Editorials

9. Yusuff HO, Zochios V, Vuylsteke A: Extracorporeal membrane
oxygenation in acute massive pulmonary embolism: A system-
atic review. Perfusion 2015; 30:611–616
10. Pasrija C, Shah A, George P, et al: Triage and optimization: A
new paradigm in the treatment of massive pulmonary embo-
lism. J Thorac Cardiovasc Surg 2018; 156:672–681
11. Scott JH, Gordon M, Vender R, et al: Venoarterial Extracorporeal
Membrane Oxygenation in Massive Pulmonary Embolism-
Related Cardiac Arrest: A Systematic Review. Crit Care Med
2020; 49:760–769
12. Extracorporeal Life Support Organization: Extracorporeal Life
Support (ECLS) Registry Report International Summary. Ann
Arbor, MI, Extracorporeal Life Support Organization, 2019
14. O’Malley TJ, Choi JH, Maynes EJ, et al: Outcomes of extra-
corporeal life support for the treatment of acute massive pul-
monary embolism: A systematic review. Resuscitation 2020;
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15. Al-Bawardy R, Rosenfield K, Borges J, et al: Extracorporeal
membrane oxygenation in acute massive pulmonary embo-
lism: A case series and review of the literature. Perfusion 2019;
34:22–28
16. Meneveau N, Guillon B, Planquette B, et al: Outcomes after
extracorporeal membrane oxygenation for the treatment of
high-risk pulmonary embolism: A multicentre series of 52
cases. Eur Heart J 2018; 39:4196–4204

13. Chen YS, Chao A, Yu HY, et al: Analysis and results of pro- 17. Ghoreishi M, DiChiacchio L, Pasrija C, et al: Predictors of re-
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tracorporeal membrane oxygenation. J Am Coll Cardiol 2003; membrane oxygenation for acute massive pulmonary embo-
41:197–203 lism. Ann Thorac Surg 2020; 110:70–75

Vasopressor Load: Sounding the Alarm in

Management of Cardiogenic Shock Associated
With Acute Myocardial Infarction*
Brandon M. Wiley, MD1
KEY WORDS: cardiogenic shock; extracorporeal membrane oxygenation;
Peter M. Eckman, MD1
inotrope; mechanical circulatory support; vasopressor
Jacob C. Jentzer, MD2

C
ardiogenic shock (CS) associated with myocardial infarction (AMI-CS)
develops when myocardial injury leads to impaired cardiac output
and end-organ hypoperfusion, which can rapidly deteriorate into
worsening shock with concomitant multiple organ system dysfunction (1, 2).
Although the average short-term mortality of AMI-CS populations remains at
30–40% despite contemporary therapy, CS encompasses a wide spectrum of
illness severity with correspondingly variable in-hospital mortality rates (1–4).
As it has for decades, initial hemodynamic support for patients with AMI-CS
continues to rely predominantly on adrenergic vasopressor and inotropic drugs
(1). Although these drugs are often effective for improving systemic hemody-
namics, they are considered a “double-edged sword,” and their use must be bal-
anced against potential harmful side effects at higher doses (5, 6). This risk of *See also p. 770.
toxicity associated with escalating doses of vasoactive medications has provided Copyright © 2021 by the Society of
the justification for the development of an armamentarium of increasingly so- Critical Care Medicine and Wolters
phisticated temporary mechanical circulatory support (MCS) devices designed Kluwer Health, Inc. All Rights
to rescue critically ill patients with CS (7). However, recent randomized clin- Reserved.
ical trials have not shown improvements in survival of patients with AMI-CS DOI: 10.1097/CCM.0000000000004906

Critical Care Medicine www.ccmjournal.org      865

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Editorials
using temporary MCS devices, raising questions re-
garding the optimal hemodynamic support strategy in
AMI-CS (1, 7). Since requirements for higher doses of
vasopressors and inotropes have been consistently as-
sociated with worse outcomes in critically ill patients,
the quantification of vasopressor load—the amount of
vasoactive therapy required to stabilize the hemody-
namic perturbation of shock—could provide clinicians
with an objective decision-making tool to identify
patients who are developing shock refractory to med-
ical therapy that may benefit from expedited transition
to MCS (5, 6, 8–11).
Choi et al (12), in this issue of Critical Care Medicine,
address the crucial issue of risk stratification using va-
sopressor load in AMI-CS by analyzing the association
between mortality and the maximal amount of vaso-
active medications used during the first 48 hours of
shock, quantified using the Vasoactive-Inotrope Score
(VIS). Using the multicenter REtrospective and pro-
spective observational Study to investigate Clinical
oUtcomes and Efficacy registry, the authors identi-
fied 836 patients with AMI-CS (excluding patients
with out-of-hospital cardiac arrest). The study popu-
lation included patients managed with either medical
therapy (39%) or temporary MCS, including intra-aor-
tic balloon pump (IABP) in 26% and extracorporeal
membrane oxygenation (ECMO) in 35%. Observed
in-hospital mortality was 36.5%, which aligns with
prior studies of AMI-CS (1, 4, 13). In-hospital mor-
tality increased incrementally with higher VIS, and a
VIS greater than 90 (the top quartile) was associated
with significantly higher in-hospital mortality regard-
less of whether management included MCS. VIS had
better discrimination for in-hospital mortality among
patients treated with medical therapy (area under the
curve [AUC], 0.80) compared with those treated with
IABP (AUC, 0.70) or ECMO (AUC, 0.64). The optimal
cutoff value for VIS as a predictor of in-hospital mor-
tality was substantially lower among patients who re-
ceived medical therapy (16.5) compared with patients
receiving MCS (40.1 in IABP and 84.0 in ECMO).
There was a significant interaction between VIS and
use of MCS for prediction of all-cause mortality, show-
ing that higher vasopressor load is more dangerous
among patients not supported with MCS. AMI-CS
patients in the lowest VIS quartile had a mortality risk
approximately half that of the overall population av-
erage, whereas patients in the highest VIS quartile had
866      www.ccmjournal.org May 2021 • Volume 49 • Number 5
Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
a mortality risk approximately double the overall pop-
ulation average.
The number of vasopressors and inotropes required
to stabilize a patient with CS has long been recognized
as both a predictor of mortality and subjective criterion
used to make decisions about initiating MCS (11, 13).
However, the dose of each individual drug is equally
important, and a useful measure of total vasopressor
load should incorporate both the number and dose of
vasoactive drugs (9, 11). There are several scores that
can be used to quantify the vasopressor load, including
the VIS, norepinephrine-equivalent (NEE) dose, car-
diovascular Sequential Organ Failure Assessment sub-
score, and the cumulative vasopressor index (CVI).(6,
14) The VIS is presumably more relevant for AMI-CS
since it includes inodilator doses (milrinone and dobu-
tamine), unlike either the CVI or NEE (14). In a retro-
spective review of 10,004 cardiac ICU patients, peak
VIS was a strong independent predictor of in-hospital
mortality after accounting for standard measures of ill-
ness severity; a stepwise association between increas-
ing VIS and higher short-term mortality was observed,
as in the study by Choi et al (12). A prior single-center
analysis likewise found a linear correlation between
peak VIS in the first 48 hours and mortality in unsel-
ected CS patients, with an interaction between VIS and
ECMO for mortality prediction (15). By using the VIS
to quantify vasopressor load, Choi et al (12) frame the
importance of vasoactive medication requirements as
a key marker of CS disease severity that is fundamental
for mortality risk assessment and may have potential
utility as an objective indicator to guide decisions on
the timing of MCS initiation.
Although measures of vasoactive drug dosage have
been consistently associated with mortality in critically
ill patients, they carry a number of important caveats
when used for risk prediction (14). Since hemody-
namic goals may be individualized for each patient,
the VIS should be evaluated in relation to the targeted
mean arterial pressure, cardiac index, or cardiac power
output (5). When treatment is guided by consistent
protocols to achieve optimal hemodynamics using vas-
oactive drug titration, the VIS becomes a particularly
powerful and objective metric of shock severity that
can be used for clinical decision-making and risk strat-
ification. The specific vasoactive drugs that are used to
achieve a given VIS may influence the association be-
tween VIS and mortality, as the dose-equivalencies for
 Editorials

Figure 1. Society for cardiovascular angiography and intervention (SCAI) shock stages classification, with potential management options at
each SCAI shock stage highlighted. Among patients with shock (SCAI shock stages C, D, and E), the Vasoactive-Inotrope Score (VIS) rises
incrementally, and the VIS can be used to define the SCAI shock stage. Figure adapted from Baran et al (2). ACEI = angiotension converting
enzyme inhibitor, ARB = angiotension II receptor blocker, BNP = brain natriuretic peptide, CI = cardiac index, CPO = cardiac power output,
CPR = cardiopulmonary resuscitation, ECMO = extracorporeal membrane oxygenation, IABP = intra-aortic balloon pump, MAP = mean
arterial pressure, MCS = mechanical circulatory support, PA = pulmonary artery, PAPI = pulmonary artery pulsatility index, PCWP = pulmonary
capillary wedge pressure, pVAD = percutaneous ventricular assist device, RAP = right atrial pressure, SBP = systolic blood pressure.

the different vasoactive drugs within the VIS are some-
what arbitrary and are likely to change across the dos-
ing range (14). Lower mortality risk has been reported
for cardiac ICU patients receiving norepinephrine
(particularly among patients with higher vasopressor
requirements) (8, 9). Although increasing vasopressor
and inotrope doses to restore hemodynamics and
organ perfusion will necessarily increase the VIS and
the estimated risk of mortality, clinicians should be
reassured that this association predominantly reflects
a greater severity of underlying shock rather than a
harmful effect of the drugs themselves. Therefore, al-
though the VIS is a useful single measure to quantify
overall vasopressor load as a measure of shock severity,
a more nuanced approach is needed when using this
metric for clinical decision-making.
Regardless, high or rising vasopressor doses should
alert the clinician that the CS patient has a severe or
Critical Care Medicine www.ccmjournal.org      867
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worsening shock state that is not responding well to
standard therapy and is likely to carry a poor prognosis
if not effectively reversed. Although randomized trials
have failed to demonstrate reductions in mortality with
the routine use of MCS devices in AMI-CS, contem-
porary guidelines emphasize that these devices may
still be appropriate when CS patients are not respond-
ing well to medical therapy (1, 7). Published data that
suggest a clinical benefit with routine use of MCS in
AMI-CS may reflect the use of clinical protocols that
use defined quantitative hemodynamic variables to
guide therapy (13). In the study by Choi et al (12),
the stronger association between VIS and mortality
and the lower VIS cutoff for prediction of mortality
for AMI-CS patients receiving medical therapy versus
MCS highlight potential vasopressor dose thresholds
that could indicate when MCS should be considered.
Patients with a low VIS are likely to do well without
Editorials
MCS, but as the VIS rises, the need for MCS poten-
tially rises in parallel along with the necessary degree
of hemodynamic support.
Initiation decisions about MCS for individual patients
are complex and typically center- and clinician-specific;
VIS alone is not adequate to make the decision regarding
whether escalate to MCS. However, the VIS can serve as
an objective indicator to help guide implementation of
rescue therapies in CS. Integrating automated VIS calcu-
lation into the electronic health record could facilitate an
early warning system for alerting clinicians to hemody-
namic deterioration. The electronic health record could
be leveraged to calculate the absolute or relative change
in VIS or the rate of change in VIS per unit time; this
could help clinicians to recognize when patients are hav-
ing a rapid escalation in vasoactive drug requirements,
suggesting impaired responsiveness to medical therapy
and implying that the risk/benefit ratio is becoming
unfavorable for further escalation of medical therapy.
Multidisciplinary shock teams could use the recently
described Society for Cardiovascular Angiography and
Intervention (SCAI) shock stage designations by inte-
grating the VIS or delta VIS, helping providers to make
more sophisticated assessments of mortality risk in order
to facilitate a structured approach to hemodynamic sup-
port in CS (Fig. 1) (2, 3). Among patients with shock
(SCAI shock stages C, D, and E), the VIS rises incre-
mentally, and the VIS can be used to define the SCAI
shock stage (3). Considering the variable hemodynamic
support provided by available MCS devices, the VIS as a
measure of shock severity could guide MCS device selec-
tion by matching the flow provided by the device to the
degree of hemodynamic compromise (7).
An important potential outcome of this work is that
it helps lay the foundation for trials evaluating the use
of VIS in therapeutic decision-making and may help
transition the VIS from a tool used to write papers
about associations and predictions in populations to
one that is practical at the bedside for clinicians for
individualized decision-making. Although the de-
cision to initiate MCS cannot be distilled to a single
number, a high VIS or rising VIS might be a useful
signpost to consistently trigger consideration of MCS.
1 Minneapolis Heart Institute at Abbott Northwestern Hospital,
Minneapolis, MN
2 Department of Cardiovascular Medicine, Mayo Clinic,
Rochester, MN
868      www.ccmjournal.org May 2021 • Volume 49 • Number 5
Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Dr. Eckman’s institution received funding from Abbott Laboratories
and Medtronic, and he received funding from Honoraria. The re-
maining authors have disclosed that they do not have any poten-
tial conflicts of interest.
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 Editorials

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Cardiovascular Effects of Prone Positioning in

Acute Respiratory Distress Syndrome Patients:
The Circulation Does Not Take It Lying Down*
Michael R. Pinsky, MD, MCCM
KEY WORDS: acute respiratory distress syndrome; cardiovascular
function; hemodynamic monitoring; heart-lung interactions; prone
positioning

P
resently, ventilatory management of patients with acute respiratory dis-
tress syndrome (ARDS) focuses primarily on improving ventilation to
perfusion matching without causing tidal volume-induced lung injury.
Tidal volume-induced acute lung injury efforts include minimizing the tidal
stress-strain changes by limiting driving pressure, peak and plateau airway
pressures, and reducing the rate of inspiratory increases in lung volume.
Ventilation-associated efforts include recruitment maneuvers to open col-
lapsed but re-expandable alveoli and by adding end-expiratory airway pressure
in excess of ambient airway pressure to keep recruited alveoli open. Minimal
attention is usually focused on improving perfusion. To a large extent, this is
done by attempting to minimize end-inspiratory overdistention as monitored
by expiratory CO2 levels. Importantly, prone positioning has the ability all at
once to improve ventilation to perfusion matching and minimize ventilation-
induced lung injury. In the prone position, the transpulmonary forces causing
lung distention are more evenly distributed and the dorsal regions, where a
majority of the lung parenchyma exists, benefit from more recruitment, as the
abdominal pressure causing diaphragmatic assent into the thorax is limited to *See also p. 781.
the ventral regions with much less lung while dorsal regional pleural pressure is Copyright © 2021 by the Society of
more negative. Blood flow within the lung is also better matched to the dorsal Critical Care Medicine and Wolters
regions because the hydrodynamic forces promoting pulmonary blood flow Kluwer Health, Inc. All Rights
preferentially direct flow to the dorsal regions. This improved ventilation-per- Reserved.

fusion matching is occasionally associated with decreased pulmonary arterial DOI: 10.1097/CCM.0000000000004858

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