Reconsidering lactate as a sepsis risk biomarker

OBJECTIVES: There has been renewed interest in lactate as a risk biomarker in sepsis and septic shock. However, the ability of the odds ratio (OR) and change in the area under the receiver operator characteristic curve (AUC-ROC) to assess biomarker added-value has been questioned. DESIGN, SETTING AND PARTICIPANTS: A sepsis cohort was identified from the ICU database of an Australian tertiary referral hospital using APACHE III diagnostic codes. Demographic information, APACHE III scores, 24-hour post-admission patient lactate levels, and hospital mortality were accessed. MEASUREMENTS AND MAIN RESULTS: Hospital mortality was modelled using a base predictive logistic regression model and sequential addition of admission lactate, lactate clearance ([lactate(admission)—lactate(final)]/lactate(admission)), and area under the lactate-time curve (LTC). Added-value was assessed using lactate index OR; AUC-ROC difference (base-model versus lactate index addition); net (mortality) reclassification index (NRI; range -2 to +2); and net benefit (NB), the number of true positives per patient adjusted for the number of false positives. The data set comprised 717 patients with mean(SD) age and APACHE III score 61.1(16.5) years and 68.3(28.2) respectively; 59.2% were male. Admission lactate was 2.3(2.5) mmol/l; with lactate of ≥ 4 mmol/L (37% hospital mortality) in 17% and patients with lactate < 4 mmol/L having 18% hospital mortality. The admission base-model had an AUC-ROC = 0.81 with admission lactate OR = 1.127 (95%CI: 1.038, 1.224), AUC-ROC difference of 0.0032 (-0.0037, 0.01615; P = 0.61), and NRI 0.240(0.030, 0.464). The over-time model had an AUC-ROC = 0.86 with (i) clearance OR = 0.771, 95%CI: 0.578, 1.030; P = 0.08; AUC-ROC difference 0.001 (-0.003, 0.014; P = 0.78), and NRI 0.109(-0.193, 0.425) and (ii) LTC OR = 0.997, 95%CI: 0.989, 1.005, P = 0.49; AUC-ROC difference 0.004 (-0.002, 0.004; P = 0.34), and NRI 0.111(-0.222, 0.403). NB was not incremented by any lactate index. CONCLUSIONS: Lactate added-value assessment is dependent upon the performance of the underlying predictive model and should incorporate risk reclassification and net benefit measures.