The time to first normalization of lactate from hyperlactatemia (>2 mmol/L and ≥3 mmol/L) did not differ between 90-day survivors and non-survivors (Table 3). The time between the first and the last lactate recording >2 mmol/L, with possible normalized values in between, was however associated with 90-day mortality, 24.0 (8.2–56.0) h in non-survivors versus 20.4 (3.9–44.2) h in survivors (P = 0.019).
The maximum dose of norepinephrine during the first 24 h in the ICU was significantly lower in 90-day survivors than in non-survivors (0.15 μg/kg/min [0.08–0.31] vs. 0.24 μg/kg/min [0.13–0.63], P < 0.001).
Independent predictors of 90-day mortality in septic shock patients (using backward logistic regression) for all patients are shown in Table 4. In separate models time-weighted mean lactate, the lactate value at 72 ± 2 h, and lactate >2 mmol/L at 72 ± 2 h were independently associated with 90-day mortality, but admission lactate (all available values) or time to first normalization of lactate were not. These associations were confirmed in a sensitivity analysis including only those 262 patients with admission lactate >2 mmol/L who fulfilled the new septic shock criteria (14) (ESM Table 3, http://links.lww.com/SHK/A493) and using enter models (data not shown).
In the present study, 52% of the patients had an arterial lactate level of over 2 mmol/L and 36% of the patients had an arterial lactate of ≥3 mmol/L at diagnosis of septic shock. The mortality rates of the current study are comparable with the mortality rates reported by the task force for developing new sepsis criteria (14, 21). The mortality rate of 45.9% in the current study was comparable to the mortality rate of 39% in patients with hyperlactatemia of ≥3 mmol/L in a mixed ICU population from the Surviving Sepsis Guidelines database (21).
We found that admission lactate and lactate at ≥72 h predicted 90-day mortality relatively poorly by ROC analyses (AUCs of 0.67 and 0.73, respectively) (22). Our findings are well in line with previous studies. A retrospective analysis of septic shock patients reported an AUC value of 0.63 for baseline lactate to 28-day mortality in a multicenter material and 0.66 in a single-center material (23). These results were later confirmed in patients with severe sepsis or septic shock admitted to the emergency department (20). In the study by Puskarich et al. (20), admission lactate was the best predictor of hospital mortality with an AUC of 0.64. Comparable results were also found in a large Australian retrospective study of critically ill patients (24).
The results of the present study indicate that failure to normalize lactate at ≥72 h is associated with 90-day mortality. For patients with values >2 mmol/L at ≥72 h the 90-day mortality was over 2-fold. Persistent hyperlactatemia and slow normalization of lactate values have been shown to predict adverse outcome and mortality in patients with septic shock as well as in other critically ill patient groups, and lactate clearance, i.e., a certain decrease of lactate over a certain time has been associated with outcome benefit (25–27). Recent studies have also indicated that intermediate levels of lactatemia and relatively small changes in lactate values (9, 11), even within the normal range, may be linked to outcome (11, 23, 28). There is also some evidence that dynamic lactate measures describing the evolution of lactate over time may be more important than single, static, lactate values (24). The results of our study point in the same direction, showing that time-weighted mean lactate, taking every measured lactate value into account, and lactate values at ≥72 h are better predictors of 90-day survival than the lactate value at admission.
We found no independent association between normalization (i.e., time to first normalization of lactate) and 90-day mortality as opposed to several earlier studies. This may in part be explained by different definitions of normalization. Previous studies have defined normalization as percentage of admission lactate, or as timeframes of time to normalization (8 or 24 h frames) used for comparison. Furthermore, the lactate level used to define normalization has also varied, as shown in a recent systematic review (29).
The present study showed that a longer duration of hyperlactatemia over 2 mmol/L and a longer time-interval between the first and the last value over 2 mmol/L were associated with higher 90-day mortality. Lactate levels may rise again after temporary normalization or during the course of the illness. Lactate levels are also influenced by liver disease (30) and/or the use of renal replacement therapy (31).
Persistent lactatemia as a continuous and binomial variable, and separately time-weighted mean lactate during ICU stay were both independently associated with 90-day mortality in septic, and separately in septic shock patients. However, time to normalization of hyperlactemia was not, which means that it may not be optimal surrogate outcome measure in future clinical trials.
In this study, all patients had infection and they were hypotensive at the time of study inclusion. However, for some patients the need for vasopressors was short lasting. Patients needing vasopressors during the first 24 h in the ICU had significantly higher lactate levels than those who did not. Vasopressors may have induced some degree of hypoperfusion and lactatemia by causing peripheral vasoconstriction. Furthermore, epinephrine may cause hyperlactatemia through beta-adrenergic stimulation and increased aerobic glycolysis (32). There is also accumulating evidence that the aetiology of hyperlactatemia in sepsis often is multifactorial and beyond tissue hypoxia only (10, 33–35). Nevertheless, even in the absence of tissue hypoxia, hyperlactatemia is indisputably an independent predictor of organ failure (25) and mortality (12, 13) and previous data supporting the clinical utility of lactate as a marker of early sepsis recovery are robust (8, 15, 16).
Our study has some strengths. First, these data were prospectively collected from consecutive patients admitted to ICUs participating in the FINNAKI study. Second, the 90-day mortality of all septic shock patients in the FINNAKI study was comparable to the mortality of the studied subgroup with multiple lactate measurements. Third, patients were treated by ICU physicians according to the current guidelines without differences in the treatment regimens between patients with different levels of lactatemia. Fourth, we updated this sub-study analysis using the updated definitions for sepsis and septic shock (14). Thus, we consider our study population to be representative and our findings to have external validity. Fifth, this study assessed the association between lactate and a long-term time-defined mortality endpoint with complete outcome data.
However, this study also has several limitations. First, due to an observational study design, the lactate measurements were not scheduled, which plausibly may have led to more blood gas samples being drawn from more severely ill patients with higher lactate values. However, the 90-day survivors and non-survivors were sampled comparably. Additionally, we calculated the time-weighted mean lactate, which adjusts for differences in frequency and aggregate time of measurements. Second, a time-dependent variable—such as normalization of lactate—has the problem of competing risks, such as discharge from the ICU and death. However, imputation of time to death into calculation of normalization of lactate in those who died in the ICU did not change the results. Furthermore, imputation of time to normalization in patients who do not normalize within a certain time also may cause bias. Furthermore, normalization may be followed by a new rise in lactate levels, which may have bearing on outcome. The median ICU LOS was, however, similar among survivors and non-survivors, and, thus, did not cause significant bias to our findings. Fourth, information on source control and appropriateness of antibiotics could not be retrieved from the collected data for assessment of their possible association with evolution of lactate levels. Finally, the selected different sub-populations and use of different regression models may yield different results. However, we could also confirm the robustness of our results in the sensitivity analysis including only patients with lactatemia fulfilling the Sepsis-3 criteria and separately using enter models instead of backward logistic regression models.
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