Elevated serum lactate is the classic biomarker of mortality risk from refractory septic shock. But workups for sepsis should also include renin levels, which may in fact be a better prognostic marker for these patients, according to Ashish K. Khanna, MD, MS, FCCM, a professor of anesthesiology and vice-chair of research with the department of anesthesiology, section on critical care medicine at the Wake Forest University School of Medicine, in Winston-Salem, NC.
“Refractory shock as we know it is usually vasopressor-refractory shock,” Dr. Khanna said during the 2025 Critical Care Congress, in Orlando, Fla. The severe and life-threatening condition occurs when a patient's blood pressure remains dangerously low despite receiving high doses of vasopressor medications.
A 2013 study found an association between 90-day all-cause mortality rates of more than 80% among intensive care patients with low blood pressure after a norepinephrine vasopressor dose approaching 1 mcg/kg per minute (Chest 2013;143[3]:664-671). A 2023 study that Dr. Khanna was part of showed almost 100% in-hospital mortality among patients who received the highest norepinephrine doses (Chest 2023;163[1]:148-151).
Dr. Khanna noted that many parts of the definition of refractory shock are unclear. For example, should shock only be called refractory if at least two vasopressors are used? Do vasopressors need to reach a certain dose? What’s the importance of poor organ perfusion, even after adequate fluid resuscitation and reaching a target mean arterial pressure (MAP), in defining refractory shock? Dr. Khanna is the co-chair of an ongoing Society of Critical Care Medicine–European Society of Intensive Medicine task force examining these questions.
Although the definition of refractory shock needs fine-tuning, renin’s role as a prognostic marker is clear. Dysfunction of the renin-angiotensin-aldosterone system has been demonstrated in septic shock, and VICTAS (Vitamin C, Thiamine, and Steroids in Sepsis) trial investigators associated elevated renin, change in renin and a trend toward increased mortality (Crit Care Med 2024;52[3]:441-451), noted Dr. Khanna, who was senior author of the VICTAS trial.
Elevated renin consistently outperforms elevated lactate as a marker of in-hospital mortality in other studies, with elevated renin typically defined as more than 40 pg/mL and elevated lactate as more than 2 mmol/L (Crit Care Med 2019;47[2]:152-158 and 2022;50[1]:50-60).
Ongoing work at Wake Forest suggests that renin, which should catalyze the production of angiotensin II to constrict blood vessels and thus raise blood pressure, does not do so in people experiencing advanced shock (Peptides 2024:176:171201).
However, even if lactate does not predict mortality from shock as well as renin, “we should not stop measuring lactate,” Dr. Khanna said, particularly because it’s possible to do so with point-of-care tests in most places in the world, with results in approximately five minutes. Such rapid results are part of the reason why lactate remains “a great screening tool for sepsis and septic shock,” she said. Conversely, it’s not that easy, yet, to measure serum renin at the bedside, she noted. Indeed, “consider this a call to biotechnology companies to develop point-of-care tools for measuring renin levels,” Dr. Khanna said.
Look Beyond the MAP
The traditional MAP goal for people who experience septic shock is more than 65 mm Hg because this level is considered sufficient for organ perfusion and thereby helps the patient to recover (Crit Care 2015;19[1]:101).
“If a patient is not meeting their goal MAP, a vasopressor is indicated, assuming they’ve received adequate fluid resuscitation,” said SCCM session speaker Pansy Elsamadisi, PharmD, a critical care pharmacy specialist at Beth Israel Deaconess Medical Center, in Boston. Data suggest that a MAP of 60 mm Hg may be adequate for some patients (Intensive Care Med 2018;44[9]:1551-1552), she noted. There is conflicting evidence regarding fluid resuscitation in septic shock, with the general guidance being 30 mL/kg of fluid, but Dr. Elsamadisi said this may be too much for some patients (Ann Intensive Care 2018;8[1]:66).
“Although norepinephrine is first line for a majority of patients in septic shock, it’s not necessarily because norepinephrine is more efficacious than other vasopressors. Studies available suggest it is safer and easier to use,” Dr. Elsamadisi said (Intensive Care Med 2021;47[11]:1181-1247).
If norepinephrine fails to achieve a patient’s goal MAP, the next steps are unclear. “We don’t have a lot of data on the appropriate stepwise vasopressor therapy, or if it even should be a stepwise approach,” Dr. Elsamadisi said. If available, vasopressin can be added as a second vasopressor, because data suggest early use of vasopressin improves clinical outcomes. However, angiotensin II and other catecholamines can also be used, albeit the evidence is not as robust as with vasopressin. Thus, the optimal vasopressor sequence is a topic for consultation among pharmacists, nurses and providers, she added.
Although achieving a goal MAP is important, it may not be the only objective. “An important question as you continue to assess and reassess your patient is whether your patient is showing signs of clinically improving,” Dr. Elsamadisi said. Those signs include improved urine output, better mentation or declining lactate, all of which suggest adequate organ perfusion, she noted.
As for when a patient is at their goal MAP but is not clinically improving, and thus might need a second or third vasopressor, “this is an area that requires further research,” Dr. Elsamadisi said.
The sources reported no relevant financial disclosures.
This article is from the July 2025 print issue.