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).
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).
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.
The authors thank James Hesson for proofreading this manuscript.
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