DR GRETCHEN L.

SACHA (Orcid ID : 0000-0002-0070-8100)

DR SETH R BAUER (Orcid ID : 0000-0002-0420-0320)

Accepted Article
DR ISHAQ LAT (Orcid ID : 0000-0001-7887-606X)

Article type : SI on Prevention Strategies in the Critically Ill (PHAR)

Title: Vasoactive Agent Use in Septic Shock: Beyond First-Line Recommendations

Running Title: Vasoactive agents in septic shock

Authors: Gretchen L. Sacha1; Seth R. Bauer1; Ishaq Lat2

1
Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio, USA
2
Department of Pharmacy, Shirley Ryan Ability Lab, Chicago, Illinois, USA

Corresponding Author: Gretchen L. Sacha

Address:

Department of Pharmacy

9500 Euclid Avenue (Hb-105)

Cleveland, Ohio 44195

Email: sachag@ccf.org

Keywords: sepsis, septic shock, vasoactive agents, norepinephrine, vasopressin, epinephrine,

phenylephrine, angiotensin II

Acknowledgements: N/A

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/phar.2220
This article is protected by copyright. All rights reserved.
 Conflict of Interest: all authors submit no conflicts of interest regarding the included original article
Accepted Article
Funding Information: none to disclose

Abstract

Septic shock is a life-threatening disorder associated with high mortality rates requiring rapid

identification and intervention. Vasoactive agents are often required to maintain goal hemodynamics

and preserve tissue perfusion. However, guidance regarding the proper administration of adjunct

agents for the management of septic shock is limited in patients who are refractory to norepinephrine.

This review will summarize vasopressor agents and describe the nuanced application of these agents

in patients with septic shock, specifically focusing on clinical scenarios with limited guidance

including patients who are nonresponsive to first-line agents and individuals with mixed shock states,

tachyarrhythmias, obesity, valvular abnormalities, or other comorbid conditions.

Sepsis is a common source of morbidity and mortality in the intensive care unit (ICU), with

mortality rates approximating 25% and nearing 40% in patients who progress to septic shock. 1-3

Although mortality rates have declined over the years due to advances in medical practice and

diagnosis, the incidence of septic shock continues to rise.2 Patients presenting with sepsis are often

critically ill and may rapidly progress to septic shock if not quickly identified and treated. Therefore,

early and appropriate therapeutic interventions are imperative to survival. Following administration of

appropriate antimicrobial therapy, administration of intravenous fluids is recommended to improve

perfusion, commonly measured by mean arterial pressure (MAP).4 Other interventions are considered

concomitantly to achieve and maintain MAP. At this juncture, vasoactive therapy is critical to

optimizing organ perfusion. Most vasoactive agents are derivatives of endogenous catecholamines

normally released in response to stress and activation of the sympathetic nervous system, often termed

the “fight or flight” response. Catecholamine release results in adrenergic stimulation and a resultant

increase in blood pressure and heart rate. In addition to catecholamine-derived vasoactive agents

(norepinephrine [NE], epinephrine, phenylephrine, and dopamine), there are also noncatecholamine-

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 derived vasopressors (vasopressin and angiotensin II). Mimicking endogenous catecholamines,

catecholamine-derived vasoactive agents act at the adrenergic alpha (α), beta (β), and dopamine
Accepted Article
receptors, whereas the noncatecholamine-derived agents primarily cause vasoconstriction via alternate

pathways.5

The Surviving Sepsis Campaign (SSC) guidelines recommend NE as the first-line vasoactive

agent in patients presenting with septic shock.6 However, in spite of the breadth of literature on this

topic, a gap exists in how to apply broad guideline recommendations to design an appropriate,

individualized vasoactive regimen for patients with septic shock. Due to the heterogeneous etiology

and presentation of sepsis from patient to patient, response to therapy may be improved with a more

precise approach. Additionally, there may be patient scenarios in which choosing a certain vasoactive

agent may cause undue harm and alternatives should be considered (e.g., using high-dose vasopressin

in a patient with a mixed septic and cardiogenic shock state when epinephrine or dobutamine may be

more appropriate). Although the SSC guidelines provide recommendations for treating the population

as a whole,6, 7 an individualized approach may be necessary in many situations, and understanding the

pharmacology, receptor targets, and pharmacodynamic actions and interactions of each agent is

imperative to designing an individualized vasoactive regimen. This review will summarize the various

vasoactive agents available and will focus on providing an approach to tailoring vasoactive therapy

for patients with septic shock, specifically focusing on common clinical scenarios often encountered

in this population.

Catecholamine-derived Vasoactive Agents

Due to the vasodilatory mechanisms of sepsis, it is critical to restore intravascular volume

with aggressive fluid resuscitation in an attempt to optimize fluid status and tissue perfusion.6

Although current guidelines recommend administering a crystalloid volume of at least 30 mL/kg, the

optimal volume for initial resuscitation is currently unclear. Patients still demonstrating signs of

hypotension and hypoperfusion despite fluid resuscitation require the administration of vasoactive

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 agents. The SSC guidelines recommend NE as the first-line vasoactive agent in patients presenting

with septic shock.6 Historically, both NE and dopamine were recommended.8, 9 However, dopamine
Accepted Article
has been associated with increased mortality and increased tachyarrhythmias when compared to NE 10-
14
As such, NE is now recommended as first-line therapy with a strong recommendation by the SSC

guidelines, in spite of only moderate evidence to support this statement.6 In fact, there are few large,

well-designed, multicenter, randomized controlled trials evaluating the most effective initial

vasoactive agent in patients with septic shock. Recent meta-analyses have consistently reported no

difference in clinical outcomes, including mortality, when comparing NE to epinephrine,

phenylephrine, and vasopressin.11, 13 Notably few studies have evaluated the initial vasoactive agent

selection for managing septic shock and many patients included in these studies were already

receiving NE at randomization. Despite the absence of strong evidence supporting the use of NE as

first-line therapy for septic shock, there is also a lack of compelling data to suggest any agent other

than NE should be used first line. Thus, NE remains the standard of care for patients presenting with

septic shock. After NE is initiated, patients should be monitored for hemodynamic response (i.e.,

achievement of goal MAP and stabilization of NE dose requirements to maintain goal MAP). If

patients do not respond to the initiation of NE and require increasing doses or have continued markers

of malperfusion (i.e., hyperlactatemia), second-line adjunctive agents should be considered. It is

important to take all patient-specific factors, as well as pharmacodynamic effects of the vasoactive

agents, into account when choosing adjunctive agents to initiate.

Epinephrine is similar to NE but with greater β1-adrenergic receptor activity in the cardiac

myocardium, exerting greater chronotropic and inotropic effects (Table 1). Pharmacologically,

because of its added β1-adrenergic effects at low doses, the use of epinephrine should be targeted for

patients with septic shock who exhibit signs of tissue hypoperfusion and a reduced cardiac output or

decreased central or mixed venous oxygen saturation.17, 19 As with all vasoactive agents, epinephrine

is not without its risks, including splanchnic hypoperfusion, digital ischemia, and tachyarrhythmias

due to its β1-receptor effects. In patients in whom tachycardia or a malignant tachyarrhythmia

prohibits further increases in NE dose, epinephrine is not an optimal agent because it may worsen

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 tachycardia. Additionally, the administration of epinephrine has been associated with hyperlactatemia

during the first 24 hours of therapy.19-25 As a result, lactate clearance may be an insufficient clinical
Accepted Article
indicator of patient response during the initial day of epinephrine therapy. The administration of

epinephrine may confound the clinical picture in patients with unresolving lactate and alternative

therapies may be considered. One prospective trial randomized patients with septic shock to either NE

(with dobutamine, as needed, to increase cardiac output) or epinephrine.25 Overall, no difference in

mortality was observed between patient groups. Similarly, both a meta-analysis and Cochrane Review

have failed to detect a differences in outcomes between NE and epinephrine.11, 13 Because of these

clinical factors, epinephrine is commonly used as a second-line adjunctive agent in septic shock and

for patients with a mixed cardiogenic component to their shock state.

Phenylephrine is a pure α-adrenergic agonist. Pharmacodynamically, because phenylephrine

causes α1-mediated vasoconstriction and primarily increases afterload, an indirect decrease in heart

rate and cardiac output may occur.26 However, this effect has not been demonstrated in clinical

studies, likely because of stimulation of α1 receptors in the myocardium causing positive inotropy

(without chronotropy).15 This effect may offset the theoretical decrease in heart rate and cardiac

output. In fact, small studies have shown similar effects on cardiac output, heart rate, and stroke

volume when comparing phenylephrine to NE in patients with septic shock.27, 28

Therefore, until

further studies are conducted, caution is warranted when initiating phenylephrine in patients with

bradycardia or mixed cardiogenic and septic shock.

The 2012 SSC guidelines recommended phenylephrine for patients with tachyarrhythmias

associated with NE, those with optimal cardiac output and low blood pressure, or as salvage therapy

after suboptimal response to other vasoactive agents.29 However, the limited data comparing the use

of phenylephrine and NE in septic shock demonstrated no difference in clinical outcomes.27, 28

A

recent multicenter cohort study evaluated clinical outcomes of patients with septic shock during a

period of NE shortage.30 During this time, NE use decreased by more than 20% and mortality

increased (absolute risk increase 3.7%, 95% Confidence Interval [CI] 1.5%-6.0%; P=0.03).

Importantly, during the NE shortage time frame, the use of other vasopressors, specifically

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 phenylephrine, increased by almost 20%. Because of the lack of available data evaluating

phenylephrine use in septic shock, the updated 2016 SSC guidelines recommend its use be limited
Accepted Article
until further research is conducted.6 Despite the lack of certainty with the use of phenylephrine, there

are some niche populations in which it plays a role. Phenylephrine is an appropriate vasoactive agent

in patients who develop tachyarrhythmias from vasoactive agents with β-adrenergic activity including

NE and epinephrine. Additionally, phenylephrine may be considered in patients with aortic stenosis

(AS) and in patients with left ventricular outflow tract (LVOT) obstructions due to systolic anterior

motion of the mitral valve, both of which will be further detailed below.

Dopamine has dose-dependent effects and primarily acts at dopamine receptors at low doses

and adrenergic receptors at moderate (predominantly β receptors) and high doses (predominantly α

receptors) (Table 1). In addition to its tachyarrhythmic potential, dopamine exerts endocrinologic

effects by decreasing prolactin, growth hormone, luteinizing hormone, thyrotrophic releasing

hormone, and thyroid stimulating hormone.31 Because of its overall adverse effect profile (particularly

tachyarrhythmias), dopamine is only recommended for patients with a low risk of tachyarrhythmias or

for those with symptomatic bradycardia.6 However, it is difficult to proactively identify which

patients can be classified as having a low risk of tachyarrhythmias. Because of this, dopamine use in

patients with septic shock should be limited to individuals with symptomatic bradycardia. Alternative

vasopressors with higher levels of recommendation (i.e., NE, epinephrine, and vasopressin) should be

utilized before dopamine in all other patients.

Adverse Drug Effect Mitigation with Catecholamine-Derived Vasoactive Agents

Despite the prioritization of catecholamines in septic shock, there is increased interest in

limiting the use of these agents to prevent the development of adverse events associated with

catecholamine administration.32, 33
Higher catecholamine doses have been independently associated

with mortality rates as high as 90% in patients receiving NE doses greater than 1 µg/kg/min.34-36

Though it is difficult to distinguish between association and causality, higher catecholamine doses

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 may be a marker of severity of septic shock and may contribute to the development of organ failure. 33

Until more research is completed, catecholamine doses should be optimized to maintain perfusion and
Accepted Article
goal MAP, and limited to the lowest effective dose, to mitigate the risks associated with

catecholamine use (e.g., tachyarrhythmias and vasoconstriction-induced hypoperfusion).

Catecholamine-derived agents with β1-receptor activity can cause malignant

tachyarrhythmias. Dopamine has been most commonly associated with arrhythmia development, with

tachyarrhythmia rates as high as 38%.14, 37, 38 However, rates of arrhythmias with NE and epinephrine

have ranged as high as 12%.25 Notably, there appears to be a dose-dependent effect between

catecholamines and the development of tachyarrhythmias. In two studies evaluating goal MAP in

patients with septic shock, higher NE doses were associated with a higher incidence of arrhythmias.39,
40
The noncatecholamine-derived agent vasopressin does not exert action on α- or β- myocardial

receptors, making it a suitable alternative to catecholamines in patients who develop

tachyarrhythmias.

Raising MAP with vasoactive agents in patients with septic shock ultimately improves global

tissue and organ perfusion. However, these vasoconstriction-mediated effects can be detrimental at

higher doses, compromising perfusion and causing side effects such as splanchnic hypoperfusion and

tissue necrosis. Splanchnic vasoconstriction and hypoperfusion can be detrimental if not identified

early, resulting in mucosal and cellular damage that can progress to intestinal ischemia. 41 Although all

vasoactive agents may theoretically cause splanchnic hypoperfusion by nature of their mechanism,

existing literature shows conflicting data on the effect of catecholamines on splanchnic perfusion. 24, 42-
47
Ultimately, the true effect of vasoactive agents on splanchnic perfusion is still in question and is

rarely documented in clinical practice. Additionally, it is difficult to specifically attribute splanchnic

hypoperfusion to catecholamines. Though it may be prudent to limit high-dose catecholamines (NE >

1 µg/kg/min) to minimize the risk of all potential adverse drug effects associated with excessive

catecholamine doses.

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 Non-catecholamine-Derived Vasoactive Agents

In addition to direct vasoconstrictive effects, the administration of exogenous vasopressin is

Accepted Article
hypothesized to improve MAP by supplementing endogenous vasopressin stores in the setting of a

relative deficiency in septic shock.48-52 Vasopressin primarily acts on the V1 receptor leading to

pronounced vasoconstriction and blood pressure augmentation (Table 1). Clinical trials evaluating

vasopressin in septic shock have been mixed. Vasopressin administration has consistently

demonstrated a NE-sparing effect, whereby NE dose requirements decreased significantly following

the administration of vasopressin.48, 53-56

However, randomized controlled trials of vasopressin in

septic shock failed to demonstrate a survival benefit with the adjunctive use of vasopressin with NE

compared to NE monotherapy.54, 55 Additionally, vasopressin may have a positive effect on kidney

function by reducing the risk of progression of acute kidney injury and the need for renal replacement
55, 57
therapy (RRT). The potential positive effects of vasopressin on kidney function should be

interpreted cautiously as they have not been corroborated in large clinical trials and may be attributed

to the lower serum creatinine values and increased urine output seen after the initiation of vasopressin,

thus impacting the clinician’s decision to start RRT.55, 57

A potential positive interaction with

vasopressin and corticosteroids has been reported, showing that corticosteroids may result in

increased V1-receptor expression (Figure 1).58, 59

Secondary analysis of a clinical trial evaluating

vasopressin versus NE found that corticosteroids and vasopressin resulted in improved survival. 60

However, this positive interaction and resultant improvement in clinical outcomes have not been

replicated in recent studies.55, 58

The package insert for vasopressin recommends starting at a dose of 0.01 units/min and

titrating to response, up to a maximum dose of 0.07 units/min.61 However, in practice, unlike most

vasoactive agents, vasopressin is not commonly titrated to response, but rather, is recommended to be

administered at a fixed, nontitrated dose of 0.03 units/min for the treatment of septic shock.6 Clinical

trials evaluating the dosing of vasopressin have evaluated vasopressin dosing up to 0.03 units/min 54

and 0.06 units/min.55 Higher doses of vasopressin may be beneficial in patients requiring high-dose

NE. A study of 50 patients with vasodilatory shock receiving high-dose NE (>0.6 µg/kg/min)

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 randomized patients to two dosing regimens of vasopressin (0.033 units/min and 0.067 units/min). 62

Both groups achieved goal MAP values with no significant differences in clinical outcomes.
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However, patients assigned to 0.067 units/min had lower NE dose requirements at 1, 12, 24, and 48

hours compared to those receiving 0.033 units/min. Given the uncertainty regarding the most effective

dose, vasopressin doses above 0.03 units/min should be used cautiously and should be reserved for

patients with refractory shock who are nonresponsive to high catecholamine doses.

Though the effect of vasopressin on cardiac output has not been shown to be clinically

relevant in clinical trials56, 62, 63

, vasopressin should be reserved for patients with adequate cardiac

function. Caution is warranted when considering vasopressin in patients with mixed septic and

cardiogenic shock due to its potent V1-mediated vasoconstrictive effects increasing afterload with no

chronotropic or inotropic effects, thereby, reducing cardiac output.64 Additionally, because of its V1

nitric oxide-mediated pulmonary vasodilatory effects, vasopressin may be useful in patients with right

ventricular failure and pulmonary hypertension.65

Following initiation of vasopressin, patients should be monitored for a positive response to

therapy. At the bedside, this can be determined by trending MAP and concomitant vasoactive doses.

One study reported that 45% of patients receiving vasopressin for septic shock in combination with

NE had a positive hemodynamic response (defined as a MAP > 65 mm Hg and a decrease in

catecholamine dose requirements 6 hours after vasopressin initiation).66 These patients had significant

improvements in clinical outcomes including ICU mortality (50% vs. 68%, P<0.01), ICU free days

(2.3 days vs 1.6 days), and catecholamine free days (6.3 days vs. 3.9 days) in responders versus

nonresponders, respectively.66 Hemodynamic response to vasopressin was associated with a reduced

odds of ICU mortality (odds ratio [OR 0].51, 95% CI 0.35-0.76; p=0.001). Additionally, markers of

severity of illness (lactate, sequential organ failure assessment score, and baseline catecholamine

dose) were associated with increased ICU mortality, and lactate was independently associated with a

reduced odds of hemodynamic response, indicating that higher severity of tissue malperfusion may

decrease the odds of both ICU survival and a positive response to vasopressin. 66 In practice, after 6

hours of vasopressin administration, hemodynamics should be re-evaluated to determine if the patient

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 has responded to vasopressin therapy (i.e., MAP goal achieved and concomitant vasopressor doses

decreasing), while alternative approaches should be considered if the patient has not responded to
Accepted Article
vasopressin.

Recently, angiotensin II was approved by the United States Food and Drug Administration for

treatment of severe hypotension.67 Angiotensin II is an endogenous hormone in the renin-angiotensin-

aldosterone system, with potent vasoconstricting properties. The administration of exogenous

angiotensin II results in a multitude of physiological effects, primarily vasoconstriction via the

angiotensin-1 receptor and release of aldosterone, endogenous NE, and vasopressin (Figure 1). To

date, only one large randomized controlled trial has evaluated the use of angiotensin II in vasodilatory

shock. The Angiotensin II for the Treatment of High-Output Shock trial (ATHOS-3) compared the

use of angiotensin II (20-200 ng/kg/min) to placebo in 321 patients with preserved cardiac function

(cardiac index > 2.3 L) requiring more than 0.2 µg/kg/min of NE.68 In this trial, more patients

randomized to angiotensin II had a positive MAP response at 3 hours (MAP ≥ 75 mm Hg or increase

of 10 mm Hg with no further increase in background vasopressors) compared to placebo. In addition,

patients in the angiotensin II arm had a significant, albeit small, decrease in NE requirements at 3

hours (-0.03 µg/kg/min with angiotensin II vs. 0.03 µg/kg/min with placebo; p<0.001). No significant

differences in 7- or 28-day all-cause mortality were detected.68 Although the role of angiotensin II in

patients with septic shock is unclear, it should be noted that 70% of patients in the aforementioned

study were receiving NE and vasopressin at the time of randomization. Therefore, at this time,

angiotensin II may be best reserved for patients with preserved cardiac function whose MAP goal is

not achieved despite use of NE and vasopressin until further data are available regarding its use as a

second-line and/or adjunctive agent. Additionally, further safety data on angiotensin II is warranted.

In one meta-analysis, the drug appeared to be well tolerated with minimal adverse effects69 (albeit this

study did not include data from the ATHOS-3 study). However, the United States product labeling for

angiotensin II warns of increased thrombotic events (rates of 12.9% with angiotensin II vs. 5.1% with

placebo in the ATHOS-3 trial), thrombocytopenia, and infection risk, among others.67, 70
As with

vasopressin use, if and when angiotensin II is administered, hemodynamic response should be

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 monitored and if a positive hemodynamic response does not occur after the initiation of angiotensin

II, alternative therapies should be considered.

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Corticosteroids exert pleiotropic effects. Noticeably, corticosteroids have been reported to

improve blood pressure and perfusion in patients with septic shock. Therefore, it may be prudent to

consider corticosteroids as a shock therapy. Although the mechanism of corticosteroids in septic

shock is multifaceted, the supplementation of corticosteroids in this population is thought to result in

hemodynamic improvements.71 However, the use of corticosteroids in septic shock remains

controversial and numerous studies have reported contradictory results. Studies have implied that

starting corticosteroids late after shock onset (1-3 days) 72, 73 and in patients who are not severely ill,73

does not improve overall patient outcomes. The potential benefit of corticosteroids appears to lie with

early initiation (within the first 12 hours of shock on set) in patients with refractory septic shock. 72, 74

Additionally, several meta-analyses and a Cochrane Review have evaluated the use of corticosteroids

in septic shock with contradictory results, albeit significant heterogeneity among the included studies

make generalizations difficult.75-78 The most recent meta-analysis of all landmark trials shows that

corticosteroid use in sepsis may result in a small, nonsignificant reduction in mortality (risk ratio [RR]

0.93, 95% CI 0.84-1.03) and significant improvements in shock reversal rates at day 7 (RR 1.26, 95%

CI 1.12-1.42).78 Overall, the question of whether or not to use corticosteroids in patients with septic

shock remains unanswered. In clinical practice, corticosteroids are commonly used in patients who are

unresponsive to fluid administration and require increasing vasoactive doses; a guideline-supported

practice, albeit with weak recommendations due to low quality of evidence. 6, 79 Regardless, the best

supporting data with corticosteroid use in patients with septic shock is for those with early refractory

shock and other uses remain controversial.

Vasoactive Agents in Refractory Septic Shock

As previously discussed, aggressive fluid resuscitation with crystalloids should be initiated as

soon as possible in all patients with septic shock. In patients refractory to fluids, vasoactive agents are

warranted. Choosing and designing a vasoactive regimen for patients with septic shock is not a one-

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 size-fits-all approach. Each agent should be carefully selected and titrated to the specific needs of the

individual patient. Hemodynamic response should be targeted and monitored in all patients, and
Accepted Article
alternative agents should be trialed in patients who are refractory to the current regimen (i.e., lactate

and vasoactive doses increasing and no achievement of MAP goal) (Figure 2). Norepinephrine

remains the first-line vasoactive agent and patients who are refractory to NE should be evaluated for

cardiac function. It may be prudent to start at a “medium” dose of NE (e.g., 10 µg/min) and titrate

every 5 minutes in either direction to achieve the desired MAP goal. If cardiac function is

compromised, epinephrine or dobutamine are necessary for their inotropic effects and should be

monitored for response (i.e., improvement in cardiac output or central or mixed venous oxygen

saturation and lactate) following initiation. If cardiac function is preserved, vasopressin should be

administered. Patients who do not promptly demonstrate an improvement in hemodynamics with

vasopressin 0.03 units/min within 1 hour should have intravenous hydrocortisone 50 mg every 6 hours

initiated and alternative vasoactive therapies should be further discussed. These include increasing

vasopressin dose to 0.04 units/min or higher, adding angiotensin II, or continuing to titrate up NE

doses (taking care to monitor for adverse effects with excessive catecholamine doses). In patients

truly refractory to these escalating approaches, requiring high catecholamine doses on multiple agents

without the achievement of goal MAP, addition of epinephrine (if not already added and if heart rate

allows) may be warranted in an attempt to restore organ perfusion. This algorithmic approach should

be tailored to patient presentation, response, and updated goals of care following discussion with the

patient and family.

Vasoactive Agents in Common Clinical Scenarios

Tachyarrhythmias

Alternative agents should be considered for patients who develop severe tachyarrhythmias,

especially while receiving catecholamine-derived vasoactive agents. A recent meta-analysis compared

vasopressin plus NE to NE alone in patients with vasodilatory shock (including both septic and post-

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 cardiac surgical patients) and found that administration of vasopressin plus NE was associated with

lower risk of atrial fibrillation development.80 Additionally, phenylephrine may be considered for its
Accepted Article
lack of β-receptor activity and would be a suitable alternative to NE or epinephrine in patients who are

already receiving vasopressin and develop tachyarrhythmias. In a proactive manner, catecholamines

should be limited in patients at high risk of developing tachyarrhythmia based on presenting factors.

In patients presenting with significant tachycardia (heart rate >140 bpm) or with a baseline

tachyarrhythmia, phenylephrine and vasopressin should be prioritized in order to not precipitate a

tachyarrhythmia. Similarly, limiting catecholamine-derived agents in patients with pronounced heart

rate variability from baseline after initiation of catecholamines (i.e., significant increase in heart rate

after the initiation of NE but no tachyarrhythmia development at present) would be advised.

Valvular Abnormalities

The presence of valvular abnormalities has significant implications in the treatment of septic

shock. Abnormalities of interest are AS and patients who present with or develop a LVOT obstruction

due to systolic anterior motion (SAM) of the mitral valve. In patients presenting with AS and septic

shock requiring vasoactive agent support to maintain MAP, phenylephrine is considered as the

vasoactive agent of choice due to its pure α agonism and lack of β-adrenergic effects on the

myocardium, thereby reducing oxygen demand.26 It is important to note that the hemodynamic and

clinical effects of different vasoactive agents for patients with septic shock complicated by AS have

not been comparatively evaluated and the use of phenylephrine relies on its theorized benefit.

Additionally, phenylephrine is preferred in patients with LVOT due to SAM.26 Patients with SAM

commonly express reduced cardiac output due to LVOT obstruction. Vasoactive agents with β-

adrenergic properties will increase heart rate (decreasing filling time) and increase cardiac

contractility, which worsens the LVOT obstruction. The α-mediated effects of phenylephrine have not

been shown to significantly impact heart rate or cardiac contractility.15 Thus, in patients with LVOT

obstruction from SAM, phenylephrine could be considered as the vasopressor of choice for sustained

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 hypotension following fluid administration.81 In both scenarios, patients with AS and LVOT

obstruction from SAM, it may be reasonable to consider administering alternative, nonadrenergic

Accepted Article
vasoactive agents, such as vasopressin, in an attempt to reduce heart rate.

Obesity

Unfortunately, no specific data guides clinicians on the superiority of specific vasoactive

agents in obese patients. Additionally, there is little pharmacokinetic data detailing the effect of

obesity on each agent. One study showed that increasing body weight significantly increases the

clearance of epinephrine in patients with septic shock82, an effect that was not seen in a

pharmacokinetic study of dobutamine.83 At this time, it is difficult to apply these data to clinical

practice and more data is needed to determine the potential effect obesity has on the pharmacokinetics

of the various vasoactive agents. Regardless, common clinical debates still held in this regard include

whether vasoactive doses should be based on body weight and whether obesity impacts the clinical

effects of vasopressors.

Critically ill obese patients have been shown to have differences in inflammatory markers,

infectious etiologies, and clinical outcomes.84 Additionally, critically ill obese patients receive less

fluids (on mL/kg basis) and lower vasopressor doses (on µg/kg/min basis) than nonobese patients.84

However, when evaluating weight-based dosing of NE versus non-weight-based dosing in obese

patients, no significant difference between goal MAP achievement was detected between dosing

strategies.85, 86 Despite the fact that initial doses will differ in obese patients, the ultimate result and

clinical outcomes should be similar, regardless of the dosing strategy, because NE is titrated to goal

MAP. With regards to vasopressin, a medication that is not commonly titrated and is typically

administered at a fixed dose, one study showed lower serum vasopressin levels in obese patients 24

and 72 hours after its initiation.88 However, several studies have reported no impact with weight or

obesity on the hemodynamic effects of vasopressin.87-89 At this time, there does not appear to be

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 sufficient evidence to alter vasoactive therapies in obese patients, and dosing and utilization should be

optimized and titrated to hemodynamic effect and response.

Accepted Article
Other Comorbidities and Medication Use

Globally, it is not known what true clinical effect, if any, other pre-existing comorbidities

(such as diabetes, immune suppression, chronic kidney disease, oncologic and hematologic disorder,

etc), home medication use, and genetic factors have on the pathophysiology of septic shock and the

subsequent effect on and response to vasoactive agent initiation. It is theorized that chronic

antihypertensive agent use may have an effect on outcomes in patients with septic shock. Patients

taking β-antagonists prior to admission for septic shock may demonstrate an upregulation in β

receptors due to chronic therapy.90 Therefore, it would be reasonable to presume that patients with

home β-blocker therapy prior to admission may require increased vasoactive doses to achieve goal

hemodynamics. Additionally, patients with an upregulation and augmentation of β 1 receptors may be

at greater risk of tachyarrhythmia development when β-blocker therapy is withdrawn, although the

clinical implications of this are largely unknown. However, contradictory to this, one study found that

patients with septic shock who were chronically receiving β blockers had lower mortality rates than

those not on chronic β blockers.91 Ultimately, further data is needed to determine the true implications

of chronic β-blocker therapy on septic shock treatment and outcomes.

Chronic use of angiotensin converting enzyme-inhibitors (ACE-Is) and angiotensin receptor

blockers (ARBs) may also have noteworthy implications in septic shock. One evaluation of patients

with septic shock and chronic β-blockers and ACE-Is use prior to hospital admission found that the

shortest time on vasopressors occurred in patients with home ACE-Is compared to patients on home β

blockers, both agents, or neither agent (19 hours vs. 24 hours vs. 30 hours vs. 30 hours, respectively;

P=0.031).92 However, no differences in clinical outcomes were detected between groups and patient

numbers were small in the cohorts evaluated.92 At this time, it is difficult to apply these data to

clinical practice when patients present with a history of chronic β-blocker and ACE-I use. The

This article is protected by copyright. All rights reserved.

 question of chronic antihypertensive use and effect on clinical outcomes in patients with septic shock

warrants further investigation and is currently being studied in a multicenter, observational evaluation
Accepted Article
(ClinicalTrials.gov Identifier: NCT03190408).93 Additionally, chronic ACE-I and ARB use may have

significant effects in patients with sepsis who receive angiotensin II. Due to potential upregulation of

angiotensin I receptors in patients receiving chronic ACE-Is, an exaggerated increase in MAP may

occur when giving angiotensin II.70 On the other hand, downregulation of angiotensin I receptors in

patients receiving ARBs may result in a diminished response to angiotensin II initiation, an effect

shown in a small subgroup analysis of the ATHOS-3 trial.68 Unfortunately, there is a need for further

published data evaluating these scenarios to determine the true clinical effects of chronic ACE-Is and

ARBs in patients who receive angiotensin II.

Whether to continue chronic antihypertensive therapies during shock treatment is unknown,

and it would seem contradictory to administer antihypertensive therapy in the setting of vasopressor

agents. However, a recent study examined whether the administration of esmolol to normalize heart

rate in the setting of septic shock would improve outcomes.94 The investigators reported

improvements in hemodynamic parameters (heart rate, cardiac index, stroke volume, and MAP) in the

cohort of patients treated with esmolol. This raises the question of whether β-blocker therapy is

beneficial in septic shock and whether β-blocker therapy should be continued in patients with a

history of receiving therapy prior to admission.

Pharmacogenomics/Genetics

The promise of pharmacogenomic therapy has recently been demonstrated for the treatment

of various cancers. Similarly, pharmacogenomic therapy holds unrealized potential for the treatment

of septic shock at the present time. The future of septic shock treatment may include a broad genomic

profile of patients on admission to determine optimal vasopressor treatments, corticosteroid response,

and predilection to adverse effects. One example of the potential uses of this field is with the detection

of genetic variations on the leucyl-cystinyl aminopeptidase (LNPEP) enzyme, which is primarily

This article is protected by copyright. All rights reserved.

 responsible for the clearance of endogenous and exogenous vasopressin. One study found that patients

with a TT genotype of the LNPEP rs4869317 single nucleotide polymorphism had increased
Accepted Article
vasopressin clearance (p=0.028) and increased 28-day mortality compared to other genotypes (51%

vs. 36.4%; adjusted hazard ratio 1.58 95% CI, 1.21-2.06 p=0.0007).95 These findings have potential

implications for all patients with septic shock, regardless of whether they receive exogenous

vasopressin. However, at the current time, we are only at the gestational phases of research and

understanding in this area.

Conclusions

Septic shock is a life-threatening disorder with mortality rates approximating 40%.

Therapeutic interventions, including vasoactive agents to maintain goal hemodynamics are imperative

to patient care and survival. Norepinephrine is the first-line vasoactive agent of choice, but alternative

and adjunctive agents such as epinephrine, vasopressin, angiotensin II, and phenylephrine may be

warranted in specific scenarios and if patients do not have an appropriate hemodynamic response to

the initiation of NE. Ultimately, more data is needed to elucidate how to best individualize care for

patients with septic shock and future research is needed to determine the effects of comorbidities,

chronic medication use, and genetics on the pathophysiology of septic shock and subsequent

implications for treatment.

This article is protected by copyright. All rights reserved.

 Table and Figure Legend
Accepted Article
Table 1: Receptor Activity and Drug Targets of Vasoactive Agents

 See separate attachment

Figure 1: Vasoactive Agents in Septic Shock

Footnote:

AT1=Angiotensin 1; V1=Vasopressin 1

Depiction of the dynamic interplay of the vasoactive agents, norepinephrine, epinephrine,

phenylephrine, dopamine, vasopressin and angiotensin II as well as corticosteroids utilized in septic
shock.

Figure 2: Vasoactive Treatment Algorithm

Footnote:

AVP=arginine vasopressin; CO=cardiac output; MAP=mean arterial pressure; NE=norepinephrine

a
Consider phenylephrine in patients with unacceptably high heart rate or malignant tachyarrhythmias;
considered vasoactive agent of choice in patients with aortic stenosis or in those with left ventricular
outflow track obstruction due to systolic anterior motion of the mitral valve
b
If heart rate is acceptable and there is no presence of tachyarrhythmias

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Accepted Article
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 Table 1: Receptor Activity and Drug Targets of Vasoactive Agents
Accepted Article
Receptor Location Action

Vascular smooth muscle Vascular smooth muscle: vasoconstriction

Alpha 1 (α1)
Myocardial tissue15 Myocardial tissue: positive inotropy

Beta 1 (β1) Myocardial tissue Positive inotropy and chronotropy

Beta 2 (β2) Vascular smooth muscle Vasodilation

Renal, mesenteric, and coronary vascular

Dopamine (DA) 1 and 2 Vasodilation
beds

Vasopressin 1 (V1) Vascular smooth muscle Vasoconstriction

Renal collecting ducts: anti-diuretic effect/

Renal collecting ducts and
Vasopressin 2 (V2) 16 water retention
some vascular smooth muscle
Vascular smooth muscle: Vasodilation
Angiotensin I: Vasoconstriction, stimulation
Angiotensin I and II: Kidney, heart, brain, of norepinephrine and vasopressin release
Angiotensin Receptors
adrenal glands, and skeletal muscle
Angiotensin II: Vasodilation

Drug Receptor Targets

Norepinephrine α1 (predominantly) and β1 receptors

Low doses ( < 4 µg/min): High doses:

Epinephrine17
β receptors (β1 predominates) α 1 predominates β receptors

Phenylephrine α1 receptors

Low doses: Moderate doses: High doses:

Dopamine5,18
DA receptors β receptors (β1 predominates) α 1 predominates β receptors

Vasopressin V1 and V2 receptors

Angiotensin II Angiotensin I receptors

The receptor locations and mediated actions detailed above are not all-inclusive and focus on those that have
clinically significant hemodynamic effect in patients with septic shock

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Accepted Article

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Accepted Article

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