Vasoactive Agent Use in Septic Shock: Beyond

First-Line Recommendations

Gretchen L. Sacha,1,* Seth R. Bauer,1 and Ishaq Lat2

1Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio; 2Department of Pharmacy, Shirley Ryan Ability

Lab, Chicago, Illinois

Septic shock is a life-threatening disorder associated with high mortality rates requiring rapid identifi-cation and intervention. Vasoactive agents are often required to maintain goal hemodynamics and pre-serve tissue perfusion. However, guidance regarding the proper administration of adjunct agents forthe management of septic shock is limited in patients who are refractory to norepinephrine. Thisreview summarizes vasopressor agents and describes the nuanced application of these agents inpatients with septic shock, specifically focusing on clinical scenarios with limited guidance includingpatients who are nonresponsive to first-line agents and individuals with mixed shock states,tachyarrhythmias, obesity, valvular abnormalities, or other comorbid conditions.KEY WORDS sepsis, septic shock, vasoactive agents, norepinephrine, vasopressin, epinephrine, phenyle-phrine, angiotensin II.(Pharmacotherapy 2019;39(3):369–381) doi: 10.1002/phar.2220

Sepsis is a common source of morbidity andmortality in the intensive care unit (ICU), withmortality rates of ~25% and nearing 40% inpatients who progress to septic shock.1–3

Although mortality rates have declined over theyears due to advances in medical practice anddiagnosis, the incidence of septic shock continuesto rise.2 Patients presenting with sepsis are oftencritically ill and may progress rapidly to septicshock if not quickly identified and treated. There-fore, early and appropriate therapeutic interven-tions are imperative to survival. Followingadministration of appropriate antimicrobial ther-apy, administration of intravenous fluids is rec-ommended to improve perfusion, commonlymeasured by mean arterial pressure (MAP).4

Other interventions are considered concomitantlyto achieve and maintain MAP. At this juncture,vasoactive therapy is critical to optimizing organ

perfusion. Most vasoactive agents are derivativesof endogenous catecholamines normally releasedin response to stress and activation of the sympa-thetic nervous system, often termed the fight-or-flight response. Catecholamine release results inadrenergic stimulation and a resultant increase inblood pressure and heart rate. In addition to cate-cholamine-derived vasoactive agents (nore-pinephrine [NE], epinephrine, phenylephrine,and dopamine), there are also noncatecholamine-derived vasopressors (vasopressin and angioten-sin II). Mimicking endogenous catecholamines,catecholamine-derived vasoactive agents act atthe adrenergic a, b, and dopamine receptors,whereas the noncatecholamine-derived agentsprimarily cause vasoconstriction via alternatepathways.5

The Surviving Sepsis Campaign (SSC) guide-lines recommend NE as the first-line vasoactiveagent in patients presenting with septic shock.6

However, in spite of the breadth of literature onthis topic, a gap exists in how to apply broadguideline recommendations to design an appro-priate individualized vasoactive regimen forpatients with septic shock. Due to the heteroge-neous etiology and presentation of sepsis from

Conflict of interest: The authors have declared no con-flicts of interest for this article.

*Address for correspondence: Gretchen L. Sacha,Department of Pharmacy, 9500 Euclid Avenue, Hb-105,Cleveland, OH 44195; e-mail: sachag@ccf.org.� 2019 Pharmacotherapy Publications, Inc.

patient to patient, response to therapy may beimproved with a more precise approach. Addi-tionally, there may be patient scenarios in whichchoosing a certain vasoactive agent may causeundue harm and alternatives should be consid-ered (e.g., using high-dose vasopressin in apatient with a mixed septic and cardiogenicshock state when epinephrine or dobutaminemay be more appropriate). Although the SSCguidelines provide recommendations for treatingthe population as a whole,6, 7 an individualizedapproach may be necessary in many situations,and understanding the pharmacology, receptortargets, and pharmacodynamic actions and inter-actions of each agent is imperative to designingan individualized vasoactive regimen. Thisreview summarizes the various vasoactive agentsavailable and focuses on providing an approachto tailoring vasoactive therapy for patients withseptic shock, specifically focusing on commonclinical scenarios often encountered in thispopulation.

Catecholamine-Derived Vasoactive Agents

Due to the vasodilatory mechanisms of sepsis,it is critical to restore intravascular volume withaggressive fluid resuscitation in an attempt tooptimize fluid status and tissue perfusion.6

Although current guidelines recommend admin-istering a crystalloid volume of at least 30 ml/kg, the optimal volume for initial resuscitation iscurrently unclear. Patients still demonstratingsigns of hypotension and hypoperfusion despitefluid resuscitation require the administration ofvasoactive agents. The SSC guidelines recom-mend NE as the first-line vasoactive agent inpatients presenting with septic shock.6 Histori-cally, both NE and dopamine were recom-mended.8, 9 However, dopamine was associatedwith increased mortality and increased tach-yarrhythmias when compared with NE.10–14 Assuch, NE is now recommended as first-line ther-apy with a strong recommendation by the SSCguidelines, in spite of only moderate evidence tosupport this statement.6 In fact, only a few largewell-designed multicenter randomized controlledtrials have evaluated the most effective initialvasoactive agent in patients with septic shock.Meta-analyses in 2015 and 2016 consistentlyreported no difference in clinical outcomes,including mortality, when comparing NE withepinephrine, phenylephrine, and vasopressin.11, 13

Notably few studies have evaluated the initialvasoactive agent selection for managing septic

shock, and many patients included in these stud-ies were already receiving NE at randomization.Despite the absence of strong evidence support-ing the use of NE as first-line therapy for septicshock, compelling data are also lacking to sug-gest any agent other than NE should be usedfirst line. Thus NE remains the standard of carefor patients presenting with septic shock. AfterNE is initiated, patients should be monitored forhemodynamic response (i.e., achievement ofgoal MAP and stabilization of NE dose require-ments to maintain goal MAP). If patients do notrespond to the initiation of NE and requireincreasing doses or have continued markers ofmalperfusion (i.e., hyperlactatemia), second-lineadjunctive agents should be considered. It isimportant to take all patient-specific factors, aswell as pharmacodynamic effects of the vasoac-tive agents, into account when choosing adjunc-tive agents to initiate.

Epinephrine is similar to NE but with greaterb1-adrenergic receptor activity in the cardiacmyocardium, exerting greater chronotropic andinotropic effects (Table 1). Pharmacologically,because of its added b1-adrenergic effects at lowdoses, the use of epinephrine should be targetedfor patients with septic shock who exhibit signsof tissue hypoperfusion and a reduced cardiacoutput or decreased central or mixed venousoxygen saturation.17, 19 As with all vasoactiveagents, epinephrine is not without its risksincluding splanchnic hypoperfusion, digitalischemia, and tachyarrhythmias due to its b1-receptor effects. In patients in whom tachycardiaor a malignant tachyarrhythmia prohibits furtherincreases in NE dose, epinephrine is not an opti-mal agent because it may worsen tachycardia.

Additionally, the administration of epinephr-ine was associated with hyperlactatemia duringthe first 24 hours of therapy.19–25 As a result,lactate clearance may be an insufficient clinicalindicator of patient response during the initialday of epinephrine therapy. The administrationof epinephrine may confound the clinical picturein patients with unresolving lactate, and alterna-tive therapies may be considered. One prospec-tive trial randomized patients with septic shockto either NE (with dobutamine, as needed, toincrease cardiac output) or epinephrine.25 Over-all, no difference in mortality was observedbetween patient groups. Similarly, both a meta-analysis and Cochrane Review failed to detectdifferences in outcomes between NE andepinephrine.11, 13 Because of these clinical fac-tors, epinephrine is commonly used as a second-

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line adjunctive agent in septic shock and forpatients with a mixed cardiogenic component totheir shock state.

Phenylephrine is a pure a-adrenergic agonist.Pharmacodynamically, because phenylephrinecauses a1-mediated vasoconstriction and primar-ily increases afterload, an indirect decrease inheart rate and cardiac output may occur.26 How-ever, this effect was not demonstrated in clinicalstudies, likely because of stimulation of a1receptors in the myocardium causing positiveinotropy (without chronotropy).15 This effectmay offset the theoretical decrease in heart rateand cardiac output. In fact, small studies showedsimilar effects on cardiac output, heart rate, andstroke volume when comparing phenylephrinewith NE in patients with septic shock.27, 28

Therefore, until further studies are conducted,caution is warranted when initiating phenyle-phrine in patients with bradycardia or mixedcardiogenic and septic shock.

The 2012 SSC guidelines recommendedphenylephrine for patients with tachyarrhyth-mias associated with NE, those with optimal car-diac output and low blood pressure, or assalvage therapy after suboptimal response toother vasoactive agents.29 However, the limited

data comparing the use of phenylephrine andNE in septic shock demonstrated no differencein clinical outcomes.27, 28 A 2017 multicentercohort study evaluated clinical outcomes ofpatients with septic shock during a period of NEshortage.30 During this time, NE use decreasedby more than 20% and mortality increased(absolute risk increase 3.7%; 95% confidenceinterval [CI] 1.5–6.0%, p=0.03). Importantly,during the NE shortage time frame, the use ofother vasopressors, specifically phenylephrine,increased by almost 20%. Because of the lack ofavailable data evaluating phenylephrine use inseptic shock, the updated 2016 SSC guidelinesrecommend its use be limited until furtherresearch is conducted.6 Despite the lack of cer-tainty with the use of phenylephrine, it plays arole in some niche populations. Phenylephrine isan appropriate vasoactive agent in patients whodevelop tachyarrhythmias from vasoactive agentswith b-adrenergic activity including NE and epi-nephrine. Additionally, phenylephrine may beconsidered in patients with aortic stenosis (AS)and in patients with left ventricular outflow tract(LVOT) obstructions due to systolic anteriormotion of the mitral valve, both of which arefurther detailed later.

Table 1. Receptor Activity and Drug Targets of Vasoactive Agents

Receptor Location Action

a1 Vascular smooth muscleMyocardial tissue15

Vascular smooth muscle: vasoconstrictionMyocardial tissue: positive inotropy

b1 Myocardial tissue Positive inotropy and chronotropyb2 Vascular smooth muscle VasodilationDopamine (DA)1 and 2

Renal, mesenteric, andcoronary vascular beds

Vasodilation

Vasopressin 1 (V1) Vascular smooth muscle VasoconstrictionVasopressin 2 (V2)

16 Renal collecting ducts and somevascular smooth muscle

Renal collecting ducts:antidiuretic effect/waterretentionVascular smooth muscle: Vasodilation

Angiotensinreceptors

Angiotensin I and II: Kidney,heart, brain, adrenal glands,and skeletal muscle

Angiotensin I: Vasoconstriction,stimulation ofnorepinephrine and vasopressin releaseAngiotensin II: Vasodilation

Drug Receptor targetsNorepinephrine a1 (predominantly) and

b1 receptorsEpinephrine17 Low doses (< 4 µg/min):

b receptors(b1 predominates)

High doses: a1 predominates b receptors

Phenylephrine a1 receptorsDopamine5, 18 Low doses: DA receptors Moderate doses: b receptors

(b1 predominates)High doses: a1 predominatesb receptors

Vasopressin V1 and V2 receptorsAngiotensin II Angiotensin I receptors

Note: The receptor locations and mediated actions detailed here are not all-inclusive and focus on those that have a clinically significanthemodynamic effect in patients with septic shock.

VASOACTIVE AGENTS IN SEPTIC SHOCK Sacha et al 371

Dopamine has dose-dependent effects and pri-marily acts at dopamine receptors at low dosesand adrenergic receptors at moderate (predomi-nantly b receptors) and high doses (predomi-nantly a receptors) (Table 1). In addition to itstachyarrhythmic potential, dopamine exertsendocrinologic effects by decreasing prolactin,growth hormone, luteinizing hormone, thy-rotrophic-releasing hormone, and thyroid-stimu-lating hormone.31 Because of its overall adverseeffect profile (particularly tachyarrhythmias),dopamine is only recommended for patientswith a low risk of tachyarrhythmias or for thosewith symptomatic bradycardia.6 However, it isdifficult to identify proactively which patientscan be classified as having a low risk of tach-yarrhythmias. Because of this, dopamine use inpatients with septic shock should be limited toindividuals with symptomatic bradycardia. Alter-native vasopressors with higher levels of recom-mendation (i.e., NE, epinephrine, andvasopressin) should be used before dopamine inall other patients.

Adverse Drug Effect Mitigation withCatecholamine-Derived Vasoactive Agents

Despite the prioritization of catecholamines inseptic shock, interest is increasing in limiting theuse of these agents to prevent the developmentof adverse events associated with catecholamineadministration.32, 33 Higher catecholamine doseswere independently associated with mortalityrates as high as 90% in patients receivingNE doses greater than 1 lg/kg/minute.34–36

Although it is difficult to distinguish betweenassociation and causality, higher catecholaminedoses may be a marker of the severity of septicshock and may contribute to the development oforgan failure.33 Until more research is com-pleted, catecholamine doses should be optimizedto maintain perfusion and goal MAP, and limitedto the lowest effective dose, to mitigate the risksassociated with catecholamine use (e.g., tach-yarrhythmias and vasoconstriction-inducedhypoperfusion).

Catecholamine-derived agents with b1-recep-tor activity can cause malignant tachyarrhyth-mias. Dopamine was most commonly associatedwith arrhythmia development, with tach-yarrhythmia rates as high as 38%.12, 14, 37 How-ever, rates of arrhythmias with NE andepinephrine have ranged as high as 12%.25 Nota-bly, there appears to be a dose-dependent effectbetween catecholamines and the development of

tachyarrhythmias. In two studies evaluating goalMAP in patients with septic shock, higher NEdoses were associated with a higher incidence ofarrhythmias.38, 39 The noncatecholamine-derivedagent vasopressin does not exert action on a- orb-myocardial receptors, making it a suitablealternative to catecholamines in patients whodevelop tachyarrhythmias.

Raising MAP with vasoactive agents inpatients with septic shock ultimately improvesglobal tissue and organ perfusion. However,these vasoconstriction-mediated effects can bedetrimental at higher doses, compromisingperfusion and causing side effects such assplanchnic hypoperfusion and tissue necrosis.Splanchnic vasoconstriction and hypoperfusioncan be detrimental if not identified early, result-ing in mucosal and cellular damage that canprogress to intestinal ischemia.40 Althoughall vasoactive agents may theoretically causesplanchnic hypoperfusion by nature of theirmechanism, existing literature shows conflictingdata on the effect of catecholamines on splanch-nic perfusion.24, 41–46 Ultimately, the true effectof vasoactive agents on splanchnic perfusion isstill in question and rarely documented in clini-cal practice. Additionally, it is difficult to attri-bute specifically splanchnic hypoperfusion tocatecholamines. It may be prudent to limit high-dose catecholamines (NE more than 1 lg/kg/min) to minimize the risk of all potentialadverse drug effects associated with excessivecatecholamine doses.

Noncatecholamine-Derived Vasoactive Agents

In addition to direct vasoconstrictive effects,the administration of exogenous vasopressin ishypothesized to improve MAP by supplementingendogenous vasopressin stores in the setting of arelative deficiency in septic shock.47–51 Vaso-pressin primarily acts on the V1 receptor leadingto pronounced vasoconstriction and blood pres-sure augmentation (Table 1). Clinical trials evalu-ating vasopressin in septic shock have beenmixed. Vasopressin administration has consis-tently demonstrated a NE-sparing effect, wherebyNE dose requirements decreased significantly fol-lowing the administration of vasopressin.47, 52–55

However, randomized controlled trials of vaso-pressin in septic shock failed to demonstrate asurvival benefit with the adjunctive use of vaso-pressin with NE compared with NE monother-apy.53, 54 Vasopressin may also have a positiveeffect on kidney function by reducing the risk of

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progression of acute kidney injury and the needfor renal replacement therapy (RRT).54, 56 Thepotential positive effects of vasopressin on kidneyfunction should be interpreted cautiously becausethey have not been corroborated in large clinicaltrials and may be attributed to the lower serumcreatinine values and increased urine output seenafter the initiation of vasopressin, thus impactingthe clinician’s decision to start RRT.54, 56 Apotential positive interaction with vasopressinand corticosteroids was reported, showing thatcorticosteroids may result in increased V1-recep-tor expression (Figure 1).57, 58 Secondary analysisof a clinical trial evaluating vasopressin versus NEfound that corticosteroids and vasopressinresulted in improved survival.59 However, thispositive interaction and resultant improvement inclinical outcomes were not replicated in studiesin 2014 and 2016.54, 57

The package insert for vasopressin recom-mends starting at a dose of 0.01 units/minuteand titrating to response, up to a maximumdose of 0.07 units/minute.60 However, in prac-tice, unlike most vasoactive agents, vasopressinis not commonly titrated to response, butrather it is recommended to be administered ata fixed nontitrated dose of 0.03 units/minutefor the treatment of septic shock.6 Clinical tri-als evaluating the dosing of vasopressin evalu-ated vasopressin dosing up to 0.03 units/minute53 and 0.06 units/minute.54 Higher doses

of vasopressin may be beneficial in patientsrequiring high-dose NE. A study of 50 patientswith vasodilatory shock receiving high-dose NE(more than 0.6 lg/kg/min) randomized patientsto two dosing regimens of vasopressin (0.033units/min and 0.067 units/min).61 Both groupsachieved goal MAP values with no significantdifferences in clinical outcomes. However,patients assigned to 0.067 units/minute hadlower NE dose requirements at 1, 12, 24, and48 hours compared with those receiving 0.033units/minute. Given the uncertainty regardingthe most effective dose, vasopressin doses above0.03 units/minute should be used cautiouslyand reserved for patients with refractory shockwho are nonresponsive to high catecholaminedoses.

Although the effect of vasopressin on cardiacoutput was not shown to be clinically relevantin clinical trials,55, 61, 62 vasopressin should bereserved for patients with adequate cardiac func-tion. Caution is warranted when consideringvasopressin in patients with mixed septic andcardiogenic shock due to its potent V1-mediatedvasoconstrictive effects increasing afterload withno chronotropic or inotropic effects, therebyreducing cardiac output.63 Additionally, becauseof its V1 nitric oxide–mediated pulmonaryvasodilatory effects, vasopressin may be useful inpatients with right ventricular failure and pul-monary hypertension.64

Figure 1. Vasoactive agents in septic shock. AT1 = angiotensin 1; V1 = vasopressin 1. Depiction of the dynamic interplay ofthe vasoactive agents norepinephrine, epinephrine, phenylephrine, dopamine, vasopressin, and angiotensin II as well ascorticosteroids used in septic shock.

VASOACTIVE AGENTS IN SEPTIC SHOCK Sacha et al 373

Following initiation of vasopressin, patientsshould be monitored for a positive response totherapy. At the bedside, this can be determinedby trending MAP and concomitant vasoactivedoses. One study reported that 45% of patientsreceiving vasopressin for septic shock in combi-nation with NE had a positive hemodynamicresponse (defined as a MAP higher than 65 mmHg and a decrease in catecholamine doserequirements 6 hrs after vasopressin initia-tion).65 These patients had significant improve-ments in clinical outcomes including ICUmortality (50% vs 68%, p<0.01), ICU-free days(2.3 days vs 1.6 days), and catecholamine-freedays (6.3 days vs 3.9 days) in responders versusnonresponders, respectively.65 Hemodynamicresponse to vasopressin was associated with areduced odds of ICU mortality (odds ratio 0.51,95% CI 0.35–0.76, p=0.001). Additionally,markers of severity of illness (lactate, sequentialorgan failure assessment score, and baseline cat-echolamine dose) were associated with increasedICU mortality, and lactate was independentlyassociated with a reduced odds of hemodynamicresponse, indicating that higher severity of tissuemalperfusion may decrease the odds of bothICU survival and a positive response to vaso-pressin.65 In practice, after 6 hrs of vasopressinadministration, hemodynamics should be reeval-uated to determine if the patient has respondedto vasopressin therapy (i.e., MAP goal achievedand concomitant vasopressor doses decreasing).Alternative approaches should be considered ifthe patient has not responded to vasopressin.

Angiotensin II was recently approved by theU.S. Food and Drug Administration for the treat-ment of severe hypotension.66 Angiotensin II isan endogenous hormone in the renin-angioten-sin-aldosterone system, with potent vasocon-stricting properties. The administration ofexogenous angiotensin II results in a multitudeof physiologic effects, primarily vasoconstrictionvia the angiotensin-1 receptor and release ofaldosterone, endogenous NE, and vasopressin(Figure 1). To date, only one large randomizedcontrolled trial has evaluated the use of angio-tensin II in vasodilatory shock. The AngiotensinII 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 patientswith preserved cardiac function (cardiacindex higher than 2.3 L) requiring more than0.2 lg/kg/minute of NE.67 In this trial, morepatients randomized to angiotensin II had a pos-itive MAP response at 3 hrs (MAP 75 mm Hg or

higher increase of 10 mm Hg with no furtherincrease in background vasopressors) comparedwith placebo. In addition, patients in the angio-tensin II arm had a significant, albeit small,decrease in NE requirements at 3 hrs(�0.03 lg/kg/min with angiotensin II vs0.03 lg/kg/min with placebo; p<0.001). No sig-nificant differences in 7- or 28-day all-causemortality were detected.67Although the role ofangiotensin II in patients with septic shock isunclear, it should be noted that 70% of patientsin the study just mentioned were receiving NEand vasopressin at the time of randomization.Therefore, at this time, angiotensin II may bebest reserved for patients with preserved cardiacfunction whose MAP goal is not achieveddespite use of NE and vasopressin until furtherdata are available regarding its use as a second-line and/or adjunctive agent. Additionally, fur-ther safety data on angiotensin II is warranted.In one meta-analysis, the drug appeared to bewell tolerated with minimal adverse effects68 (al-beit this study did not include data from theATHOS-3 study). However, the U.S. productlabeling for angiotensin II warns of increasedthrombotic events (rates of 12.9% with angioten-sin II vs 5.1% with placebo in the ATHOS-3trial), thrombocytopenia, and infection risk,among others.66, 69 As with vasopressin use, ifand when angiotensin II is administered, hemo-dynamic response should be monitored, and if apositive hemodynamic response does not occurafter the initiation of angiotensin II, alternativetherapies should be considered.

Corticosteroids exert pleiotropic effects.Noticeably, corticosteroids have been reportedto improve blood pressure and perfusion inpatients with septic shock. Therefore, it may beprudent to consider corticosteroids as a shocktherapy. Although the mechanism of corticos-teroids in septic shock is multifaceted, thesupplementation of corticosteroids in this popu-lation is thought to result in hemodynamicimprovements.70 However, the use of corticos-teroids in septic shock remains controversial,and numerous studies reported contradictoryresults. Studies implied that starting corticos-teroids late after shock onset (1–3 days)71, 72

and in patients who are not severely ill72 doesnot improve overall patient outcomes. Thepotential benefit of corticosteroids appears to liewith early initiation (within the first 12 hrs ofshock onset) in patients with refractory septicshock.71, 73 Additionally, several meta-analysesand a Cochrane Review evaluated the use of

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corticosteroids in septic shock with contradic-tory results, albeit significant heterogeneityamong the included studies make generalizationsdifficult.74–77 The most recent meta-analysis ofall landmark trials showed that corticosteroiduse in sepsis may result in a small nonsignificantreduction in mortality (risk ratio [RR] 0.93, 95%CI 0.84–1.03) and significant improvements inshock reversal rates at day 7 (RR 1.26, 95% CI1.12–1.42).77 Overall, the question of whetheror not to use corticosteroids in patients withseptic shock remains unanswered. In clinicalpractice, corticosteroids are commonly used inpatients who are unresponsive to fluid adminis-tration and require increasing vasoactive doses, aguideline-supported practice, albeit with weakrecommendations due to low quality of evi-dence.6, 78 Regardless, the best supporting datawith corticosteroid use in patients with septicshock are for those with early refractory shock,and other uses remain controversial.

Vasoactive Agents in Refractory Septic Shock

As previously discussed, aggressive fluid resus-citation with crystalloids should be initiated assoon as possible in all patients with septic shock.In patients refractory to fluids, vasoactive agentsare warranted. Choosing and designing a vasoac-tive regimen for patients with septic shock is nota one-size-fits-all approach. Each agent should becarefully selected and titrated to the specific needsof the individual patient. Hemodynamic responseshould be targeted and monitored in all patients,and alternative agents should be trialed inpatients who are refractory to the current regimen(i.e., lactate and vasoactive doses increasing andno achievement of MAP goal) (Figure 2). Nore-pinephrine remains the first-line vasoactive agent,and patients who are refractory to NE should beevaluated for cardiac function. It may be prudentto start at a “medium” dose of NE (e.g., 10 lg/min) and titrate every 5 minutes in either direc-tion to achieve the desired MAP goal. If cardiacfunction is compromised, epinephrine or dobu-tamine are necessary for their inotropic effectsand should be monitored for response (i.e.,improvement in cardiac output or central ormixed venous oxygen saturation and lactate) fol-lowing initiation. If cardiac function is preserved,vasopressin should be administered. Patients whodo not promptly demonstrate an improvement inhemodynamics with vasopressin 0.03 units/min-ute within 1 hour should have intravenous hydro-cortisone 50 mg every 6 hours initiated, and

alternative vasoactive therapies should be furtherdiscussed. These include increasing vasopressindose to 0.04 units/minute or higher, addingangiotensin II, or continuing to titrate up NEdoses (taking care to monitor for adverse effectswith excessive catecholamine doses). In patientstruly refractory to these escalating approaches,requiring high catecholamine doses on multipleagents without the achievement of goal MAP,addition of epinephrine (if not already added andif heart rate allows) may be warranted in anattempt to restore organ perfusion. This algorith-mic approach should be tailored to patient pre-sentation, response, and updated goals of carefollowing discussion with the patient and family.

Vasoactive Agents in Common ClinicalScenarios

Tachyarrhythmias

Alternative agents should be considered forpatients who develop severe tachyarrhythmias,especially while receiving catecholamine-derivedvasoactive agents. A recent meta-analysis com-pared vasopressin plus NE to NE alone inpatients with vasodilatory shock (including bothseptic and postcardiac surgical patients) andfound that administration of vasopressin plusNE was associated with a lower risk of atrial fib-rillation development.79 Phenylephrine may alsobe considered for its lack of b-receptor activityand would be a suitable alternative to NE or epi-nephrine in patients who are already receivingvasopressin and develop tachyarrhythmias. In aproactive manner, catecholamines should be lim-ited in patients at high risk of developing tach-yarrhythmia based on presenting factors. Inpatients presenting with significant tachycardia(heart rate higher than 140 bpm) or with a base-line tachyarrhythmia, phenylephrine and vaso-pressin should be prioritized to not precipitate atachyarrhythmia. Similarly, limiting cate-cholamine-derived agents in patients with pro-nounced heart rate variability from baseline afterinitiation of catecholamines (i.e., significantincrease in heart rate after the initiation of NEbut no tachyarrhythmia development at present)would be advised.

Valvular Abnormalities

The presence of valvular abnormalities hassignificant implications in the treatment of septicshock. Abnormalities of interest are AS and

VASOACTIVE AGENTS IN SEPTIC SHOCK Sacha et al 375

Figure 2. Vasoactive treatment algorithm. AVP = arginine vasopressin; CO = cardiac output; MAP = mean arterial pressure;NE = norepinephrine. aConsider phenylephrine in patients with unacceptably high heart rate or malignant tachyarrhythmias. Itis considered the vasoactive agent of choice in patients with aortic stenosis or in those with left ventricular outflow trackobstruction due to systolic anterior motion of the mitral valve. bIf heart rate is acceptable and tachyarrhythmias are not present.

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patients who present with or develop a LVOTobstruction due to systolic anterior motion(SAM) of the mitral valve. In patients presentingwith AS and septic shock requiring vasoactiveagent support to maintain MAP, phenylephrineis considered the vasoactive agent of choice dueto its pure a agonism and lack of b-adrenergiceffects on the myocardium, thereby reducingoxygen demand.26 It is important to note thatthe hemodynamic and clinical effects of differentvasoactive agents for patients with septic shockcomplicated by AS have not been comparativelyevaluated, and the use of phenylephrine relieson its theorized benefit. Additionally, phenyle-phrine is preferred in patients with LVOT due toSAM.26 Patients with SAM commonly expressreduced cardiac output due to LVOT obstruc-tion. Vasoactive agents with b-adrenergic prop-erties will increase heart rate (decreasing fillingtime) and increase cardiac contractility thatworsens the LVOT obstruction. The a-mediatedeffects of phenylephrine were not shown toimpact heart rate or cardiac contractility signifi-cantly.15 Thus in patients with LVOT obstruc-tion from SAM, phenylephrine could beconsidered as the vasopressor of choice for sus-tained hypotension following fluid administra-tion.80 In both scenarios, patients with AS andLVOT obstruction from SAM, it may be reason-able to consider administering alternative nona-drenergic vasoactive agents, such as vasopressin,in an attempt to reduce heart rate.

Obesity

Unfortunately, no specific data guide clinicianson the superiority of specific vasoactive agents inobese patients. Additionally, there is little phar-macokinetic data detailing the effect of obesity oneach agent. One study showed that increasingbody weight significantly increases the clearanceof epinephrine in patients with septic shock,81 aneffect that was not seen in a pharmacokineticstudy of dobutamine.82 At this time, it is difficultto apply these data to clinical practice, and moredata are needed to determine the potential effectof obesity on the pharmacokinetics of the variousvasoactive agents. Regardless, common clinicaldebates still held in this regard include whethervasoactive doses should be based on body weightand whether obesity impacts the clinical effects ofvasopressors.

Critically ill obese patients were shown tohave differences in inflammatory markers, infec-tious etiologies, and clinical outcomes.83

Additionally, critically ill obese patients receiveless fluids (on ml/kg basis) and lower vasopres-sor doses (on lg/kg/min basis) than nonobesepatients.83 However, when evaluating weight-based dosing of NE versus non–weight-baseddosing in obese patients, no significant differ-ence between goal MAP achievement wasdetected between dosing strategies.84, 85 Despitethe fact that initial doses will differ in obesepatients, the ultimate result and clinical out-comes should be similar, regardless of the dos-ing strategy, because NE is titrated to goal MAP.With regard to vasopressin, a medication that isnot commonly titrated and is typically adminis-tered at a fixed dose, one study showed lowerserum vasopressin levels in obese patients 24and 72 hours after its initiation.87 However, sev-eral studies reported no impact with weight orobesity on the hemodynamic effects of vaso-pressin.86–88 At this time, evidence is insufficientto alter vasoactive therapies in obese patients,and dosing and utilization should be optimizedand titrated to hemodynamic effect andresponse.

Other Comorbidities and Medication Use

Globally, it is not known what true clinicaleffect, if any, other preexisting comorbidities(such as diabetes, immune suppression, chronickidney disease, oncologic and hematologic disor-ders, etc.), home medication use, and geneticfactors have on the pathophysiology of septicshock and the subsequent effect on and responseto vasoactive agent initiation. It is theorized thatchronic antihypertensive agent use may have aneffect on outcomes in patients with septic shock.Patients taking b-antagonists before admissionfor septic shock may demonstrate an upregula-tion in b receptors due to chronic therapy.89

Therefore, it would be reasonable to presumethat patients with home b-blocker therapy beforeadmission may require increased vasoactivedoses to achieve goal hemodynamics. Addition-ally, patients with an upregulation and augmen-tation of b1-receptors may be at greater risk oftachyarrhythmia development when b-blockertherapy is withdrawn, although the clinicalimplications are largely unknown. However,contradictory to this, one study found thatpatients with septic shock who were chronicallyreceiving b-blockers had lower mortality ratesthan those not on chronic b-blockers.90 Ulti-mately, further data are needed to determine the

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true implications of chronic b-blocker therapyon septic shock treatment and outcomes.

Chronic use of angiotensin-converting enzymeinhibitors (ACEIs) and angiotensin receptorblockers (ARBs) may also have noteworthyimplications in septic shock. One evaluation ofpatients with septic shock and use of chronic b-blockers and ACEIs before hospital admissionfound that the shortest time on vasopressorsoccurred in patients with home ACEIs comparedwith patients on home b-blockers, both agents,or neither agent (19 hrs vs 24 hrs vs 30 hrs vs30 hrs, respectively; p=0.031).91 However, nodifferences in clinical outcomes were detectedbetween groups, and patient numbers were smallin the cohorts evaluated.91 At this time, it is dif-ficult to apply these data to clinical practicewhen patients present with a history of chronicb-blocker and ACEI use. The question ofchronic antihypertensive use and effect on clini-cal outcomes in patients with septic shock war-rants further investigation and is currently beingstudied in a multicenter observational evaluation(ClinicalTrials.gov identifier NCT03190408).92

Chronic ACEI and ARB use may also have sig-nificant effects in patients with sepsis whoreceive angiotensin II. Due to potential upregu-lation of angiotensin I receptors in patientsreceiving chronic ACEIs, an exaggerated increasein MAP may occur when giving angiotensin II.69

However, downregulation of angiotensin I recep-tors in patients receiving ARBs may result in adiminished response to angiotensin II initiation,an effect shown in a small subgroup analysis ofthe ATHOS-3 trial.67 Unfortunately, there is aneed for further published data evaluating thesescenarios to determine the true clinical effects ofchronic ACEIs and ARBs in patients who receiveangiotensin II.

Whether to continue chronic antihypertensivetherapies during shock treatment is unknown,and it would seem contradictory to administerantihypertensive therapy in the setting of vaso-pressor agents. However, a 2013 study examinedwhether the administration of esmolol to nor-malize heart rate in the setting of septic shockwould improve outcomes.93 The investigatorsreported improvements in hemodynamic param-eters (heart rate, cardiac index, stroke volume,and MAP) in the cohort of patients treated withesmolol. This raises the question of whether b-blocker therapy is beneficial in septic shock andwhether b-blocker therapy should be continuedin patients with a history of receiving therapybefore admission.

Pharmacogenomics/Genetics

The promise of pharmacogenomic therapywas recently demonstrated for the treatment ofvarious cancers. Similarly, pharmacogenomictherapy holds unrealized potential for the treat-ment of septic shock at the present time. Thefuture of septic shock treatment may include abroad genomic profile of patients on admissionto determine optimal vasopressor treatments,corticosteroid response, and predilection toadverse effects. One example of the potentialuses of this field is with the detection of geneticvariations on the leucyl-cystinyl aminopeptidase(LNPEP) enzyme that is primarily responsiblefor the clearance of endogenous and exogenousvasopressin. One study found that patients witha homozygous (TT) genotype of the LNPEPrs4869317 single nucleotide polymorphism hadincreased vasopressin clearance (p=0.028) andincreased 28-day mortality compared with othergenotypes (51% vs 36.4%; adjusted hazard ratio1.58, 95% CI, 1.21–2.06, p=0.0007).94 Thesefindings have potential implications for allpatients with septic shock, regardless of whetherthey receive exogenous vasopressin. However, atthe current time, we are only at the gestationalphases of research and understanding in thisarea.

Conclusions

Septic shock is a life-threatening disorder withmortality rates ~40%. Therapeutic interventions,including vasoactive agents to maintain goalhemodynamics, are imperative to patient careand survival. Norepinephrine is the first-linevasoactive agent of choice, but alternative andadjunctive agents such as epinephrine, vaso-pressin, angiotensin II, and phenylephrine maybe warranted in specific scenarios and if patientsdo not have an appropriate hemodynamicresponse to the initiation of NE. Ultimately,more data are needed to elucidate how to bestindividualize care for patients with septic shock,and future research is needed to determine theeffects of comorbidities, chronic medication use,and genetics on the pathophysiology of septicshock and subsequent implications fortreatment.

References

1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Car-cillo J, Pinsky MR. Epidemiology of severe sepsis in the Uni-ted States: analysis of incidence, outcome, and associated costsof care. Crit Care Med 2001;29:1303–10.

378 PHARMACOTHERAPY Volume 39, Number 3, 2019

2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiologyof sepsis in the United States from 1979 through 2000. N EnglJ Med 2003;348:1546–54.

3. Singer M, Deutschman CS, Seymour CW, et al. The ThirdInternational Consensus Definitions for Sepsis and SepticShock (Sepsis-3). JAMA 2016;315:801–10.

4. Russell JA. Management of sepsis. N Engl J Med2006;355:1699–713.

5. Hollenberg SM. Vasoactive drugs in circulatory shock. Am JRespir Crit Care Med 2011;183:847–55.

6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving SepsisCampaign: International Guidelines for Management of Sepsisand Septic Shock: 2016. Intensive Care Med 2017;43:304–77.

7. Dellinger RP, Schorr CA, Levy MM. A users’ guide to the2016 Surviving Sepsis Guidelines. Intensive Care Med2017;43:299–303.

8. Dellinger RP, Carlet JM, Masur H, et al. Surviving SepsisCampaign guidelines for management of severe sepsis and sep-tic shock. Crit Care Med 2004;32:858–73.

9. MacCannell KL, McNay JL, Meyer MB, Goldberg LI. Dopa-mine in the treatment of hypotension and shock. N Engl JMed 1966;275:1389–98.

10. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine admin-istration in shock influence outcome? Results of the SepsisOccurrence in Acutely Ill Patients (SOAP) study. Crit CareMed 2006;34:589–97.

11. Gamper G, Havel C, Arrich J, et al. Vasopressors for hypoten-sive shock. Cochrane Database Syst Rev 2016;2:CD003709.

12. De Backer D, Biston P, Devriendt J, et al. Comparison ofdopamine and norepinephrine in the treatment of shock. NEngl J Med 2010;362:779–89.

13. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A.Vasopressors for the treatment of septic shock: systematicreview and meta-analysis. PLoS ONE 2015;10:e0129305.

14. De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine ver-sus norepinephrine in the treatment of septic shock: a meta-analysis. Crit Care Med 2012;40:725–30.

15. Landzberg JS, Parker JD, Gauthier DF, Colucci WS. Effects ofmyocardial alpha 1-adrenergic receptor stimulation and block-ade on contractility in humans. Circulation 1991;84:1608–14.

16. Barrett LK, Singer M, Clapp LH. Vasopressin: mechanisms ofaction on the vasculature in health and in septic shock. CritCare Med 2007;35:33–40.

17. Moran JL, O’Fathartaigh MS, Peisach AR, Chapman MJ, Lep-pard P. Epinephrine as an inotropic agent in septic shock: adose-profile analysis. Crit Care Med 1993;21:70–7.

18. McDonald RH Jr, Goldberg LI, McNay JL, Tuttle EP Jr. Effectof dopamine in man: augmentation of sodium excretion,glomerular filtration rate, and renal plasma flow. J Clin Invest1964;43:1116–24.

19. Bollaert PE, Bauer P, Audibert G, Lambert H, Larcan A.Effects of epinephrine on hemodynamics and oxygen metabo-lism in dopamine-resistant septic shock. Chest 1990;98:949–53.

20. Watt MJ, Howlett KF, Febbraio MA, Spriet LL, HargreavesM. Adrenaline increases skeletal muscle glycogenolysis, pyru-vate dehydrogenase activation and carbohydrate oxidation dur-ing moderate exercise in humans. J Physiol 2001;534:269–78.

21. Zhou SX, Qiu HB, Huang YZ, Yang Y, Zheng RQ. Effects ofnorepinephrine, epinephrine, and norepinephrine-dobutamineon systemic and gastric mucosal oxygenation in septic shock.Acta Pharmacol Sin 2002;23:654–8.

22. Myburgh JA, Higgins A, Jovanovska A, et al. A comparison ofepinephrine and norepinephrine in critically ill patients. Inten-sive Care Med 2008;34:2226–34.

23. Levy B, Perez P, Perny J, Thivilier C, Gerard A. Comparisonof norepinephrine-dobutamine to epinephrine for hemodynam-ics, lactate metabolism, and organ function variables in cardio-genic shock. A prospective, randomized pilot study. Crit CareMed 2011;39:450–5.

24. Levy B, Bollaert PE, Charpentier C, et al. Comparison ofnorepinephrine and dobutamine to epinephrine for hemody-namics, lactate metabolism, and gastric tonometric variables in

septic shock: a prospective, randomized study. Intensive CareMed 1997;23:282–7.

25. Annane D, Vignon P, Renault A, et al. Norepinephrine plusdobutamine versus epinephrine alone for management of sep-tic shock: a randomised trial. Lancet 2007;370:676–84.

26. Thiele RH, Nemergut EC, Lynch C 3rd. The clinical implica-tions of isolated alpha(1) adrenergic stimulation. Anesth Analg2011;113:297–304.

27. Jain G, Singh DK. Comparison of phenylephrine and nore-pinephrine in the management of dopamine-resistant septicshock. Indian J Crit Care Med 2010;14:29–34.

28. Morelli A, Ertmer C, Rehberg S, et al. Phenylephrine versusnorepinephrine for initial hemodynamic support of patientswith septic shock: a randomized, controlled trial. Crit Care2008;12:R143.

29. Dellinger RP, Levy MM, Rhodes A, et al. Surviving SepsisCampaign: International Guidelines for Management of SevereSepsis and Septic Shock, 2012. Intensive Care Med2013;39:165–228.

30. Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G,Wunsch H. Association between US norepinephrine shortageand mortality among patients with septic shock. JAMA2017;317:1433–42.

31. Van den Berghe G, de Zegher F, Lauwers P. Dopamine sup-presses pituitary function in infants and children. Crit CareMed 1994;22:1747–53.

32. Rudiger A, Singer M. Decatecholaminisation during sepsis.Crit Care 2016;20:309.

33. Andreis DT, Singer M. Catecholamines for inflammatoryshock: a Jekyll-and-Hyde conundrum. Intensive Care Med2016;42:1387–97.

34. Dunser MW, Ruokonen E, Pettila V, et al. Association of arte-rial blood pressure and vasopressor load with septic shockmortality: a post hoc analysis of a multicenter trial. Crit Care2009;13:R181.

35. Martin C, Medam S, Antonini F, et al. Norepinephrine: nottoo much, too long. Shock 2015;44:305–9.

36. Brown SM, Lanspa MJ, Jones JP, et al. Survival after shockrequiring high-dose vasopressor therapy. Chest 2013;143:664–71.

37. Patel GP, Grahe JS, Sperry M, et al. Efficacy and safety ofdopamine versus norepinephrine in the management of septicshock. Shock 2010;33:375–80.

38. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med2014;370:1583–93.

39. Lamontagne F, Meade MO, Hebert PC, et al. Higher versuslower blood pressure targets for vasopressor therapy in shock:a multicentre pilot randomized controlled trial. Intensive CareMed 2016;42:542–50.

40. Hass DJ, Kozuch P, Brandt LJ. Pharmacologically mediatedcolon ischemia. Am J Gastroenterol 2007;102:1765–80.

41. Ruokonen E, Takala J, Kari A, Saxen H, Mertsola J, HansenEJ. Regional blood flow and oxygen transport in septic shock.Crit Care Med 1993;21:1296–303.

42. Meier-Hellmann A, Specht M, Hannemann L, Hassel H, Bre-dle DL, Reinhart K. Splanchnic blood flow is greater in septicshock treated with norepinephrine than in severe sepsis. Inten-sive Care Med 1996;22:1354–9.

43. Marik PE, Mohedin M. The contrasting effects of dopamineand norepinephrine on systemic and splanchnic oxygen uti-lization in hyperdynamic sepsis. JAMA 1994;272:1354–7.

44. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of per-fusion pressure on tissue perfusion in septic shock. Crit CareMed 2000;28:2729–32.

45. Krejci V, Hiltebrand LB, Sigurdsson GH. Effects of epinephr-ine, norepinephrine, and phenylephrine on microcirculatoryblood flow in the gastrointestinal tract in sepsis. Crit CareMed 2006;34:1456–63.

46. De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopa-mine, norepinephrine, and epinephrine on the splanchnic cir-culation in septic shock: which is best? Crit Care Med2003;31:1659–67.

VASOACTIVE AGENTS IN SEPTIC SHOCK Sacha et al 379

47. Holmes CL, Walley KR, Chittock DR, Lehman T, Russell JA.The effects of vasopressin on hemodynamics and renal func-tion in severe septic shock: a case series. Intensive Care Med2001;27:1416–21.

48. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressorhypersensitivity in vasodilatory septic shock. Crit Care Med1997;25:1279–82.

49. Landry DW, Levin HR, Gallant EM, et al. Vasopressin defi-ciency contributes to the vasodilation of septic shock. Circula-tion 1997;95:1122–5.

50. Holmes CL, Patel BM, Russell JA, Walley KR. Physiology ofvasopressin relevant to management of septic shock. Chest2001;120:989–1002.

51. Holmes CL. Vasopressin in septic shock: does dose matter?Crit Care Med 2004;32:1423–4.

52. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficialeffects of short-term vasopressin infusion during severe septicshock. Anesthesiology 2002;96:576–82.

53. Russell JA, Walley KR, Singer J, et al. Vasopressin versusnorepinephrine infusion in patients with septic shock. N EnglJ Med 2008;358:877–87.

54. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect ofearly vasopressin vs norepinephrine on kidney failure inpatients with septic shock: the VANISH randomized clinicaltrial. JAMA 2016;316:509–18.

55. Gordon AC, Wang N, Walley KR, Ashby D, Russell JA. Thecardiopulmonary effects of vasopressin compared with nore-pinephrine in septic shock. Chest 2012;142:593–605.

56. Gordon AC, Russell JA, Walley KR, et al. The effects of vaso-pressin on acute kidney injury in septic shock. Intensive CareMed 2010;36:83–91.

57. Gordon AC, Mason AJ, Perkins GD, et al. The interaction ofvasopressin and corticosteroids in septic shock: a pilot ran-domized controlled trial. Crit Care Med 2014;42:1325–33.

58. Ertmer C, Bone HG, Morelli A, et al. Methylprednisolonereverses vasopressin hyporesponsiveness in ovine endotox-emia. Shock 2007;27:281–8.

59. Russell JA, Walley KR, Gordon AC, et al. Interaction of vaso-pressin infusion, corticosteroid treatment, and mortality ofseptic shock. Crit Care Med 2009;37:811–8.

60. Par Pharmaceutical. Vasostrict (vasopressin) package insert.Chestnut Ridge, NY; 2016.

61. Torgersen C, Dunser MW, Wenzel V, et al. Comparing twodifferent arginine vasopressin doses in advanced vasodilatoryshock: a randomized, controlled, open-label trial. IntensiveCare Med 2010;36:57–65.

62. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin inadvanced vasodilatory shock: a prospective, randomized, con-trolled study. Circulation 2003;107:2313–9.

63. Dunser MW, Mayr AJ, Ulmer H, et al. The effects of vaso-pressin on systemic hemodynamics in catecholamine-resistantseptic and postcardiotomy shock: a retrospective analysis.Anesth Analg 2001;93:7–13.

64. Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonaryvascular and right ventricular dysfunction in adult criticalcare: current and emerging options for management: a system-atic literature review. Crit Care 2010;14:R169.

65. Sacha GL, Lam SW, Duggal A, et al. Predictors of response tofixed-dose vasopressin in adult patients with septic shock. AnnIntensive Care 2018;8:35.

66. La Jolla Pharmaceutical Company. GIAPREZA (angiotensin II)package insert. San Diego, CA; 2018.

67. Khanna A, English SW, Wang XS, et al. Angiotensin II for thetreatment of vasodilatory shock. N Engl J Med 2017;377:419–30.

68. Busse LW, Wang XS, Chalikonda DM, et al. Clinical experi-ence with IV angiotensin II administration: a systematic reviewof safety. Crit Care Med 2017;45:1285–94.

69. Bauer SR, Sacha GL, Lam SW. Safe use of vasopressin andangiotensin II for patients with circulatory shock. Pharma-cotherapy 2018;38:851–61.

70. Annane D. Corticosteroids for severe sepsis: an evidence-basedguide for physicians. Ann Intensive Care 2011;1:7.

71. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisoneplus fludrocortisone for adults with septic shock. N Engl JMed 2018;378:809–18.

72. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapyfor patients with septic shock. N Engl J Med 2008;358:111–24.

73. Annane D, Sebille V, Charpentier C, et al. Effect of treatmentwith low doses of hydrocortisone and fludrocortisone on mor-tality in patients with septic shock. JAMA 2002;288:862–71.

74. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, KupferY. Corticosteroids for treating sepsis. Cochrane Database SystRev 2015;12:CD002243.

75. Volbeda M, Wetterslev J, Gluud C, Zijlstra JG, van der HorstIC, Keus F. Glucocorticosteroids for sepsis: systematic reviewwith meta-analysis and trial sequential analysis. Intensive CareMed 2015;41:1220–34.

76. Sligl WI, Milner DA Jr, Sundar S, Mphatswe W, MajumdarSR. Safety and efficacy of corticosteroids for the treatment ofseptic shock: a systematic review and meta-analysis. ClinInfect Dis 2009;49:93–101.

77. Rochwerg B, Oczkowski SJ, Siemieniuk RAC, et al. Corticos-teroids in sepsis: an updated systematic review and meta-ana-lysis. Crit Care Med 2018;46:1411–20.

78. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for thediagnosis and management of critical illness-related corticos-teroid insufficiency (CIRCI) in Critically Ill Patients (Part I):Society of Critical Care Medicine (SCCM) and European Soci-ety of Intensive Care Medicine (ESICM) 2017. Crit Care Med2017;45:2078–88.

79. McIntyre WF, Um KJ, Alhazzani W, et al. Association of vaso-pressin plus catecholamine vasopressors vs catecholamines alonewith atrial fibrillation in patients with distributive shock: a sys-tematic review and meta-analysis. JAMA 2018;319:1889–900.

80. Dugar S, Latifi M, Moghekar A, Duggal A. All shock statesare not the same. Systolic anterior motion of mitral valve caus-ing left ventricular outflow tract obstruction in septic shock.Ann Am Thorac Soc 2016;13:1851–5.

81. Abboud I, Lerolle N, Urien S, et al. Pharmacokinetics of epi-nephrine in patients with septic shock: modelization and inter-action with endogenous neurohormonal status. Crit Care2009;13:R120.

82. Klem C, Dasta JF, Reilley TE, Flancbaum LJ. Variability indobutamine pharmacokinetics in unstable critically ill surgicalpatients. Crit Care Med 1994;22:1926–32.

83. Wacharasint P, Boyd JH, Russell JA, Walley KR. One sizedoes not fit all in severe infection: obesity alters outcome, sus-ceptibility, treatment, and inflammatory response. Crit Care2013;17:R122.

84. Radosevich JJ, Patanwala AE, Erstad BL. Norepinephrine dos-ing in obese and nonobese patients with septic shock. Am JCrit Care 2016;25:27–32.

85. Vadiei N, Daley MJ, Murthy MS, Shuman CS. Impact of nore-pinephrine weight-based dosing compared with non-weight-based dosing in achieving time to goal mean arterial pressurein obese patients with septic shock. Ann Pharmacother2017;51:194–202.

86. Lam SW, Bauer SR, Cha SS, Oyen LJ. Lack of an effect ofbody mass on the hemodynamic response to arginine vaso-pressin during septic shock. Pharmacotherapy 2008;28:591–9.

87. Torbic H, Sacha GL, Bauer SR, Lam SW. Body mass’s impacton response to fixed-dose vasopressin in patients with septicshock. Shock 2018;50:388–94.

88. Hodge EK, Hughes DW, Attridge RL. Effect of body weighton hemodynamic response in patients receiving fixed-dosevasopressin for septic shock. Ann Pharmacother 2016;50:816–23.

89. Haeusler G. Pharmacology of beta-blockers: classical aspectsand recent developments. J Cardiovasc Pharmacol 1990;16(Suppl 5):S1–9.

90. Macchia A, Romero M, Comignani PD, et al. Previous pre-scription of beta-blockers is associated with reduced mortalityamong patients hospitalized in intensive care units for sepsis.Crit Care Med 2012;40:2768–72.

380 PHARMACOTHERAPY Volume 39, Number 3, 2019

91. DeMott JM, Patel G, Lat I. Effects of chronic antihypertensiveson vasopressor dosing in septic shock. Ann Pharmacother2018;52:40–7.

92. US National Institutes of Health. ClinicalTrials.gov. Availablefrom https://clinicaltrials.gov/ct2/show/NCT03190408. AccessedOctober 26, 2016.

93. Morelli A, Ertmer C, Westphal M, et al. Effect of heart ratecontrol with esmolol on hemodynamic and clinical outcomesin patients with septic shock: a randomized clinical trial.JAMA 2013;310:1683–91.

94. Nakada TA, Russell JA, Wellman H, et al. Leucyl/cystinylaminopeptidase gene variants in septic shock. Chest 2011;139:1042–9.

VASOACTIVE AGENTS IN SEPTIC SHOCK Sacha et al 381