Editorials

healthy persons (8). Whether IL-6 removal efficiency REFERENCES

by CytoSorb in such patients is similar to those with
higher baseline IL-6 values cannot be concluded.
Should such a phenomenon exist with CytoSorb,
wherein the efficiency of the device depends on the
magnitude of baseline substance concentrations and
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1. Murad MH, Montori VM, Ioannidis JPA, et al: How to read a
systematic review and meta-analysis and apply the results to
patient care: Users’ guides to the medical literature. JAMA
2014; 312:171–179
2. Murad MH, Asi N, Alsawas M, et al: New evidence pyramid.

Evid Based Med 2016; 21:125–127

declines over time, meta-analysis estimates may not
3. Heymann M, Schorer R, Putzu A: The Effect of CytoSorb on
be reliable without a meta-regression that accounts for Inflammatory Markers in Critically Ill Patients: A Systematic
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baseline IL-6 values. Review and Meta-Analysis of Randomized Controlled Trials.

In conclusion, due to high certainty and inconclu-
sive evidence about surrogate outcomes, along with
a signal of increased mortality, routine use of the
CytoSorb device in critically ill patients cannot be
recommended. The device should be studied further
in trials that evaluate patient-important outcomes (9)
and not surrogate inflammatory markers.
1 Department of Pharmacy, Mayo Clinic, Rochester, MN.
2 Department of Anesthesiology, Mayo Clinic, Rochester, MN.
3 Division of Public Health, Infectious Diseases and
Occupational Medicine, Mayo Clinic, Rochester, MN.
Dr. Wieruszewski received funding from La Jolla Pharmaceutical
Company. Dr. Murad has disclosed that he does not have any
potential conflicts of interest.
Crit Care Med 2023; 51:1659–1673
4. Zeng L, Brignardello-Petersen R, Hultcrantz M, et al: GRADE
Guidance 34: Update on rating imprecision using a minimally
contextualized approach. J Clin Epidemiol 2022; 150:216–224
5. CytoSorb: CytoSorbents Europe GmbH. Available at: https://
cytosorb-therapy.com. Accessed July 17, 2023
6. Poli EC, Rimmelé T, Schneider AG: Hemoadsorption with
CytoSorb®. Intensive Care Med 2019; 45:236–239
7. Schneider AG, André P, Scheier J, et al: Pharmacokinetics of
anti-infective agents during CytoSorb hemoadsorption. Sci
Rep 2021; 11:10493
8. Said EA, Al-Reesi I, Al-Shizawi N, et al: Defining IL-6 levels
in healthy individuals: A meta-analysis. J Med Virol 2021;
93:3915–3924
9. Gandhi GY, Murad MH, Fujiyoshi A, et al: Patient-important
outcomes in registered diabetes trials. JAMA 2008;
299:2543–2549

Is It Time to Reconsider the Concept of

“Salvage Therapy” in Refractory Shock?*
Patrick M. Wieruszewski, PharmD1,2
KEY WORDS: angiotensin; norepinephrine; perfusion; timing; vasopressin; Jonathan E. Sevransky, MD, MHS3,4
vasopressor
Russel J. Roberts, PharmD5

D
istributive shock is the most common form of circulatory failure and
is characterized by a systemic arterial tone insufficient to adequately
deliver oxygenated blood and clear metabolic waste products (1). This
syndrome may lead to an impairment in effective oxygen extraction at the level
of the tissues, inadequate cellular utilization of oxygen, rapid conversion to
anaerobic respiration, and progressive multiple organ failure. As such, distri-
butive shock must be considered a medical emergency that warrants prompt
diagnosis and reestablishment of perfusion. In patients requiring restoration
*See also p. 1674.
of systemic arterial tone despite adequate fluid resuscitation, the Surviving
Sepsis Campaign recommends vasopressor support with norepinephrine as Copyright © 2023 by the Society of
Critical Care Medicine and Wolters
the first-line choice (2). For patients that fail to achieve desired hemodynamic
Kluwer Health, Inc. All Rights
targets, recommendations regarding timing and selection of secondary agents Reserved.
are vague and have been contested widely in the literature, leaving clinicians
with varying opinions (3). DOI: 10.1097/CCM.0000000000006003

Critical Care Medicine www.ccmjournal.org     1821

Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
 Editorials
In this issue of Critical Care Medicine, Smith et al
(4) report a retrospective observational analysis of
persons with refractory distributive shock who re-
ceived angiotensin II in a so-called “salvage” fashion,
which they compared with a matched angiotensin
II-unexposed group. Importantly, the mean baseline
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vasopressor dose in norepinephrine equivalents (NEE)
was 0.62 mcg/kg/min, which was the only criterion
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used to identify the matched group, leaving multiple
differences between the treatment groups, such that
angiotensin II recipients appeared to be sicker than the
control group with higher Sequential Organ Failure
Assessment scores (12 vs 10; p < 0.001), higher lactate
concentrations (8.5 vs 5.9 mmol/L; p < 0.001), lower
mean arterial pressures (69 vs 73 mm Hg; p = 0.004),
and greater frequency of various comorbid condi-
tions, suggesting they may be, at baseline, more likely
to experience a suboptimal outcome than the control
group. Additionally, those patients in the angiotensin
II group had already progressed to more organ failures
than the control group at the time of angiotensin II re-
ceipt with nearly twice as many receiving kidney re-
placement therapy (33% vs 17%; p < 0.001), and more
were mechanically ventilated (92% vs 71%; p < 0.001)
compared with unexposed controls. Despite these
imbalances, the authors found similar 30-day (60% vs
56%; p = 0.292) and 90-day (65% vs 63%; p = 0.440)
mortality rates between angiotensin II recipients and
the control group, respectively. In their multivariable
model, receipt of angiotensin II did not alter odds of
30-day mortality (odds ratio [OR], 0.95; 95% CI, 0.61–
1.48), nor the odds of new kidney replacement therapy
or mechanical ventilation, or the propensity to experi-
ence thrombotic complications. The report by Smith
et al (4) suggests that administering angiotensin II in
patients with distributive shock that is refractory to
high-dose vasopressors may not change outcomes, but
leaves critically unanswered questions including: 1) is
refractory shock the optimal setting to apply alterna-
tive vasopressors and 2) should we reconsider the con-
cept of “salvage therapy” in shock?
Refractory shock appears to be a distinct subset of
distributive shock that presents with additional molec-
ular mechanisms that lead to impaired responsiveness
to vasopressors and promote complete cardiovascular
collapse, such as dysregulated mitochondrial respira-
tion, membrane hyperpolarization, vascular hyper-
reactivity, and compromised microcirculatory flow
1822     www.ccmjournal.org
Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
(5). Although the diagnostic criteria, risk factors, and
frequency of refractory shock are not universally ac-
cepted, most clinicians would consider the require-
ment of high doses of vasopressor agents to be an
important part of the diagnosis (6). Indeed, shock
refractory to high doses of vasopressors is associated
with extraordinarily high mortality rates, ranging from
60% to greater than 90% (7). These high mortality rates
are consistent with those observed by Smith et al (4)
in their sample of patients with a mean baseline NEE
vasopressor dose of approximately 0.62 mcg/kg/min.
This poses additional questions, such as, in the hostile
chemical environment of refractory shock requiring
extremely high doses of vasopressors, has the oppor-
tunity to meaningfully intervene passed, such that the
concept of applying a “salvage therapy” could be con-
sidered inherently flawed? Are the opportunities for
reversing organ hypoxia and restoring vascular integ-
rity the same in refractory shock as they are in shock
that has not progressed to this extent? Is it plausible for
discrete interventions to drastically alter the course of
refractory shock?
As the vasopressor requirements rise in refractory
shock, it seems apparent that the likelihood of a bene-
ficial outcome to secondary and tertiary vasopressors
declines. There is some suggestion that delayed addi-
tion of vasopressin to catecholamine vasopressors is
associated with worse outcomes: the odds of death rise
by over 20% (OR, 1.21; 95% CI, 1.09–1.34) for every
10 mcg/min increase in vasopressor dose at the time
vasopressin is added to catecholamine vasopressors
(8). Furthermore, patients randomized to vasopressin
when the norepinephrine dose was low (< 15 mcg/
min), had a lower risk of death (risk ratio, 0.78; 95%
CI, 0.61–0.99) than those who received continued es-
calation of norepinephrine, an effect not seen at higher
vasopressor doses (9). Similarly, when the vasopressor
dose at the time of randomization to angiotensin II
was low (≤ 0.25 mcg/kg/min), the hazard of death was
nearly half that of continued escalation of other vaso-
pressors (hazard ratio, 0.51; 95% CI, 0.27–0.95) (10).
Importantly, a similar relationship was not seen when
the baseline vasopressor dose was high (> 0.25 mcg/kg/
min). Taken altogether, these data suggest that contrary
to the environment in which Smith et al (4) assessed
angiotensin II, potential benefits of the addition of al-
ternative vasopressors, including angiotensin II, to cat-
echolamine vasopressors such as norepinephrine, may
December 2023 • Volume 51 • Number 12

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Figure 1. Simplified conceptual framework of a stepwise approach and an early multimodal approach to vasopressor application in the
resuscitation of distributive shock. Created with BioRender.
be realized in settings where progression to refractory
shock has not yet occurred.
The stepwise approach to vasopressor management
in distributive shock consists of application of a first-
line vasopressor, with subsequent dose up-titration
in an effort to achieve hemodynamic and perfusion
goals (Fig. 1). While many will respond to this first-
line vasopressor, those not achieving goals—at some
specified timepoint and vasopressor dose—a sec-
ondary vasopressor agent is added and adjunct treat-
ments (e.g., corticosteroids) are considered (2). One
of the most important limitations of such a strategy
is the time lost in providing satisfactory perfusion
when allowing each vasopressor an opportunity to
restore hemodynamics. Therefore, once the time has
come to add a secondary, tertiary, quaternary agent,
there has been greater exposure to hypotension,
subsatisfactory perfusion, tissue hypoxia, and organ
failure. Indeed, as the time spent under mean arterial
pressure less than 65 mm Hg increases, the odds of
acute kidney injury (OR, 1.07; 95% CI, 1.047–1.095),
myocardial injury (OR, 1.05; 95% CI, 1.004–1.087),
and death (OR, 1.11; 95% CI, 1.078–1.151) increase
(11). Similarly, as the vasopressor load increases for
Critical Care Medicine
Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Editorials
every 10 mcg/min during early resuscitation, the
odds of death increase dramatically (OR, 1.33; 95%
CI, 1.16–1.53) (12). Progressive decline in vaso-
pressor responsiveness, a characteristic of refractory
shock, must also be considered a flaw of the stepwise
vasopressor approach, as for every 1 mmol/L increase
in lactate concentrations, the odds of a favorable he-
modynamic response to the addition of vasopressin
(OR, 0.93; 95% CI, 0.89–0.97) (13) and angiotensin
II (OR, 0.89; 95% CI, 0.83–0.95) (14) in vasopressor-
refractory shock decline.
Taken altogether, it may be reasonable to ration-
alize an early multimodal vasopressor strategy (Fig. 1),
where vasopressors bearing differing mechanisms, and
adjunctive treatments, are instituted in concert from
the onset. The goals of deploying such a strategy are
to maximize the number of treatment responders and
minimize the time spent under subsatisfactory perfu-
sion targets. Some key factors we must understand to
operationalize such a strategy include how to enrich
responders to specific vasopressor agents with biologic
endotypes, better predict who will otherwise progress
to refractory shock, and ultimately shift to perfusion-
focused resuscitation.
www.ccmjournal.org     1823
 Editorials

As we continue to investigate the optimal settings
and approaches to vasopressor treatment in shock, the
findings of Smith et al (4) should remind us that we
must critically reconsider the potentially flawed con-
cept of “salvage therapy” and seek every opportunity
possible to prevent progression to refractory shock.
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4. Smith LM, Mentz GB, Engoren MC: Angiotensin II for the
Treatment of Refractory Shock: A Matched Analysis. Crit Care
Med 2023; 51:1674–1684
5. Jentzer JC, Vallabhajosyula S, Khanna AK, et al: Management
of refractory vasodilatory shock. Chest 2018; 154:416–426
6. Antonucci E, Polo T, Giovini M, et al: Refractory septic shock
and alternative wordings: A systematic review of literature. J

Crit Care 2023; 75:154258

7. Wieruszewski PM, Khanna AK: Vasopressor choice and timing
1 Department of Pharmacy, Mayo Clinic, Rochester, MN. in vasodilatory shock. Crit Care 2022; 26:76
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 11/17/2023

2 Department of Anesthesiology, Mayo Clinic, Rochester, MN.
3 Division of Pulmonary, Allergy, Critical Care, and Sleep
Medicine, Emory University School of Medicine, Atlanta,
GA.
4 Emory Critical Care Center, Emory Healthcare, Atlanta GA.
5 Department of Pharmacy, Massachusetts General Hospital,
Boston, MA.
Dr. Wieruszewski received funding from La Jolla Pharmaceutical
Company. Dr. Sevransky reports grants to institution from the
Department of Defense, the Centers for Disease Control and
Prevention Foundation, the Department of Health and Human
Services, and Regeneron Pharmaceuticals. His institution also
receives a stipend from Society of Critical Care Medicine for
his work as an associate editor for Critical Care Medicine. Dr.
Roberts has disclosed that he does not have any potential con-
flicts of interest.
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2. Evans L, Rhodes A, Alhazzani W, et al: Surviving sepsis
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3. Scheeren TWL, Bakker J, De Backer D, et al: Current use of
vasopressors in septic shock. Ann Intensive Care 2019; 9:20
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mine dose, lactate, and shock duration at vasopressin initia-
tion with mortality in patients with septic shock. Crit Care Med
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9. Russell JA, Walley KR, Singer J, et al; VASST Investigators:
Vasopressin versus norepinephrine infusion in patients with
septic shock. N Engl J Med 2008; 358:877–887
10. Wieruszewski PM, Bellomo R, Busse LW, et al; Angiotensin
II for the Treatment of High-Output Shock 3 (ATHOS-3)
Investigators: Initiating angiotensin II at lower vasopressor
doses in vasodilatory shock: An exploratory post-hoc analysis
of the ATHOS-3 clinical trial. Crit Care 2023; 27:175
11. Maheshwari K, Nathanson BH, Munson SH, et al: The rela-
tionship between ICU hypotension and in-hospital mortality
and morbidity in septic patients. Intensive Care Med 2018;
44:857–867
12. Roberts RJ, Miano TA, Hammond DA, et al; Observation
of VariatiOn in fLUids adMinistEred in shock-CHaracter-
izAtion of vaSoprEssor Requirements in Shock (VOLUME-
CHASERS) Study Group and SCCM Discovery Network:
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with septic shock*. Crit Care Med 2020; 48:1445–1453
13. Sacha GL, Lam SW, Duggal A, et al: Predictors of response to
fixed-dose vasopressin in adult patients with septic shock. Ann
Intensive Care 2018; 8:35
14. Wieruszewski PM, Wittwer ED, Kashani KB, et al: Angiotensin
II infusion for shock: A multicenter study of postmarketing use.
Chest 2021; 159:596–605

Measuring Bundle Implementation Work

Requires a Calibrated Scale*
Brian J. Anderson, MD, MSCE
KEY WORDS: ABCDEF bundle; intensive care unit liberation; intensive care unit William D. Schweickert, MD
survivorship; post-intensive care syndrome; sedation

I
n 2013, the Society of Critical Care Medicine launched the ICU Liberation *See also p. 1685.
Campaign (www.iculiberation.org) serving as a large-scale quality im- Copyright © 2023 by the Society of
provement effort to implement the (since updated) Clinical Practice Critical Care Medicine and Wolters
Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Kluwer Health, Inc. All Rights
Delirium, Immobility, and Sleep Disruption (1). This program developed the Reserved.
innovative ICU Liberation Bundle, known by many as the ABCDEF bundle, DOI: 10.1097/CCM.0000000000006005

1824     www.ccmjournal.org December 2023 • Volume 51 • Number 12

Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.