Since the publication of the sepsis trilogy, PROMISE, ARISE, and PROCESS ¹,²,³, abruptly displaced early goal directed therapy (EGDT) as the cornerstone of sepsis management, we have been searching to fill the therapeutic vacuum its sudden departure left behind. The Center for Medicare and Medicaid Services (CMS) and the Surviving Sepsis Campaign (SSC) have both rushed to offer guidance on the appropriate management strategies for patients presenting with septic shock. In both cases a lactate-guided resuscitation approach is strongly recommended, in fact CMS incorporates its use into their mandated treatment bundles. But this obligatory performance measure is based more on opinion and conjecture than empiric data. With the recent publication of the ANDROMEDA-SHOCK in JAMA, examining a lactate-based resuscitative strategy for patients presenting with septic shock, we finally have empiric evidence to assess its therapeutic value⁴.

Hernandez et al randomized adult patients presenting with septic shock (defined as a serum lactate ≥2.0 mmol/L, requiring vasopressors to maintaining a MAP of 65 mm Hg after a fluid bolus of at least 20 mL/kg) to one of two resuscitation strategies for the first 8-hours of management. The two groups were the peripheral perfusion group and the lactate-guided group. In both groups end-organ perfusion was assessed using either capillary refill time (CRT) or serum lactate. If perfusion was determined to be inadequate, patients were evaluated for fluid responsiveness and given a fluid bolus if they were deemed responsive. If perfusion continued to be inadequate, the patients continued to receive fluid resuscitation until they were determined to no longer be responsive. At which point patients underwent vasopressor and/or inotrope testing to determine if either corrected their perfusion inadequacies. The two groups differed only in the manner they entered this pathway. In the peripheral perfusion group only patients with inadequate CRT underwent further fluid loading and vasopressor/inotropic testing. While in the lactate group it was an inability to clear ones lactate by 20% that initiated further hemodynamic testing.

The authors enrolled 424 patients over a year long period from 28 sites, the majority (71%) were enrolled from the Emergency Department. A lactate-guided strategy led to a higher volume of fluid administered, more vasopressor use, and more frequent use of epinephrine. But this failed to translate into an improvement in clinical outcomes. In fact, when patients underwent a lactate guided strategy they tended to fare worse when compared to a perfusion targeted approach. 28-day mortality was 34.9% in the peripheral perfusion group and 43.4% in the lactate group (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06). This 8.5% absolute difference, while not statistically significant, bordered on demonstrating harm associated with a lactate guided resuscitation approach. In fact, there was significantly less organ dysfunction at 72 hours in the peripheral perfusion group.

There are a number of conclusions that can be drawn from these results. One could deduce that there is no difference between these two resuscitative strategies and either approach to the early hemodynamic management of patients in septic shock is adequate. An alternative interpretation is a lactate guided-therapy is harmful and the authors powering their study to demonstrate a 15% ARR left their study immensely underpowered to detect an 8.5% in 28-day mortality. The majority of lactate produced in the early stages of sepsis is not due to end-organ malperfusion, therefore incorporating it into a treatment algorithm that treats it as a marker of tissue hypoxia cannot help but lead us astray.

A third possibility is neither of these strategies are the ideal method for resuscitating a patient in septic shock, rather the peripheral perfusion approach merely represents the lesser of two evils. It may very well be that a fluid restrictive, damage control resuscitation strategy, that does not concern itself with identifying and eliminating fluid responsiveness is optimal. The peripheral perfusion strategy likely appeared superior simply because it triggered activation of the ANDROMEDA-SHOCK resuscitation pathway less frequently, sparing a greater proportion of patients from our overly enthusiastic therapeutic intentions.

A number of trials examining patients in septic shock have called into question use of a hemodynamic-guided resuscitative strategy. In the FEAST trial⁵, patients who received a fluid bolus more frequently experienced improvements in early hemodynamic markers compared to patients who did not receive a bolus⁶. They also happened to die more frequently. Andrews et al observed a similar phenomenon in their cohort of adult patients presenting in septic shock, finding patients randomized to a resuscitation strategy intent on correcting early hemodynamic abnormalities led to an increase in mortality⁷. Hjortrup et al found that an aggressive response to hemodynamic perturbations led to an increase in frequency of AKI⁸. While these aggressive resuscitative strategies were all associated with timelier improvements in early hemodynamic markers, this came at the cost of downstream morbidity and mortality.

Resuscitating patients in septic shock with an eye towards hemodynamic perfection is likely to be detrimental. And while monitoring serum lactate is unlikely to be harmful, our reflexive therapeutic response may very well be. In light of the current evidence, continued recommendations supporting a lactate guided resuscitation strategy will only encourage over-resuscitation and the downstream harms associated with such aggressive strategies.

1. The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-1693
2. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-1506
3. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015;372:1301-1311
4. Hernández G, Ospina-tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;
5. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-95.
6. Myburgh J, Finfer S. Causes of death after fluid bolus resuscitation: new insights from FEAST. BMC Med. 2013;11:67.
7. Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233-1240.
8. Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42(11):1695-1705.

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Rory Spiegel

EM and Critical Care Attending
University of Georgetown
Resuscitation and Critical Care Fellowship Graduate

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