Sepsis is a life-threatening state of organ dysfunction caused by dysregulated response
of host to infection. It is the most common form of circulatory shock encountered in
patients admitted in intensive care unit. In physiological state, blood pressure is
maintained by the interplay of three major mechanisms namely sympathetic nervous system,
vasopressin system and renin aldosterone system. However in the states of vasodilatory
shock, these homeostatic mechanisms are disturbed. The initial management involves fluid
resuscitation but if hypotension doesn't get resolved solely by it, then vasopressors
become the mainstay of the management of shock to maintain adequate mean arterial
pressure (MAP).
Norepinephrine has been recommended as the first line vasopressor for management of
septic shock since 2004 and the latest guideline recommends addition of vasopressin along
with norepinephrine when the target MAP is not achieved. However, in clinical practice
various other vasopressors are used in the management of septic shock. Different
vasopressors have different modes of action and pharmacological effects on hemodynamics.
Therefore, there evolved the need of development of a formula that would reflect the
potency of each vasopressor in a standardized manner. Thus, the concept of Norepinephrine
Equivalence (NEE) came into existence. It is a scale to quantify the exposure to various
vasopressors, by converting their dose as an equivalent of norepinephrine. It allows us
to combine the dose of other vasopressors in a single scale and quantitatively assess the
severity of shock when norepinephrine is being used along with other vasopressors.
Annane et al conducted a study in 2007 in 330 patients of septic shock with the primary
objective of comparing the efficacy and safety of norepinephrine plus dobutamine with
those of epinephrine alone in septic shock. They inferred from their study that the doses
of vasopressors needed to achieve the MAP target were same for epinephrine and
norepinephrine. Similarly, Myburgh et al studied in 280 patients of circulatory shock in
the year 2008 to determine whether there was any difference between epinephrine and
norepinephrine in achievement of MAP goal in the ICU patients and found that the maximal
daily infusion of epinephrine and norepinephrine didn't have difference to achieve a
target MAP. De Becker et al conducted a study in 2003 on 20 septic shock patients with
the primary objective to assess the effects of different doses of dopamine,
norepinephrine and epinephrine on the splanchnic circulation in patients of septic shock.
They found that the final infusion rate of epinephrine was 0.62 mcg/kg/min, which was
comparable to 0.45 mcg/kg/min rate of norepinephrine infusion to achieve the target MAP,
suggesting a conversion ratio of 1.4:1. Hussain et al found in their study on 42 patients
of septic shock in 2014 to determine the efficacy of phenylephrine in comparison to
norepinephrine in patients of septic shock in ICU, that phenylephrine was 1.1 times
equipotent to norepinephrine. Gordon et al studied on 409 patients of septic shock in
2016 to compare the effect of early vasopressin versus norepinephrine on kidney failure.
They concluded from their study that 0.04U/min of vasopressin to be equivalent to 0.1
mcg/kg/min of norepinephrine.
Goradia et al proposed a norepinephrine equivalent formula in 2021 in their review
article as Norepinephrine dose (mcg/kg/min) + epinephrine dose (mcg/kg/min) + 2.5 x
vasopressin (U/min) + 0.1 × phenylephrine dose (mcg/kg/min). Kotani et al proposed a
different norepinephrine equivalent formula in 2023 as follows Norepinephrine dose
(µg/kg/min) + epinephrine dose (µg/kg/ min) + 0.06 × phenylephrine dose (µg/kg/min) + 2.5
× vasopressin dose (U/min).
However, since these calculations of NEE are based on assumptions and not standardized,
there are several different formulae for calculation of the same. Different studies were
conducted in different parts of the world with different primary objectives, the authors
proposed different NEE formulas of the used vasopressor as an inference from their
studies.
Presently, there are no studies available in the existing literature where a prospective
study is done to primarily determine the Norepinephrine equivalence of other vasopressors
namely vasopressin, phenylephrine and epinephrine, in patients of septic shock. Hence,
the investigators aimed to study the NEE dose of the commonly used vasopressors in the
ICU in septic shock patients.
During the study period, all adult ICU patients having septic shock will be considered
for inclusion. Once the patient meets the inclusion/exclusion criteria, informed written
consent will be obtained at the beginning of the study. The weight of the patient will be
noted from the weight-measuring beds and the drug preparations are made accordingly. The
transducer will be zeroed to the atmospheric pressure and baseline MAP will be recorded.
A second vasopressor will be connected to the central venous catheter (CVC) as per the
standard preparation. Then Norepinephrine infusion dose will be deescalated over 5-10
minutes by 0.1 mcg/kg/min. Simultaneously, the dose of the second vasopressor will be
titrated to achieve the baseline MAP (±1 mmHg). Two readings of the dose of the second
vasopressor will be recorded at least 5 minutes apart and their mean will be calculated.
Evaluation with more than one vasopressor will depend upon the clinical condition of the
patient as decided by the treating team. However, if more than one vasopressor are being
assessed for NEE dose, then the next drug will be assessed after at least one hour gap.
The same patient can be included for the study for more than once if they receive
norepinephrine in three different dose ranges viz 0.1-0.5 mcg/kg/min, 0.5-1 mcg/kg/min
and >1 mcg/kg/min.
Demographic and clinical characteristics of included patients will be recorded in
structured case report forms. Candidates who qualify for the inclusion criteria will be
included in the study. The baseline MAP will be recorded. The norepinephrine infusion
will be tapered down gradually by 0.1 mcg/kg/min and in the meanwhile a second
vasopressor will be introduced to maintain the baseline MAP recorded at the beginning of
the study. After 15 minutes of stabilization of the dose of the second vasopressor, two
readings of the dose of the second vasopressor will be taken 5 minutes apart and their
mean will be taken as a NEE of that particular vasopressor.