The first-line treatment for hypotension remains volume resuscitation,
but the addition of vasopressor therapy may be required
to achieve hemodynamic goals. Norepinephrine remains the
most commonly used vasopressor for the treatment of hypotension
in septic shock.
The vasopressor “toolbox” has other
potent pharmacologic interventions as well. Other vasopressors,
including dopamine, epinephrine, phenylephrine and vasopressin,
can be used in combination with, or instead of, norepinephrine
based on patient-specific parameters for different
clinical indications, mechanism of action or adverse effects. The
toolbox also offers some novel drugs such as selepressin and
angiotensin II. Though the basic pharmacology of vasopressors
is beyond the scope of this article, Table 1 provides a
precise summary of the commonly used agents and their sites
of receptor action.
Norepinephrine is a catecholamine biosynthetic precursor
of epinephrine and mixed adrenergic receptor agonist with
potent α-adrenergic receptor stimulation and additional less
pronounced β-1 adrenergic agonist activity.3,4 Norepinephrine
was previously referred to as “leave ’em dead.” Concerns of
potent vasoconstriction limited the use of norepinephrine to
second-line treatment for septic shock.4,5
The initial concerns of an increased risk of end-organ
ischemia with norepinephrine compared to other
vasopressors have been disproven when patients in septic
shock are adequately volume resuscitated.6,7
De Backer and the Sepsis Occurrence in Acutely
Ill Patients (SOAP II) Investigators compared norepinephrine
to dopamine, the previous first-line vasopressor
for septic shock, and found that there was no difference
in mortality, but patients who received dopamine
had an increased incidence of arrhythmias compared to
norepinephrine.8–10 In addition, patients with cardiogenic
shock appeared to have the worst outcomes with dopamine
as a vasopressor agent. No difference was seen with
time to goal mean arterial pressure (MAP) when norepinephrine
was evaluated against epinephrine in septic
shock but there was a higher percentage of patients who
withdrew from the study due to adverse metabolic effects
of epinephrine, including lactic acidosis and tachycardia.11
Norepinephrine is dosed in µg/min or µg/kg/
min (weight-based). Both strategies have been utilized in
major randomized clinical trials in septic shock.8,12 There
is little clinical information and no recommendation on
the preferred dosing strategy of vasopressors in critically
ill patients. Obese patients who receive weight-based
dosing are at risk of increased norepinephrine exposure
potentially leading to increased adverse effects at the cost
of increased efficacy. In obese patients with septic shock,
there was no difference in time to goal MAP comparing
weight-based-dosed norepinephrine to non-weight-based-dosed
norepinephrine.13 Current evidence supports
the recommendation from the 2016 Surviving Sepsis
Campaign Guidelines, which support norepinephrine as
the first-choice vasopressor.14
Vasopressin, also known as antidiuretic hormone, is
released within the body in response to hypotension or
hypovolemia.15 In septic shock, vasopressin levels are elevated,
then become depleted by 96 hours, with one study
identifying 32% of patients having relative vasopressin
deficiency (≤ 3.6 pg/mL).16 Vasopressin causes vascular
smooth muscle constriction through binding to V1
receptors, it has no catecholamine receptor activity, and it
increases clinical response to other vasopressors.15 Doses
greater than 0.06 units/min, when used for septic shock,
have been associated with the risk of developing ischemic
skin lesions.17 The question of whether norepinephrine
or vasopressin should be our primary tool for defending
blood pressure in septic shock has been an ongoing
The 2008 Vasopressin and Septic Shock Trial (VASST)
randomized patients with septic shock to norepinephrine
versus norepinephrine plus low-dose vasopressin (0.01
to 0.03 units/min). No difference in mortality or safety
was seen, but a slightly surprising secondary analysis
showed a statistically significant reduction in mortality
with vasopressin in patients with a predefined stratum of
less severe septic shock.18 Another VASST analysis looked
for evidence of an interaction between vasopressin and
corticosteroid treatment.19 The combination of vasopressin
and corticosteroids led to a lower mortality compared
with norepinephrine plus corticosteroids. Further, patients
who received vasopressin without corticosteroids had an
increased mortality compared with patients who received
norepinephrine and no corticosteroids.
Importantly, a post hoc analysis of the VASST study
showed that vasopressin may reduce progression to
renal failure, prompting development of the Vasopressin
Versus Noradrenaline as Initial Therapy in Septic Shock
(VANISH) study.20 The VANISH study enrolled patients
with septic shock and randomized them to one of four treatment arms: (1) vasopressin (0.01 to 0.06 units/min)
and hydrocortisone, (2) vasopressin and placebo, (3) norepinephrine
and hydrocortisone, and (4) norepinephrine
and placebo. No difference was seen in incidence of
kidney failure, survivors without kidney failure, median
number of kidney failure-free days and mortality at 28
days. However, there was less use of renal replacement
therapy with vasopressin.12 Based on the VANISH study,
vasopressin has not yet achieved the status of a first-line
vasopressor treatment for septic shock.
The Vasopressin Versus Norepinephrine After Cardiac
Surgery (VANCS) trial was yet another attempt to assess
whether vasopressin had a place as a first-line vasopressor.21
This trial looked at a specific clinical indication
(vasoplegia after cardiac surgery, comparable to the
vasoplegic syndrome that sets in during high-output
septic shock). Vasopressin had a reduction in the primary
composite end point compared to norepinephrine. The
composite end point included mortality or severe complications
(stroke, requirement for mechanical ventilation
for longer than 48hours, deep sternal wound infection,
reoperation or acute renal failure) within 30 days, and
on closer analysis it is clear that this composite outcome
is largely driven by severe complications, namely acute
renal failure and atrial fibrillation, and not a mortality
difference at all.
All in all, vasopressin has been shown to be as safe as
norepinephrine at lower doses and remains a key component
of the vasopressor toolbox. Vasopressin is not
titrated to clinical effect as are other vasopressors and
could be thought of more as a replacement therapy
and treatment of relative vasopressin deficiency. The
2016 Surviving Sepsis Campaign Guidelines suggest
adding vasopressin (doses up to 0.03 units/min) to
norepinephrine to help achieve MAP target or decrease
Selepressin, a selective V1a agonist, offers the benefits
of vasopressin with fewer undesirable side effects such as
oxytocin and V2 receptor activation (seen with vasopressin)
that may worsen fluid overload and microvascular
thrombosis. The superiority of selepressin over vasopressin
has already been proven in the ovine model of septic
shock.22 The Selepressin Evaluation Program for SepsisInduced
Shock – Adaptive Clinical Trial (SEPSIS-ACT)
is currently enrolling and aims to answer questions specific
to the safety and efficacy of this agent. Angiotensin
is a peptide hormone that causes vasoconstriction and a
subsequent increase in blood pressure.
The renin-angiotensin-aldosterone system is operated
via the final end product angiotensin II, which further stimulates the release of aldosterone, another hormone,
from the adrenal cortex. Pilot information from the
Intravenous Angiotensin II for the Treatment of High Output
Shock (ATHOS) trial showed promising results.23
Indeed, the data showed a norepinephrine-sparing effect
and established the efficacy of angiotensin II, though only
as a proof of concept since the data were not adequately
powered. The recently concluded ATHOS-3 trial was a
multicenter, randomized, double-blind, placebo-controlled
phase III clinical study of LJPC-501 (synthetic human
angiotensin II) in patients with catecholamine-resistant
hypotension.24 The preliminary results from ATHOS-3
show a highly significant outcome in the percentage of
patients achieving the primary efficacy end point of a
prespecified target blood pressure (MAP of >75mmhg or
an increase of >10mmhg from baseline). In addition, a
trend to improved survival has been seen. It thus appears
that angiotensin II may be an integral part of the vasopressor
toolbox in the years to come.
The most common adverse effects of vasopressors as
a class include arrhythmias, extravasation and ischemia.
Patients who are not adequately fluid resuscitated are at
increased risk of arrhythmias. Clinicians should try to
avoid using epinephrine and dopamine in patients who
are at risk of, or who have experienced, arrhythmias with
other vasopressors. It is recommended that vasopressors
be administered a through central venous catheters to
reduce the incidence of extravasation and local tissue
ischemia.25 Recent clinical evidence suggests that shortterm
and low-dose peripheral administration of vasopressors
may be safe, but this has largely not translated to
widespread use in clinical practice.25–27 Peripheral tissue
ischemia secondary to prolonged hypotension or highdose
vasopressor therapy can occur.28 Routine clinical
monitoring in addition to using the lowest effective
vasopressor dose can help prevent tissue ischemia. These
agents are titrated to clinical endpoints but should not be
titrated faster than every 5 to 15 minutes to avoid potentially
overshooting hemodynamic targets.29
In clinical practice, vasopressin is commonly administered
as a fixed dose with no bedside nurse titration.
Vasopressin titration parameters are adapted from the
VASST study, in which infusions were down-titrated by
0.005 units/min every hour.18 There is little guidance on
which vasopressor to titrate off first in patients requiring
multiple vasopressors to maintain hemodynamics. A small
study showed an increase in hypotensive events when
vasopressin was discontinued before norepinephrine.30
Clinicians can consider weaning norepinephrine before
vasopressin in septic shock, but vasopressors should be weaned based on patient-specific factors, including
adverse effects and effect on hemodynamics.
The message for the bedside clinician and practicing
intensivist is simple. When faced with a hypotensive
and septic patient, while doing everything else, treat the
hypotension and defend a target MAP. There is strong
evidence from the intraoperative world suggesting
that MAPs of less than 65 mm Hg are associated with
myocardial injury after noncardiac surgery, acute kidney
injury and mortality.31–33 This target is no different from a
drop in blood pressure from a higher baseline and therefore,
simplistically, we are closer to an empirical definition
of hypotension in the intraoperative period.32 Though the
septic hypotensive patient may have a complex interplay
of factors that make defining a blood pressure a particularly
difficult challenge, there is room and interest for an
optimal blood pressure finding study in this population as
How should this target MAP be defended? There is a
reason that evolution provided us with multiple mechanisms
of defending our blood pressure. The vasopressor toolbox approach is precisely this concept of a multimodal
approach to vasopressor management in shock. This
may not be any different from using multiple antihypertensive
medications for higher blood pressure and a
simple, rather logical approach of targeting multiple
physiologic mechanisms to help a hypotensive patient.
Indeed, the consequences of excessive norepinephrine
(catecholamine) use in terms of tachyphyllaxis and the
burden on the myocardium has been well-documented in
the shape of Takotsubo, or stress-induced, cardiomyopathy.34
Whether there is a precise dose response to catecholamine
overdose is not yet known. The vasopressor
toolbox is available to the bedside intensivist. This means
an early consideration for transitioning to vasopressin and
consideration of a multiple vasopressor approach that
includes other agents as well, some of which are old and
time tested, and some of which are new and still need to
be proven via robust clinical trials.
1. Fawzy A, Evans SR, Walkey AJ. Practice patterns and outcomes associated with choice of initial vasopressor therapy for septic shock. Crit Care Med. 2015 Oct;43(10):2141-2146.
2. Lamontagne F, Cook DJ, Adhikari NK, et al. Vasopressor administration and sepsis: a survey of Canadian intensivists. J Crit Care. 2011 Oct;26(5):532.e1-e7.
3. Desjars P, Pinaud M, Potel G, Tasseau F, Touze MD. A reappraisal of norepinephrine therapy in human septic shock. Crit Care Med. 1987 Feb;15(2):134-137.
4. Hesselvik JF, Brodin B. Low dose norepinephrine in patients with septic shock and oliguria: effects on afterload, urine flow, and oxygen transport. Crit Care Med. 1989 Feb;17(2):179-180.
5. Nasraway SA. Norepinephrine: no more “leave ‘em dead”? Crit Care Med. 2000 Aug;28(8):3096-3098.
6. Martin C, Eon B, Saux P, Aknin P, Gouin F. Renal effects of norepinephrine used to treat septic shock patients. Crit Care Med. 1990 Mar;18(3):282-285.
7. Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000 Aug;28(8):2758-2765.
8. De Backer D, Biston P, Devriendt J, et al; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-789.
9. Dellinger RP, Levy MM, Carlet JM, et al; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327.
10. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006 Mar;23(3):589-597.
11. Myburgh JA, Higgins A, Jovanovska A, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2226-2234.
12. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016 Aug 2;316(5):509-518.
13. Vadiei N, Daley MJ, Murthy MS, Shuman CS. Impact of norepinephrine weight-based dosing compared with non-weight-based dosing in achieving time to goal mean arterial pressure in obese patients with septic shock. Ann Pharmacother. 2017 Mar;51(3):194-202.
14. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552.
15. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vasopressin relevant to management of septic shock. Chest. 2001 Sep;120(3):989-1002.
16. Sharshar T, Blanchard A, Paillard M, Raphael JC, Gajdos P, Annane D. Circulating vasopressin levels in septic shock. Crit Care Med. 2003 Jun;31(6):1752-1758.
17. Dünser MW, Mayr AJ, Tür A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003 May;31(5):1394-1398.
18. Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-887.
19. Russell JA, Walley KR, Gordon AC, et al; Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators. Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med. 2009 Mar;37(3):811-818.
20. Gordon AC, Russell JA, Walley KR, et al. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83-91.
21. Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: the VANCS randomized controlled trial. Anesthesiology. 2017 Jan;126(1):85-93.
22. He X, Su F, Taccone FS, et al. A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med. 2016 Jan;44(1):23-31.
23. Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5)5:534.
24. Chawla LS, Russell JA, Bagshaw SM, et al. Angiotensin II for the treatment of high-output shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial. Crit Care Resusc. 2017 Mar;19(1):43-49.
25. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015 Jun;30(3):653.e9-e17.
26. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015 Sep;10(9):581-585.
27. Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med. 2017 Jan 1:885066616686035.
28. Bockenstedt TL, Baker SN, Weant KA, Mason MA. Review of vasopressor therapy in the setting of vasodilatory shock. Adv Em Nurs J. 2012 Jan-Mar;34(1):16-23.
29. Allen JM. Understanding vasoactive medications: focus on pharmacology and effective titration. J Infus Nurs. 2014 Mar-Apr;37(2):82-86.
30. Bauer SR, Aloi JJ, Ahrens CL, Yeh JY, Culver DA, Reddy AJ. Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study. J Crit Care. 2010 Jun;25(2):362.e7-362.e11.
31. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013 Sep;119(3)3:507-515.
32. Salmasi V, Maheshwari K, Yang D, et al. Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology. 2017 Jan;126(1):47-65.
33. Mascha EJ, Yang D, Weiss S, Sessler DI. Intraoperative mean arterial pressure variability and 30-day mortality in patients having noncardiac surgery. Anesthesiology. 2015 Jul;123(1):79-91.
34. Veillet-Chowdhury M, Hassan SF, Stergiopoulos K. Takotsubo cardiomyopathy: a review. Acute Card Care. 2014 Mar;16(1):15-22.