Our main finding is that a multimodal perfusion monitoring in sepsis-3 septic shock patients may aid to differentiate two clinical patterns according to the presence of a hypoperfusion context. Patients with hyperlactatemia associated with either low ScvO
2, or high P(cv-a)CO
2, or high CRT values exhibit a more severe circulatory dysfunction. The absence of a hypoperfusion context among septic shock patients with hyperlactatemia is associated with a good outcome. These findings do not support sepsis-3 statement that the new septic shock definition identifies a group of patients with a homogenous high mortality risk [
1]. On the other hand, they provide the basis for the development of a prospective study aimed at testing a safe restrictive fluid resuscitation strategy in septic shock patients without a hypoperfusion context, while concentrating resuscitation efforts in those with hypoperfusion criteria. The presence of a low ScvO
2 in the setting of persistent hyperlactatemia clearly indicates an imbalance in the oxygen transport/oxygen consumption relationship [
7,
11]. A high Pcv–aCO
2 might identify patients who remain inadequately resuscitated and constitutes a marker of global perfusion that could aid in identifying a hypoperfusion-related hyperlactatemia [
12,
13]. Assessment of peripheral perfusion may provide additional physiological information. An abnormal peripheral perfusion may be caused by adrenergic-induced skin vasoconstriction secondary to a low systemic blood flow and should prompt a reassessment of the hemodynamic state, in particular the volume status [
10,
14]. Under the best of our knowledge, this is the first study that uses the three variables together to define a hypoperfusion context, an aspect that has to be highlighted because of the individual limitations of every isolated parameter. As a matter of fact, ScvO
2 can be normal in the setting of severe microcirculatory abnormalities [
4,
12], Pcv-aCO
2 might be normal in hyperdynamic states even in the presence of tissue hypoxia [
13], and peripheral perfusion may be difficult to assess under some circumstances. However, our results show that when the three are normal in hyperlactatemic patients, mortality as well as morbidity is very low, and thus the presence of tissue hypoxia as the cause of hyperlactatemia appear as unlikely in this setting, although of course it cannot be ruled out completely.
Remarkably, lactate values were comparable between subgroups at baseline (mean of 4.7–4.8 mmol/l) at a level where patients would not only have been diagnosed as septic shock according to sepsis-3 criteria [
1], but also considered for inclusion in the EDGT trial [
11]. However, adding hypoperfusion-context criteria to clinical assessment might aid in differentiating two clinical patterns with marked different risks as demonstrated by our study. Of course our design does not allow us to establish sensitivity or specificity or predictive value of these criteria to track real hypoxia-related hyperlactatemia, but at least our findings are hypothesis-generating, and might build up the foundations for future trials on septic shock patients that focus resuscitation efforts on selected populations. Anyway, hypoxia is a cellular event that is hardly diagnosed by clinical means. In the past, lactate/pyruvate ratio or more recently, the venous-arterial CO
2 to arterial-venous O
2 content difference ratio have been proposed for this purpose, although both ratios have important theoretical and practical drawbacks [
3,
8]. Our study has several drawbacks related to its retrospective nature and inclusion of a relatively small number of patients. Several variables exhibited a trend to be worse in the hypoperfusion-related subgroup but were short of significance, thus weakening our conclusions. Additionally, each variable proposed to define a hypoperfusion context has its own limitations. We also did not calculate the lactate/pyruvate or venous-arterial CO
2 to arterial-venous O
2 content difference ratios, closers indicators of tissue hypoxia according to several physiological studies. The parallel decrease in lactate levels in subgroups with versus without a hypoperfusion context could be viewed as contradictory, but when addressing this aspect more profoundly, the rate of decrease in lactate values in presumably hypoperfused patients was slowed by the performance of non-survivors who tended to increase lactate over time as compared to survivors (Additional file
1: Figure S1). This highlights the difficulties in interpreting lactate dynamics in septic shock patients subjected to a nonselective resuscitation strategy, as was also observed in another previous study [
7]. However, despite these limitations, we could effectively differentiate two clinical patterns among hyperlactatemic septic shock patients when applying a monitoring model that includes three easily assessable perfusion-related parameters.