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Normal-Range Blood Lactate Concentration in Septic Shock Is Prognostic and Predictive

Wacharasint, Petch; Nakada, Taka-aki; Boyd, John H.; Russell, James A.; Walley, Keith R.

doi: 10.1097/SHK.0b013e318254d41a
Clinical Aspects

We hypothesized that lactate levels even within the normal range are prognostic and that low lactate levels predict a beneficial response to vasopressin infusion in septic shock. We conducted a retrospective analysis using the Vasopressin in Septic Shock Trial (VASST) as a derivation cohort (n = 665), then validated using another single-center septic shock cohort, St Paul’s Hospital (SPH) cohort (n = 469). Lactate levels were divided into quartiles. The primary outcome variable was 28-day mortality in both cohorts. We used receiver operating characteristic (ROC) curve analysis to compare the prognostic value of lactate concentrations versus Acute Physiology and Chronic Health Evaluation II scores. We then explored whether lactate concentrations might predict beneficial response to vasopressin compared with noradrenaline in VASST. Normal lactate range is less than 2.3 mmol/L. At enrolment, patients in the second quartile (1.4 < lactate < 2.3 mmol/L) had significantly increased mortality and organ dysfunction compared with patients who had lactate ≤1.4 mmol/L (quartile 1) (P < 0.0001). Quartile 2 outcomes were as severe as quartile 3 (2.3 ≤ lactate < 4.4 mmol/L) outcomes. Baseline lactate values (area under the ROC curve = 0.63, 0.66; VASST, SPH) were as good as Acute Physiology and Chronic Health Evaluation II scores (area under the ROC curve = 0.66, 0.73; VASST, SPH) as prognostic indicators of 28-day mortality. Lactate concentrations of 1.4 mmol/L or less predicted a beneficial response in those randomized to vasopressin compared with noradrenaline in VASST (P < 0.05). Lactate concentrations within the “normal” range can be a useful prognostic indicator in septic shock. Furthermore, patients whose lactate level is less than or equal to 1.4 mmol/L may benefit from vasopressin infusion.

ABBREVIATIONS: APACHE—Acute Physiology and Chronic Health Evaluation

ATP—adenosine triphosphate

COPD — chronic obstructive pulmonary disease

ScvO2—central venous oxygen saturation

SPH—St Paul’s Hospital

VASST—Vasopressin and Septic Shock Trial

University of British Columbia, Critical Care Research Laboratories, Institute for Heart+Lung Health, St Paul’s Hospital, Vancouver, British Columbia, Canada

Received 24 Jan 2012; first review completed 9 Feb 2012; accepted in final form 8 Mar 2012

Address reprint requests to Keith R. Walley, MD, FRCP(C), Institute for Heart+Lung Health, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6. E-mail:

The VASST study was funded by the Canadian Institutes of Health Research.

There were no conflicts of interest in undertaking this study. No authors have potential conflicts related to this manuscript.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (

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Septic shock is an extreme clinical condition involving tissue hypoperfusion where tissue oxygen demand can exceed the ability of tissues to extract oxygen from the limited oxygen supply. Sepsis additionally impairs the ability of tissues to extract oxygen so that ATP generation from glucose oxidation is supplemented by ATP generation from glycolysis, leading to lactate production (1–3). Hepatic and muscle clearance of lactate may also be impaired. Thus, blood lactate concentrations are often elevated. The most recent guidelines for severe sepsis or septic shock management indicate that a blood lactate concentration of greater than 4 mmol/L mandates prompt resuscitation of severe sepsis or septic shock (4, 5).

There is no doubt that a blood lactate concentration of greater than 4 mmol/L is concerning. However, several recent studies have suggested that minimal elevations in blood lactate concentrations, much lower than 4 mmol/L, may be a prognostic marker of adverse outcome and, by extension, may warrant early aggressive resuscitation (6, 7). We were therefore interested in understanding the importance of relatively low blood lactate concentrations in septic shock patients, even within the conventional “normal” range (lactate <2.0–2.5 mmol/L) (8–10). We first asked whether blood lactate concentrations, even within the normal range, are prognostic for 28-day mortality in septic shock patients. Because lactate concentrations may be easier and faster to measure than an Acute Physiology and Chronic Health Evaluation II (APACHE II) (or equivalent) severity-of-illness score (11), we also wondered whether blood lactate measurements compare favorably to APACHE II scores. To address these questions, we used the Vasopressin and Septic Shock Trial (VASST) cohort of septic shock patients as a derivation cohort and tested for replication in another single-center septic shock cohort; the St Paul’s Hospital (SPH) cohort. Because VASST was a large multicenter randomized controlled trial of vasopressin added to conventional noradrenaline (norepinephrine) therapy, in the VASST derivation cohort only we explored whether normal range lactate concentrations might predict response to vasopressin.

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Patient cohorts

VASST cohort

The VASST is a large multicenter, randomized, double-blind, controlled trial evaluating the efficacy of vasopressin versus noradrenaline on mortality in 778 septic shock patients (12). Septic shock was defined by the presence of two or more diagnostic criteria for the systemic inflammatory response syndrome, proven or suspected infection, at least one new organ dysfunction by Brussels criteria, and hypotension despite adequate fluid resuscitation (13, 14). Of these, 665 patients who had arterial lactate measurements at study enrolment were included in this analysis as a derivation cohort. Because patient identification and enrolment took time, this baseline arterial lactate was obtained on average 18.0 ± 9.2 h after the onset of septic shock. The protocol of VASST was approved by the research ethics boards of all participating centers, and written informed consent was obtained from all patients or their relatives.

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SPH cohort

All patients admitted to the intensive care unit at SPH in Vancouver, British Columbia, Canada, between July 2000 and January 2004 were screened (n = 1,626). Septic shock was defined using the same consensus definition as above (13, 14). Of these, 469 patients had arterial lactate measurements within the first 4 h after study enrolment. This septic shock cohort was used as a validation cohort. The institutional review board at SPH and the University of British Columbia approved the study.

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Measurements in both cohorts

Baseline characteristics of the patients were measured at study enrolment and included age, sex, and preexisting conditions. Patients with preexisting liver disease were identified based on patients’ medical history, and we stratified severity based on bilirubin at study enrolment using the Brussels criteria (14, 15). Hemodynamic variables (mean arterial pressure, central venous pressure, heart rate) and baseline laboratory variables (lactate, creatinine, white blood cell count, platelet count) were also measured. Baseline lactate concentrations were measured by each individual hospital’s clinical laboratory.

Organ dysfunction as previously described (15) was also measured in both cohorts. To assess organ dysfunction and to correct organ dysfunction scoring for deaths in the 28-day observation period, we calculated days alive and free of organ dysfunction. During each 24-h period (8 AM to 8 AM) for each variable, days alive and free was scored as 1 if the patient was alive and free of organ dysfunction [normal or mild dysfunction using the Brussels criteria (14)]. Days alive and free was scored as 0 if the patient had organ dysfunction (moderate or worse) or was not alive. Every day over the 28-day observation after intensive care unit (ICU) admission was scored in this way. Thus, the lowest score possible for each variable was zero, and the highest score possible was 28. A low score indicates more organ dysfunction, whereas a high score indicates less organ dysfunction. The full vasopressin treatment protocol in VASST has been previously described (12). Briefly, the patient was randomized to receive blinded treatment of either vasopressin infusion (target, 0.03 U/min) added to conventional noradrenaline therapy or blinded noradrenaline infusion (target, 15 μg/min) added to conventional noradrenaline therapy.

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Statistical analysis

We divided patients from VASST into quartiles of arterial lactate concentration at enrolment. We tested for differences in baseline characteristics by lactate interval using a Kruskal-Wallis test for continuous data or a χ2 test for categorical data and reported the median and interquartile ranges. The primary outcome variable was 28-day mortality, and differences by lactate quartile were tested using Cox regression analysis. The secondary outcome variables were days alive and free of organ failure (16) (including cardiovascular, respiratory, renal, hepatic, neurologic, and coagulation) and days alive and free of organ support (including vasopressors, mechanical ventilation, and hemodialysis), tested by lactate quartile using a Kruskal-Wallis test and χ2 test. We then tested for replication of primary and secondary outcomes in the SPH cohort using the same lactate quartiles derived from VASST. We tested for the influence of covariates affecting 28-day mortality including age, APACHE II score, and preexisting liver disease using logistic regression analysis. We compared the prognostic value of arterial lactate to APACHE II scores using receiver operating characteristic (ROC) curves. Finally, we tested for the ability of lactate concentrations to predict response to vasopressin treatment in VASST. Differences were considered significant using a 2-tailed P < 0.05. Analyses were performed using SPSS (SPSS Inc., version 17.0, Chicago, IL) and MedCalc (MedCalc Software, version, Mariakerke, Belgium) statistical software packages.

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Quartiles of blood lactate concentration at study enrolment in the 665 patients in VASST were quartile 1 (Q1): lactate 1.4 mmol/L or less, quartile 2 (Q2): 1.4 < lactate < 2.3 mmol/L, quartile 3 (Q3): 2.3 ≤ lactate < 4.4 mmol/L, and quartile 4 (Q4): lactate 4.4 mmol/L or greater (Table 1). The median lactate concentrations of each quartile were 1.1 (Q1), 1.8 (Q2), 3.0 (Q3), and 6.7 (Q4) mmol/L (P < 0.001). The differences at baseline between these quartiles in VASST were that the patients in Q1 had significantly lower APACHE II scores (P < 0.001), fewer patients had liver disease (P < 0.01), and fewer patients had COPD (P < 0.001) compared with patients in Q2, Q3, and Q4. Patients in Q1 had significantly higher white cell counts (P < 0.001) and platelet counts (P < 0.001) and lower creatinine (P < 0.001) at enrolment. Patients in the SPH replication cohort demonstrated similar differences or trends (Table 1). In terms of the primary site of septic shock, patients in Q1 of VASST had more pulmonary infection (P = 0.002) and less intra-abdominal infection (P = 0.015) compared with the other three quartiles. This difference with respect to the primary site of infection was not replicated in the SPH cohort (Table 1).

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Q2 normal-range lactate is associated with worse 28-day mortality and organ dysfunction in septic shock patients

At the extremes, patients in Q1 had decreased 28-day mortality, and patients in Q4 had increased 28-day mortality compared with the other quartiles of patients (P < 0.001) (Fig. 1A), and this result replicated in SPH (P < 0.001) (Fig. 1B). Notably, mortality rates increased from Q1 (VASST 25.7%, SPH 33.9%) to Q2 (VASST 41.0%, SPH 46%), indicating the importance of a minimal increase in arterial lactate concentration within the normal range. Adjusting for age, sex, APACHE II score, and preexisting liver disease did not alter this conclusion (see Figure, Supplemental Digital Content 1, at, illustrating lactate interval versus 28-day mortality in all patients, exclude preexisting liver disease, and adjusted for age, APACHE II, preexisting liver disease in VASST; logistic regression analysis, P value between quartiles 1 and 2, quartiles 1 and 3, and quartiles 1 and 4 were less than 0.05. Interestingly, patients in Q2 had significant increased mortality compared with patients in Q1 [hazard ratio {HR}, 1.782; 95% confidence interval {CI}, 1.215–2.611, P = 0.003], whereas the patients in Q2 had no significant difference in 28-day mortality compared with patients in Q3). For secondary outcomes in VASST, patients in Q1 had more and patients in Q4 had fewer days alive and free of any organ failure (cardiovascular, respiratory, renal, hepatic, neurologic, and coagulation) and days alive and free of any organ support (vasopressors, mechanical ventilation, hemodialysis) during the first 28 days (all P < 0.0001) (Table 2). This result also replicated in SPH (all P < 0.0001) (Table 2).

We also found that there was no difference in 28-day mortality between Q2 patients (lactate concentration between 1.4 and 2.3 mmol/L) and Q3 patients (lactate concentration of 2.3–4.4 mmol/L (Fig. 1). This result replicated in SPH. Adjusting for age, sex, APACHE II score, and preexisting liver disease did not alter this conclusion (see Figure, Supplemental Digital Content 1, at Similarly, in both cohorts, there were no differences in days alive and free of organ failure or organ support between Q2 and Q3 (Table 2). In the analysis for HR of 28-day mortality in VASST, we found that 28-day mortality was significantly higher in Q2 compared with Q1 (HR, 1.782; 95% CI, 1.215–2.611), but again, there was no significant difference of HR between Q2 and Q3 (Table 3).

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Comparison of baseline arterial lactate to APACHE II score

In VASST, the ROC curves for baseline lactate and APACHE II almost overlap (Fig. 2), and this observation replicated in SPH. Furthermore, by plotting individual lactate and APACHE II scores on these ROC curves, it is apparent that baseline lactate concentrations of 1.4, 2.3, and 4.4 mmol/L compare closely in sensitivity and specificity to APACHE II scores of 22, 27, and 33, respectively (Fig. 2). The baseline lactate corresponded in a similar way to APACHE II score where lactate 1.4 mmol/L (VASST sensitivity 86%, specificity 27%, SPH sensitivity 84%, specificity 31%) was similar to APACHE II of 22 (VASST sensitivity 89%, specificity 26%, SPH sensitivity 88%, specificity 35%); lactate 2.3 mmol/L (VASST sensitivity 60%, specificity 55%, SPH sensitivity 66%, specificity 60%) was similar to APACHE II of 27 (VASST sensitivity 63%, specificity 60%, SPH sensitivity 71%, specificity 62%); and lactate 4.4 (VASST sensitivity 36%, specificity 82%, SPH sensitivity 41%, specificity 84%) was similar to APACHE II of 33 (VASST sensitivity 37%, specificity 85%, SPH sensitivity 43%, specificity 87%). The areas under the ROC curve (AUCs) for lactate were 0.63 in VASST (95% CI, 0.59–0.67) and 0.66 in SPH (95% CI, 0.61–0.71). This was similar to the AUC for the APACHE II score (VASST AUC = 0.66 [95% CI, 0.62–0.69]; SPH AUC = 0.73 [95% CI, 0.68–0.77]), so that the difference between AUCs was minimal (0.02 ± 0.03; 95% CI, −0.03 to 0.08; P = 0.41).

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Predictive value of normal-range arterial lactate concentration

Having found that Q2 normal-range lactate concentrations are prognostic of outcome in septic shock, we were interested in knowing whether normal-range lactate concentrations could also be predictive of response to vasopressin compared with noradrenaline infusion. Because VASST was our derivation cohort and also a randomized blinded controlled trial of vasopressin versus conventional catecholamine therapy, we tested for differences in response to vasopressin compared with noradrenaline infusion by lactate quartiles. In VASST, there was a significantly lower mortality rate in the vasopressin (18.9%) compared with the noradrenaline treatment group (33.8%) (P = 0.025; Fig. 3) only in the lowest lactate quartile.

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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 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.

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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)].

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Sepsis; septic shock; lactate; vasopressin; prognosis

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