than the control group (25).
We found diabetes mellitus to be a protective factor for 28-day mortality in patients with severe sepsis and septic shock. Although patients with diabetes have an increased risk of infections and sepsis (26, 27) due to depressed humoral and cellular immunity (28, 29), conflicting data exist on whether the outcomes of septic patients are affected by the presence of diabetes (30). Although some authors reported increased mortality among patients with diabetes with infection (31, 32), others reported improved survival (33–35). The exact mechanisms responsible for these controversial findings remain unclear (30, 36). It was demonstrated that administration of exogenous insulin was associated with improvement on host immunity and decreased production of proinflammatory mediators, such as tumor necrosis factor alpha (37), decreased production of macrophage migration inhibitory factor, and intranuclear factor kappa B and reactive oxygen species generation by mononuclear cells in obese patients (38). Therefore, we can hypothesize that blood glucose control with exogenous insulin administration, which is routinely used in ICU patients (39), could explain, at least partially, the mechanism related to the observed protective effect of diabetes on 28-day mortality in our study population. In addition, besides the effect of insulin on the immune and inflammatory response, diabetes has been associated with reduced risk of acute respiratory dysfunction, which may have positively affected our population of critically ill patients (40).
Our study has limitations. First, this was a single-center study. Therefore, our results may have limited external validity. Second, because of the retrospective nature of our study, we are subject to selection and information bias. We analyzed variables that were routinely collected and documented as part of patient care. Third, patients admitted to the ED after 2010 could have received fluids, vasopressors, inotropes, and red blood cells transfusion guided by lactate clearance (41). Nevertheless, because all patients received their first dose of broad-spectrum antibiotics within 1 h from the admission and received an initial fluid load (20–30 mL/kg of crystalloids), it is unlikely that additional therapeutic interventions guided by the lactate clearance or ScvO2 would have biased our results. Fourth, survival bias could have undervalued the observed association between lactate clearance and 28-day mortality in our study. Thus, our results must be interpreted with caution. Finally, patients recovering from surgery and those with a higher risk of delayed resuscitation (ward and hospital referrals) were not included in this analysis, which might have had an impact on our observed mortality rate and death prediction.
In our retrospective cohort study, severe sepsis or septic shock patients admitted to the ICU from the ED with initial blood lactate more than 2.5 mmol/L were at increased risk of death. Further prospective multicenter studies should address the impact of lower serum lactate cutoffs as a trigger to resuscitation on morbidity and mortality in this population of critically ill patients.
The authors thank James Hesson for proofreading this manuscript.
1. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med
2014; 370 18:1683–1693.
2. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med
2014; 371 16:1496–1506.
3. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med
2015; 372 14:1301–1311.
4. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
2001; 29 7:1303–1310.
5. Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data. Crit Care
2009; 13 1:R28.
6. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care
2014; 18 5:503.
7. 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
2005; 45 5:524–528.
8. Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C, Milcarek B, Hollenberg SM, Parrillo JE. Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med
2007; 33 6:970–977.
9. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI. Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med
2007; 33 11:1892–1899.
10. 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
2009; 37 5:1670–1677.
11. 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
2010; 14 1:R25.
12. Kang YR, Um SW, Koh WJ, Suh GY, Chung MP, Kim H, Kwon OJ, Jeon K. Initial lactate level and mortality in septic shock patients with hepatic dysfunction. Anaesth Intensive Care
2011; 39 5:862–867.
13. Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR. Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock
2012; 38 1:4–10.
14. Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med
1996; 14 2:218–225.
15. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med
2013; 41 2:580–637.
16. Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference CommitteeAmerican 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
1992; 20 6:864–874.
17. Assuncao MS, Teich V, Shiramizo SC, Araujo DV, Carrera RM, Serpa NA, Silva E. The cost-effectiveness ratio of a managed protocol for severe sepsis. J Crit Care
2014; 29 4:692–696.
18. Palomba H, Correa TD, Silva E, Pardini A, Assuncao MS. Comparative analysis of survival between elderly and non-elderly severe sepsis and septic shock resuscitated patients. Einstein (Sao Paulo)
2015; 13 3:357–363.
19. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med
1985; 13 10:818–829.
20. Vincent JL, Moreno R, Takala J, Willatts S, De MA, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med
1996; 22 7:707–710.
21. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC, Kline JA, Jones AE. Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest
2013; 143 6:1548–1553.
22. Ronco JJ, Fenwick JC, Tweeddale MG, Wiggs BR, Phang PT, Cooper DJ, Cunningham KF, Russell JA, Walley KR. Identification of the critical oxygen delivery for anaerobic metabolism in critically ill septic and nonseptic humans. JAMA
1993; 270 14:1724–1730.
23. Friedman G, De BD, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock. Intensive Care Med
1998; 24 2:118–123.
24. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA
2016; 315 8:801–810.
25. Jansen TC, van BJ, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med
2010; 182 6:752–761.
26. Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care
2003; 26 2:510–513.
27. Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, Rutten GE. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis
2005; 41 3:281–288.
28. Alexiewicz JM, Kumar D, Smogorzewski M, Klin M, Massry SG. Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. Ann Intern Med
1995; 123 12:919–924.
29. Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med
1997; 14 1:29–34.
30. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med
1999; 341 25:1906–1912.
31. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA, Kapoor WN. Prognosis and outcomes of patients with community-acquired pneumonia. A meta-analysis. JAMA
1996; 275 2:134–141.
32. Thomsen RW, Hundborg HH, Lervang HH, Johnsen SP, Schonheyder HC, Sorensen HT. Diabetes mellitus as a risk and prognostic factor for community-acquired bacteremia due to enterobacteria: a 10-year, population-based study among adults. Clin Infect Dis
2005; 40 4:628–631.
33. Thomsen RW, Hundborg HH, Lervang HH, Johnsen SP, Sorensen HT, Schonheyder HC. Diabetes and outcome of community-acquired pneumococcal bacteremia: a 10-year population-based cohort study. Diabetes Care
2004; 27 1:70–76.
34. Esper AM, Moss M, Martin GS. The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study. Crit Care
2009; 13 1:R18.
35. Graham BB, Keniston A, Gajic O, Trillo Alvarez CA, Medvedev S, Douglas IS. Diabetes mellitus does not adversely affect outcomes from a critical illness. Crit Care Med
2010; 38 1:16–24.
36. Schuetz P, Castro P, Shapiro NI. Diabetes and sepsis: preclinical findings and clinical relevance. Diabetes Care
2011; 34 3:771–778.
37. Das UN. Is insulin an antiinflammatory molecule? Nutrition
2001; 17 5:409–413.
38. Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab
2001; 86 7:3257–3265.
39. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med
2001; 345 19:1359–1367.
40. Moss M, Guidot DM, Steinberg KP, Duhon GF, Treece P, Wolken R, Hudson LD, Parsons PE. Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med
2000; 28 7:2187–2192.
41. 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; 303 8:739–746.