Point: Should Lactate Clearance Be Substituted for Central Venous Oxygen Saturation as Goals of Early Severe Sepsis and Septic Shock Therapy? Yes

Quantitative resuscitation in critically ill patients consists of structured cardiovascular interventions, such as intravascular volume expansion and vasoactive agent support, to achieve explicit predefined physiologic parameters or goals. The concept of quantitative resuscitation (also referred to as hemodynamic optimization or goal-directed therapy) as a treatment strategy to improve clinical outcome was first reported in high-risk surgery patients.¹ A recent meta-analysis of randomized clinical trials that compared quantitative resuscitation with standard resuscitation in septic shock found that when therapy was initiated within 24 h of the onset of sepsis (six trials, 740 patients), resuscitation targeting specific physiologic end points improved mortality compared with standard resuscitation (39% vs 57%: OR, 0.50; 95% CI, 0.37-0.69).² In contrast, when therapy was initiated > 24 h after the onset of sepsis (three trials, 261 patients), resuscitation targeting specific physiologic end points did not improve mortality (64% vs 58% for standard resuscitation; OR, 1.16; 95% CI, 0.60-2.22). Although the data supporting the use of early quantitative resuscitation are robust, the optimal end points or goals of such therapy are controversial.

Currently, consensus guidelines recommend the use of central venous pressure (CVP), mean arterial pressure (MAP), urine output, and central venous oxygen saturation (Scvo₂) as resuscitation goals.³ These recommendations are based largely on an ED-based clinical trial of quantitative resuscitation for septic shock, an approach termed “early goal-directed therapy,” which was a single-center study published by Rivers et al⁴ in 2001. In this trial, 263 patients with severe sepsis or septic shock were randomly assigned to therapy targeting an Scvo₂ of ≥70% or to conventional therapy that did not target an Scvo₂. In both groups, therapy targeted CVP, MAP, and urine output. Mortality was significantly lower in the group that targeted an Scvo₂ of ≥70% (31% vs 47%). Given that the only difference in the treatment protocols in this trial was the Scvo₂ target, the observed treatment effect appears to hinge on achieving this node of the algorithm. In contrast, earlier studies of critically ill patients that targeted mixed venous oxygen saturation (Svo₂) of ≥70% found no mortality benefit.⁵

Multiple studies have unfortunately documented important barriers to implementing and maintaining an ED-based quantitative resuscitation protocol for septic shock.^6-8 Among these, the use of a central venous catheter and the need for specialty equipment such as a continuous central venous oxygen spectrophotometer, and the training required for it, were major barriers that limited generalizability. To begin to address these barriers, the Lactate Assessment in the Treatment of Early Sepsis (LACTATES) randomized multicenter noninferiority trial, the largest ED-based early sepsis resuscitation trial completed to date, was designed to compare the use of lactate clearance to Scvo₂ as the final goal of early sepsis resuscitation.⁹ In the study, enrolled patients were randomly assigned to one of two groups. Each group received structured quantitative resuscitation while in the ED. The Scvo₂ group (n=150) was resuscitated by sequentially providing the therapy needed to meet thresholds of CVP, followed by MAP, and then Scvo₂ of ≥70%. The lactate clearance group (n=150) had similarly targeted thresholds in CVP and MAP, and then lactate clearance of ≥10% or more. The study protocol was continued until all end points were achieved or for a maximum of 6 h. The published results of this study showed a 6% (95% CI, −3% to 14%) in-hospital mortality difference between the two study groups (17% in the lactate clearance group vs 23% in Scvo₂ group), confirming the primary hypothesis of noninferiority.

There are many evidence-based, data-driven, and logical arguments as to why lactate clearance monitoring is a superior therapeutic target to oxygen-derived variables such as Scvo₂. First, the published experimental (randomized trial) evidence supporting the use of lactate clearance as a therapeutic target is more robust in terms of the number of multicenter studies.^9,10 Similar published experimental evidence supporting Scvo₂ is derived only from single-center studies.^4,11 Furthermore, multicenter studies have failed to show the use of Svo₂ as a resuscitation goal⁵; however, unlike Scvo₂ or other oxygen-derived variables, the ability to clear lactate has consistently predicted better survival in published studies of sepsis resuscitation.^12-15

Second, elevated lactate levels reflect the total picture of energy metabolism in the acutely stressed patient with sepsis. Elevated blood lactate has long been known to reflect anaerobic metabolism from tissue hypoxia in critically ill patients.¹⁶ However, besides these anaerobic processes, aerobic (metabolic) mechanisms that affect the host’s efficiency of energy transfer contribute to lactate production in sepsis. Cytokine-mediated glucose uptake and catecholamine-stimulated Na-K pump overactivity can both result in increased pyruvate production that eventually will overwhelm the catalytic capacity of pyruvate dehydrogenase (PDH) and result in increased lactate because of either mass effect, sepsis-induced PDH dysfunction, or both. This mechanism may explain part of the lactate production observed from the lungs and WBC in response to the inflammatory stress, rather than tissue hypoxia of sepsis.¹⁷ Additionally, reduced lactate clearance may reflect globally impaired metabolic function by the liver and kidney, both of which normally contribute to systemic lactate disposal through anaplerosis, a mechanism that carboxylates lactate and delivers it to the tricarboxylic acid cycle, independent of the action of PDH.¹⁸ Recent studies have shown that early lactate clearance is associated with improvement in the biomarkers of inflammation and organ dysfunction.¹⁹ Thus, as opposed to Scvo₂, which is a rudimentary indicator of only the balance between oxygen supply and demand, lactate clearance biologically reflects more of the general homeostasis of the host and provides more meaningful data about the overall adequacy of the resuscitative processes.

Third, in some circumstances the use of Scvo₂ might erroneously lead a clinician to believe that the physiologic status of the patient has improved, when in fact it may not have improved. A recent multicenter study of 619 patients demonstrated that venous hyperoxia (Scvo₂ >89%) is present in 36% of ED patients with septic shock and is associated with an increased risk of death, and, when adjusted for confounders, venous hyperoxia was actually associated with a higher risk of death than venous hypoxia (Scvo₂ <70%).²⁰ In this situation, high Scvo₂ values represent either an inability to exchange oxygen because of impaired flow in the small vessels from dysfunctional vascular autoregulatory mechanisms and functional shunting of oxygen or the inability of cells to use the oxygen because of derangement of cellular respiration, so-called “cytopathic hypoxia.”²¹ Although the Rivers et al⁴ protocol focuses on the correction of a low Scvo₂ level signifying impairment in macrovascular oxygen delivery, the algorithm treats venous hyperoxia the same as normoxia (Scvo₂ 70%-90%). The finding that a high Scvo₂ is associated with increased mortality reminds us that tissue dysoxia may occur despite adequate global oxygen delivery and that this situation is not identified by the presence of normal venous oxygen levels. However, impaired oxygen transfer at any point from the lungs to the nicotinamide adenine dinucleotide dehydrogenase enzyme will cause lactic acidosis, and clearing lactate levels almost always signifies improvement in host oxygen use.⁶

Finally, a recently reported secondary analysis of the LACTATES study⁹ reported no significant concordance in achieving lactate clearance and Scvo₂ goals when measured simultaneously in the same subject, suggesting that these tests may be measuring and/or providing data about physiologically distinct processes. If lactate clearance was <10%, the mortality was 40%, but if the Scvo₂ was <70%, the mortality was 11% (proportion difference 29%; 95% CI, 6%-50%).²²

In conclusion, early sepsis resuscitation remains a dynamic topic of research interest, with many important questions that have yet to be answered. As summarized in this report, the best available evidence suggests that if a clinician has to choose a single goal of early sepsis resuscitation, lactate clearance, as opposed to Scvo₂, is the more appropriate goal to choose.

Abbreviations

CVP

central venous pressure

Do₂

systemic oxygen delivery

EGDT

early goal-directed therapy

GTH

global tissue hypoxia

MAP

mean arterial pressure

OER

systemic oxygen extraction

PDH

pyruvate dehydrogenase

Scvo₂

central venous oxygen saturation

Svo₂

mixed venous oxygen saturation

$\dot{\text{V}}$o₂

oxygen consumption