Kotani et al.

Critical Care (2023) 27:29

https://doi.org/10.1186/s13054-023-04322-y

PERSPECTIVE Open Access

An updated “norepinephrine equivalent”

score in intensive care as a marker of shock
severity
Yuki Kotani1,2,3, Annamaria Di Gioia1, Giovanni Landoni1,2*, Alessandro Belletti1 and Ashish K. Khanna4,5

Abstract
Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock
recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical
practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative
vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE)
is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized
manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically
includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also
an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of
conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of
high-quality data to support the equation and validate its predictive performance in all types of critical care practice.
This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and
adjuncts.
Keywords Norepinephrine, Norepinephrine equivalence, Vasopressor, Hemodynamic management, Vasopressin,
Angiotensin II, Methylene blue

Introduction
Shock is common and associated with mortality in
patients admitted to intensive care units (ICUs) [1, 2].
In the physiological state, blood pressure is maintained
within normal range by the interplay of three major
*Correspondence: mechanisms: the sympathetic nervous system, vasopres-
Giovanni Landoni sin system, and renin–angiotensin–aldosterone system
[email protected]
1
Department of Anesthesia and Intensive Care, IRCCS San Raffaele [3]. However, in patients with vasodilatory shock, these
Scientific Institute, Via Olgettina 60, 20132 Milan, Italy homeostatic mechanisms are disturbed [4, 5]. When
2
School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, hypotension is not resolved solely by fluid resuscitation,
20132 Milan, Italy
3
Department of Intensive Care Medicine, Kameda Medical Center, 929 vasopressor agents are the cornerstone of shock manage-
Higashi‑cho, Kamogawa, Chiba 296‑8602, Japan ment to maintain adequate mean arterial pressure (MAP)
4
Section on Critical Care Medicine, Department of Anesthesiology, [6, 7].
Wake Forest Center for Biomedical Informatics, Perioperative Outcomes
and Informatics Collaborative, Wake Forest University School of Medicine, It is common among clinicians and researchers to use
Medical Center Boulevard, Winston‑Salem, NC 27157, USA the dose of vasopressor agents to grade the severity of
5
Outcomes Research Consortium, Cleveland, OH 44195, USA shock. Norepinephrine has been recommended as the

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Kotani et al. Critical Care (2023) 27:29 Page 2 of 7

first-line vasopressor since 2004 [8], and the latest guide- min) + epinephrine dose (µg/min) + 1/4 × dopamine dose
lines suggest starting vasopressin on top of norepineph- (µg/kg/min) [22]. In 2008, the VASST (Vasopressin and
rine when a target MAP is not achieved [9]. On the other septic shock trial) study modified the previous NEE dose
hand, many uncertainties remain in the care of shock, as norepinephrine dose (µg/min) + 1/2 × dopamine dose
including how and when to start other vasopressor (µg/kg/min) + epinephrine dose (µg/min) + 1/10 × phe-
agents [10]. Although new vasopressors (e.g., angioten- nylephrine dose (µg/min) [13]. Reflecting the increasing
sin II, methylene blue) have become popular in intensive use of vasopressin after the VASST study in septic shock,
care practice, there is little evidence from high-quality different NEE formulas, which incorporate vasopressin,
randomized trials and no clear recommendation in the started to be used [13–15, 17–19], which are slightly dif-
guidelines to guide clinical decisions on when and how to ferent from each other. A clinical trial assessing the effect
initiate these new vasopressor agents so far [11]. In addi- of selepressin, a cyclic nonapeptide vasopressin analog,
tion, there are conditions where these and other vaso- used a unique NEE equation without vasopressin due to
pressors are used with or without norepinephrine, such the trial design with strict restriction of vasopressin use
as catecholamine-resistant vasodilatory shock [12]. Since [16]. However, selepressin is not commercially available
different vasopressors have different pharmacological since this trial failed to show any clinically relevant supe-
characteristics and effects on hemodynamics, a calcula- riority in patients assigned to selepressin over a placebo.
tion formula that reflects the potency of each vasopressor Since the conversion ratio of each calculation is based
is frequently necessary to describe the degree of vaso- on unclear evidence, a recent scoping review proposed
pressor support in a standardized manner. This is espe- another approach to determine a calculation formula
cially true when designing and conducting clinical trials. [20]. The authors extracted the conversion ratios from
Norepinephrine equivalence (NEE) is a scale to quan- 21 clinical trials comparing the equipotency of different
tify vasopressor exposure, which converts the dose of vasopressors to achieve the target blood pressure. With
each vasopressor equivalent to that of norepinephrine. the data of the eligible 21 studies, the scoping review sug-
NEE has been used in clinical trials to set an inclusion gested the following formula: norepinephrine dose (µg/
criterion, define trial protocols, report baseline char- kg/min) + epinephrine dose (µg/kg/min) + 1/10 × phe-
acteristics, and assess outcomes [13–19]. For example, nylephrine dose (µg/kg/min) + 1/100 × dopamine
inclusion criteria in the Angiotensin II for the treatment dose (µg/kg/min) + 1/8 × metaraminol dose (µg/kg/
of high-output shock 3 (ATHOS-3) trial necessitated a min) + 2.5 × vasopressin dose (U/min) + 10 × angiotensin
norepinephrine equivalence calculator for patient enroll- II dose (µg/kg/min).
ment at doses > 0.2 µg/kg/min of NEE. However, the Table 1 summarizes different NEE equations reported
major issue with NEE is that there is no standardized in the literature so far.
method for measuring the potency of vasopressors. As
a result, there are several different calculation formulas Need for using norepinephrine equivalence
for NEE [12, 13, 15, 16, 20–23]. Inconsistent calculation NEE allows us to combine the dose of different vasopres-
methods for NEE will make it difficult to compare or sor agents into a single scale, and this characteristic is
interpret the results between clinical studies. In addition, advantageous when patients receive multiple vasopres-
whenever a new vasopressor enters intensive care prac- sors simultaneously. Although norepinephrine is the
tice, there is a need to update the last NEE formula. first-line vasopressor in critical care, adding secondary
This review aims to describe the evolution of NEE, its agents is suggested when norepinephrine alone can-
utility in clinical research and practice, its pitfalls, and not attain the target pressure or when the norepineph-
future perspectives and opportunities with a proposal to rine dose required to achieve the target MAP becomes
produce an updated version of the score. excessive [9]. From a pathophysiological point of view,
several different mechanisms are implicated in vasodila-
Evolution of calculation formulas tory hypotension, such as inadequate secretion of vaso-
In 1995, the history of quantifying the amount of hemo- pressin from the posterior pituitary and down-regulation
dynamic support began when the inotrope score (IS) was of angiotensin receptors, which would make the use of
developed for neonates after congenital cardiac surgery non-catecholamine vasopressor along with norepineph-
[24]. The IS was calculated as dopamine dose (µg/kg/ rine reasonable [3]. NEE would also help to quantitatively
min) + dobutamine dose (µg/kg/min) + 100 × epineph- compare the severity of shock when norepinephrine is
rine dose (µg/kg/min) [25]. In 2002, the first attempt not readily available, e.g., in norepinephrine shortage [26]
to integrate the dose of different vasopressors, includ- or low-middle income countries [27].
ing norepinephrine, into one scale, especially in adult Furthermore, NEE can serve as an eligibility criterion
septic shock, defined NEE as norepinephrine dose (µg/ in clinical trials. Although clinical research, especially
Kotani et al. Critical Care (2023) 27:29 Page 3 of 7

Table 1 Summary of norepinephrine equivalent formulas

Author Year Journal Calculation

Patel et al. [22] 2002 Anesthesiology Norepinephrine dose (µg/min) + epinephrine dose (µg/min) + 1/4 × dopa-
mine dose (µg/kg/min)
Russell et al. [13] (VASST) 2008 New England Journal of Medicine Norepinephrine dose (µg/min) + 1/2 × dopamine dose (µg/kg/min) + epi-
nephrine dose (µg/min) + 1/10 × phenylephrine dose (µg/min)
Brown et al. [12] 2013 Chest Norepinephrine dose (µg/kg/min) + epinephrine dose (µg/kg/
min) + 1/100 × dopamine dose (µg/kg/min) + 5 × vasopressin dose (U/
min) + 0.45 × phenylephrine dose (µg/kg/min)
Ralib et al. [23] 2013 Clinical Nephrology Norepinephrine dose (μg/min) + 500 × vasopressin dose (U/
min) + epinephrine dose (μg/min) + 1/3 × phenylephrine dose (μg/
min) + 1/100 × dopamine dose (μg/min)
Gutsche et al. [21] 2017 Anesthesia & Analgesia Norepinephrine dose (μg/min) + 1/2 × dopamine dose (μg/kg/min) + epi-
nephrine dose (μg/min) + 1/10 × phenylephrine dose (μg/min) + 200 × vas-
opressin dose (U/min)
Khanna et al. [15] (ATHOS-3) 2017 New England Journal of Medicine Norepinephrine dose (µg/kg/min) + epinephrine dose (µg/kg/
min) + 1/150 × dopamine dose (µg/kg/min) + 1/10 × phenylephrine dose
(µg/kg/min) + 2.5 × vasopressin dose (U/min)
Laterre et al. [16] (SEPSIS-ACT) 2019 JAMA Norepinephrine dose (µg/min) + epinephrine dose (µg/
min) + 1/100 × dopamine dose (µg/min) + 1/2.2 × phenylephrine dose (µg/
kg/min)
Goradia et al. [20] 2021 Journal of Critical Care Norepinephrine dose (µg/kg/min) + epinephrine dose (µg/kg/
min) + 1/10 × phenylephrine dose (µg/kg/min) + 1/100 × dopamine dose
(µg/kg/min) + 1/8 × metaraminol (µg/kg/min) + 2.5 × vasopressin dose (U/
min) + 10 × angiotensin II dose (µg/kg/min)
Our manuscript 2022 Norepinephrine dose (µg/kg/min) + epinephrine dose (µg/kg/
min) + 1/100 × dopamine dose (µg/kg/min) + 0.06 × phenylephrine dose
(µg/kg/min) + 2.5 × vasopressin dose (U/min) + 0.0025 × angiotensin II
dose (ng/kg/min) + 10 × terlipressin dose (µg/kg/min) + 0.2 × methylene
blue dose (mg/kg/h) + 8 × metaraminol dose (µg/kg/min) + 0.02 × hydrox-
ocobalamin dose (g) + 0.4 × midodrine dose (µg/kg/min)

randomized controlled trials, should determine which target MAP or estimating the reduction in norepineph-
patient is eligible for enrolment accurately and objec- rine dose when used in combination. This drawback is
tively, the precise definition of eligibility criteria is not especially important given the recent evidence support-
always easy. For example, it would be difficult to decide ing a multimodal vasopressor approach [3]. The calcu-
whether a patient on norepinephrine of 0.3 µg/kg/min lation ratio in NEE (e.g., 1/100–1/150 for dopamine in
and vasopressin 0.03 U/min is eligible when “receiving some established formulas) is generally defined according
norepinephrine ≥ 0.4 µg/kg/min” is listed in the inclusion to the equipotency of each vasopressor compared to nor-
criteria of a randomized trial. NEE can overcome this epinephrine to achieve the same MAP target. As a result,
challenge by standardizing the potency of vasopressors, due to the different hemodynamic effects of vasopressors
and several randomized trials used NE as an inclusion (e.g., vasopressors with inotropic effect or pure vasocon-
criterion [13, 15]. NEE can also be the primary endpoint, strictors) and the complex interaction between vascular
especially in feasibility, pilot trials, and observational tone, volume status, and cardiac contractility, similar
studies. Figure 1 summarizes the need for using NEE MAPs may correspond to very different hemodynamic
score. profile despite comparable NEE. On the other hand, NEE
A novel measure of hypotension using NEE has been allows clinicians to compare the hemodynamic, micro-
recently proposed, i.e., the ratio of MAP and NEE [28]. circulatory, or metabolic effects of different vasopres-
Like ­PaO2/FiO2 ratio as a measure of oxygenation, MAP/ sor agents by adjusting the dose of each drug in terms of
NEE can be used as a measure of vasopressor responsive- vasoconstrictive effects.
ness and severity of shock. Second, NEE may sometimes not reflect the total
amount of hemodynamic support. Since NEE only con-
Pitfalls siders vasopressor effects, NEE fails to measure the effect
NEE has several pitfalls. First, with scarce evidence, the of other hemodynamic interventions, such as mechani-
conversion ratio for each vasopressor agent is determined cal circulatory support and drugs with predominantly
arbitrarily, either comparing the dose needed to achieve a inotropic profiles. For example, consider a patient with
Kotani et al. Critical Care (2023) 27:29 Page 4 of 7

Fig. 1 Visual summary of an updated norepinephrine equivalent score and need for using norepinephrine equivalence

severe low cardiac output syndrome who receives veno- Proposed updated norepinephrine equivalent
arterial extracorporeal membrane support and moder- score
ate to a high dose of inotropes in addition to low-dose We propose an updated NEE equation based on the best
norepinephrine. In that case, it will be obvious that the available evidence on the equipotency of various vaso-
NEE for this patient is disproportionately low compared pressors. Two randomized controlled trials comparing
to the total hemodynamic support. However, it is quite epinephrine and norepinephrine found that the dose
challenging to integrate the intensity of mechanical cir- necessary to achieve the same MAP target was similar
culatory support or inotropic agents with vasopressors. between the two vasopressors [29, 30]. Therefore, we
In general, MAP is the single measure of efficacy to assigned 1 as a conversion ratio to epinephrine.
guide vasopressors, while mechanical circulatory sup- Most previous NEE formulas used 1/100 or 1/150 as
port or inotropes require other parameters (e.g., cardiac the conversion ratio for dopamine [12, 15, 16, 20, 23].
index—CI) on top of MAP, where it becomes difficult Two randomized trials showed that approximately 80 and
to ascertain how much a combination of vasopressor 140 times the dose of dopamine was required to reach
and inotrope contributes to MAP or CI. Therefore, NEE the same MAP target when compared with norepineph-
should be used and interpreted cautiously in studies, rine, respectively [31, 32]. These results were followed by
including patients requiring mechanical circulatory sup- the largest randomized trial comparing dopamine and
port or high-dose inotropes. Although a scoping review norepinephrine (SOAP II trial), which demonstrated the
proposed a calculation formula based on the available potency of dopamine is 1/100 times that of norepineph-
evidence on the equipotency of different vasopressors, rine [33]. Accordingly, we assigned 1/100 to the conver-
the small number of included studies on each vasopres- sion ratio for dopamine.
sor limits its generalizability [20]. A small, non-randomized study in septic shock patients
Third, we need to renew the NEE equation whenever found that 3.2 µg/kg/min of phenylephrine was equiva-
a new vasopressor emerges. Any new vasopressor comes lent to 0.2 µg/kg/min to obtain MAP ≥ 65 mmHg [34].
with less evidence that, in most cases, is not enough to A randomized trial in patients under spinal anesthe-
allow an accurate construct of a validated and updated sia found 39.1 µg/min of phenylephrine was equivalent
NEE equation. This questions our traditional approach to 2.4 µg/min of norepinephrine [35]. Based on these
with complication derivations of the NEE equation and studies, 0.06 was assigned to the conversion ratio of
pushes us to think to simplify this process. phenylephrine.
There are two large randomized controlled trials
comparing vasopressin and norepinephrine in septic
shock [13, 36]. In one trial, 0.03 U/min of vasopressin
Kotani et al. Critical Care (2023) 27:29 Page 5 of 7

corresponded to 7.5 µg/min of norepinephrine [13], A randomized trial compared metaraminol and nor-
while another trial found that 0.06 U/min of vasopressin epinephrine in septic shock [38]. Based on the findings of
resulted in norepinephrine infusion rate by 0.15 µg/kg/ this trial suggesting 2.5 μg/kg/min of metaraminol corre-
min [36]. Thus, the conversion ratio of 2.5 would be rea- sponded to 0.3 μg/kg/min of norepinephrine, we defined
sonable for vasopressin. a correction factor of 8 to metaraminol dose in μg/kg/
Since ATHOS-3 is the only multicenter randomized min.
controlled trial to assess the equipotency of angioten- A recent randomized trial found that 5 g of hydroxo-
sin II in intensive care settings, we adopted the result of cobalamin reduced norepinephrine by 0.08 µg/kg/min
this trial to calculate a conversion factor for angiotensin [39], which led us to apply 0.02 as a correction factor to
II. This trial reported that 20 ng/kg/min of angiotensin II hydroxocobalamin dose in g.
infusion resulted in a mean decrease of 0.05 µg/kg/min of A randomized trial comparing oral midodrine with
norepinephrine compared with the placebo to maintain a intravenous norepinephrine found that 30 mg/day of
target MAP of 75 mmHg or 10 mmHg greater than base- midodrine reduced 73 mg of norepinephrine during six
line in the first 3 h of drug initiation, and a target MAP of days in septic shock [40], which gave a correction factor
65 mmHg afterward. Thus, we applied a correction factor of 0.4 to midodrine dose in μg/kg/min.
of 0.0025 to the angiotensin II dose in ng/kg/min. On the other hand, there is no randomized trial com-
Similarly, data from a recent multicenter randomized paring the potency of methylene blue with that of other
trial comparing terlipressin with norepinephrine in septic vasoconstrictors. A single-center randomized trial
shock [37], we applied a correction factor of 10 to the ter- assessing the efficacy of methylene blue in septic shock
lipressin dose in μg/kg/min. [41] reported that the doses for methylene blue infusion

Table 2 Studies to determine the conversion ratio of each vasopressor agent in our updated NEE formula
Author Year Journal Equipotency with norepinephrine

Epinephrine
Myburgh et al. [29] 2008 Intensive Care Med There was no difference in the maximal daily infusion dose between norepineph-
rine and epinephrine
Annane et al. [30] 2007 Lancet The doses of vasopressors needed to achieve the mean arterial pressure target
were not different between epinephrine and norepinephrine
Dopamine
Marik et al. [32] 1994 JAMA 26 µg/kg/min of dopamine was equivalent to 0.18 µg/kg/min of norepinephrine
De Backer et al. [31] 2003 Crit Care Med The median dose of dopamine was 15 µg/kg/min, while that of norepinephrine
was 0.18 µg/kg/min
De Backer et al. [33] 2010 New England Journal of Medicine The dose of dopamine was consistently 100 times as much as that of norepi-
nephrine during seven days after randomization
Phenylephrine
Reinelt et al. [34] 1999 Crit Care Med 3.2 µg/kg/min of phenylephrine was equipotent to 0.2 µg/kg/min of norepi-
nephrine
Ngan Kee et al. [35] 2015 Anesthesiology 39.1 µg/min of phenylephrine was equivalent to 2.4 µg/min of norepinephrine
Vasopressin
Russell et al. [13] (VASST) 2008 New England Journal of Medicine The addition of 0.03 U/min of vasopressin reduced 7.5 µg/min of norepinephrine
Gordon et al. [36] 2016 JAMA The addition of 0.06 U/min of vasopressin reduced norepinephrine dose by
0.15 µg/kg/min
Other vasopressor agents
Khanna et al. [15] 2017 New England Journal of Medicine 20 ng/kg/min of angiotensin II infusion resulted in a mean reduction of 0.05 µg/
kg/min of norepinephrine compared with the placebo
Liu et al. [37] 2018 Intensive Care Med The dose of terlipressin required to reach the mean arterial pressure target was
ten times lower than that norepinephrine dose
Natalini et al. [38] 2005 Intensive Care Med 2.5 μg/kg/min of metaraminol corresponded to 0.3 μg/kg/min of norepinephrine
Patel et al. [39] 2022 Chest 5 g of hydroxocobalamin reduced norepinephrine requirement by 0.08 µg/kg/
min
Adly et al. [40] 2022 Ir J Med Sci 30 mg/day of midodrine reduced 73 mg of norepinephrine during six days
Kirov et al. [41] 2001 Crit Care Med Methylene blue infusion ranged from 0.25 to 2 mg/kg/h, while norepinephrine
ranged from 0.1 to 0.7 µg/kg/min
Kotani et al. Critical Care (2023) 27:29 Page 6 of 7

ranged from 0.25 to 2 mg/kg/h. Accordingly, we arbitrar- Author contributions

YK, ADG, GL, and AB conceived the study. YK, ADG, GL, AB, and AKK wrote
ily applied a correction factor of 0.2 to the dose of meth- the manuscript. All authors provided crucial revisions and approved the final
ylene blue in mg/kg/h. manuscript.
Therefore, we have updated the NEE equation incorpo-
Funding
rating vasoconstrictors commonly used in recent years. This research did not receive any specific grant from funding agencies in the
Figure 1 and Table 1 describe our final modified NEE public, commercial, or not-for-profit sectors. Dr. Yuki Kotani receives support
calculation formula. If we compare our formula with from the Uehara Memorial Foundation. The funding agency had no role in the
study design; collection, management, analysis, and interpretation of data;
the one by Goradia et al. [20], the correction factors for writing of the report, or the decision to submit the report for publication.
angiotensin II are inconsistent even after the adjustment
of the unit used (2.5 vs. 10). The main reason for the dif- Availability of data and materials
Further information is available from the corresponding authors upon reason-
ference is the data source for the correction factor esti- able request.
mation. While Goradia et al. used a pilot single-center
randomized trial published in 2012 in intensive care unit Declarations
settings [42], we used a subsequent multicenter rand-
omized trial published in 2017 [15]. Since the pilot trial Ethics approval and consent to participate
Not applicable.
was small in sample size and had baseline imbalances
between angiotensin and placebo arms, we used only the Consent for publication
larger trial to better estimate the equipotency of angio- Not applicable.
tensin II. Competing interests
All the studies we used to update the NEE formula are The authors declare that they have no competing interests.
listed in Table 2.
Received: 24 December 2022 Accepted: 14 January 2023
Future perspectives
There are several unanswered questions concerning
NEE. The current trend toward a multimodal vasopres-
sor strategy will require a valuable measure to stand- References
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Acknowledgements
Not applicable.
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