Since the publication of the sepsis trilogy—PROMISE, ARISE, and PROCESS—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. (N Engl J Med. 2014;370:1683; http://bit.ly/2Ffxe9o; N Engl J Med. 2014;371:1496; http://bit.ly/2WerSlC; N Engl J Med. 2015;372:1301; http://bit.ly/2WdYSKu.)
The Centers for Medicare and Medicaid Services and the Surviving Sepsis Campaign 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 study in JAMA examining a lactate-based resuscitative strategy for patients presenting with septic shock, we finally have empiric evidence to assess its therapeutic value. (JAMA. 2019;321:65; http://bit.ly/2HwwCj3.)
Hernandez, et al., randomized adults presenting with septic shock (defined as a serum lactate ≥2.0 mmol/L, requiring vasopressors to maintain a MAP of 65 mm Hg after a fluid bolus of at least 20 mL/kg) to one of two resuscitation strategies—the peripheral perfusion group and the lactate-guided group—for the first eight hours of management. End-organ perfusion was assessed in both groups using capillary refill time (CRT) or serum lactate. If perfusion were inadequate, patients were evaluated for fluid responsiveness and given a fluid bolus if deemed responsive.
If perfusion continued to be inadequate, the patients continued to receive fluid resuscitation until they were no longer responsive, at which point patients underwent vasopressor or inotrope testing to determine if either corrected their perfusion inadequacies. The two groups differed only in the manner they entered this pathway. Only patients with inadequate CRT in the peripheral perfusion group underwent further fluid loading and vasopressor/inotropic testing. An inability to clear one's lactate by 20 percent initiated further hemodynamic testing in the lactate group.
The authors enrolled 424 patients over a year from 28 sites, the majority (71%) enrolled from the ED. 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, patients fared worse when they underwent a lactate-guided strategy compared with a perfusion-targeted approach.
Twenty-eight-day mortality was 34.9 percent in the peripheral perfusion group and 43.4 percent in the lactate group (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; p=0.06). This 8.5 percent absolute difference, while not statistically significant, bordered on demonstrating harm associated with lactate-guided resuscitation. In fact, there was significantly less organ dysfunction at 72 hours in the peripheral perfusion group.
A number of conclusions can be drawn from these results. One could deduce no difference between these two resuscitative strategies and that either approach to the early hemodynamic management of patients in septic shock is adequate.
An alternative interpretation is that 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 percent difference in 28-day mortality. The majority of lactate produced in the early stages of sepsis is not due to end-organ malperfusion, and incorporating it into a treatment algorithm that treats it as a marker of tissue hypoxia cannot help leading us astray.
A third possibility is that neither of these strategies is the ideal method for resuscitating a patient in septic shock and that 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. Patients in the FEAST trial (N Engl J Med. 2011;364:2483; http://bit.ly/2ApcB9j) who received a fluid bolus more frequently experienced improvements in early hemodynamic markers compared with patients who did not receive a bolus. (BMC Med. 2013;11:67; http://bit.ly/2TZUGRc.) 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 that patients randomized to a resuscitation strategy intent on correcting early hemodynamic abnormalities led to an increase in mortality. (JAMA. 2017;318(13):1233; http://bit.ly/2UHk5MG.)
Hjortrup, et al., found that an aggressive response to hemodynamic perturbations led to an increase in the frequency of AKI. (Intensive Care Med. 2016;42:1695; http://bit.ly/2HP3in8.) These aggressive resuscitative strategies were associated with timelier improvements in early hemodynamic markers, but this came at the cost of downstream morbidity and mortality.
Resuscitating patients in septic shock with an eye toward hemodynamic perfection is likely to be detrimental. 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.
Share this article on Twitter and Facebook.
Access the links in EMN by reading this on our website, www.EM-News.com.
Comments? Write to us at email@example.com.
Dr. Spiegelis a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog athttp://emnerd.com, follow him on Twitter @emnerd_, and read his past articles athttp://bit.ly/EMN-MythsinEM.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.