In this study, both 6-hour lactate levels and 6-hour lactate clearance showed prognostic value for predicting the 30-day mortality in patients with sepsis and septic shock in accordance with the Sepsis-3 definitions. Nguyen and colleagues defined lactate clearance as the percentage decrease in lactate levels from ED presentation to 6 hours later [8]. They reported that a lactate clearance of <10% was the optimal cutoff value with a sensitivity of 44.7% and specificity of 84.4% in predicting in-hospital mortality. In our study, a lactate clearance of <10% had a sensitivity of 43.2% and specificity of 77.7% in predicting the 30-day mortality, and lactate clearance of <24.4% was the optimal cutoff in predicting the 30-day mortality (sensitivity, 63.5%; specificity, 63.7%).
A recent study concluded that 6-hour lactate levels and lactate clearance were associated with 28-day mortality rates in septic shock patients diagnosed based on the Sepsis-3 definitions [16].16 The study also compared the lactate level metrics (≥2, ≥3, and ≥4 mmol/L) and lactate clearance metrics (<10%, <20%, and <30%) to predict the 28-day mortality. Similar to the findings in our study, the previous study also showed that subsequent 6-hour lactate levels ≥2 mmol/L had the highest sensitivity for predicting mortality among the overall metrics. However, the previous study included only septic shock patients (lactate level >2 mmol/L and vasopressor required). Despite the difference in inclusion criteria, the previous study reported that 6-hour lactate levels had better prognostic value than lactate clearance, which is consistent with our results. Furthermore, our study showed that 6-hour lactate levels were superior to initial lactate levels in predicting the 30-day mortality.
Another study compared mortality prediction between subsequent lactate levels (≥4 mmol/L) and lactate clearance (<10% and <20%) in severe sepsis and septic shock patients [14]. According to the study, subsequent lactate levels ≥4 mmol/L and lactate clearance <20% were associated with increased in-hospital mortality, whereas lactate clearance <10% did not increase hospital mortality [14]. In contrast to the findings of that study, our results showed that all lactate clearance metrics (<10%, <20%, and <30%) were associated with 30-day mortality. Definitions (Sepsis-2), inclusion criteria, outcome measure (in-hospital mortality), and measurement time of the subsequent lactate level used in the previous study were different from those in our study, which might be attributable for the difference in results between the two studies. In particular, the analysis of the previous study was limited by variations in the time of lactate level measurements.
Serum lactate levels indicate an interaction between the production and elimination of lactate [11]. Previous studies reported that serial lactate measurements are better prognosticators than a single lactate measurement in the shock state [21, 22]. A recent study reported that the raw value of a second lactate measurement (AUC = 0.85) within 24 hours had a greater ability to predict short-term mortality than the initial lactate levels (AUC = 0.73) and lactate clearance (AUC = 0.77) in severely injured patients [22]. Given the different conditions, our study also showed that 6-hour lactate levels had a better prognostic value than the initial lactate levels and lactate clearance. A previous study [23] reported that the optimal cutoff values to predict survival are <3.7 mmol/L for the second lactate measurement and ≥32% for lactate clearance. The results of this study were similar to those of our study (≥3.5 mmol/L for 6-hour lactate and <24.4% for lactate clearance to predict 30-day mortality).
We found that the 6-hour lactate level of ≥3.5 mmol/L and initial lactate level of ≥7.6 mmol/L were the optimal cutoff values to predict mortality. Our results showed that initial lactate levels had a poor prognostic value (AUC: 0.612 [95% CI, 0.560–0.662]) when compared with the 6-hour lactate levels. A previous study reported that initial lactate levels had fair prognostic value (AUC 0.70 [95% CI, 0.62–0.79]) with an optimal cutoff value of ≥2.5 mmol/L to predict 28-day mortality among severe sepsis and septic shock patients [12]. This previous study used Sepsis-2 definitions and initial lactate levels in the analysis, which might have caused the differences in results. Among all lactate metrics analyzed in our study, the subsequent 6-hour lactate levels of ≥2 mmol/L showed the highest sensitivity of 89.2% for predicting mortality. Despite the low specificity (35.3%) of 6-hour lactate levels of ≥2 mmol/L, we postulate that the cutoff value of ≥2 mmol/L can be reasonable and practical to predict mortality quickly in sepsis and septic shock patients because of the fatality of the disease.
In accordance with our study, a recent study reported that higher lactate levels and decreased lactate clearance were associated with 7-day and in-hospital mortality among sepsis patients regardless of the presence of shock [12]. Our study included both sepsis (without shock) and septic shock patients diagnosed based on the Sepsis-3 definitions. A retrospective cohort study showed that the optimal cutoff values of initial lactate level and lactate clearance per hour to predict 30-day mortality were 4 mmol/L and 2.5%/h, respectively [24]. A lactate clearance of 2.5% per hour may be estimated to be 14.1% at 6 hours. In our study, we found that the optimal cutoff values of 6-hour lactate level and lactate clearance were 3.5 mmol/L and 24.4%, respectively.
Previous studies showed that initial lactate levels had prognostic value for predicting mortality in septic patients [12, 15, 24, 25]. However, we found that 6-hour lactate levels had better prognostic value than initial lactate levels in sepsis and septic shock patients. Our results suggest that subsequent lactate kevel measurement is essential for lactate-based sepsis management.
There were some limitations to this study. First, because our study was conducted in a single tertiary teaching hospital, the generalizability of our results to external populations remains uncertain. Second, this study was a retrospective study limited by characteristics inherent to retrospective analyses and interpretations. Third, the present study included sepsis and septic shock patients with a positive qSOFA score upon arrival to the ED, which might have resulted in a selection bias. Fourth, because there are numerous factors that may alter lactate metabolism, clinicians should be cautious when applying our results to sepsis and septic shock patients.