Catecholamine-Sparing Strategies in Septic Shock

Source and Scope

• Primary source: Dubech A, Picod A, Pierre A, Preau S, Favory R, Garcia B. Current and Future Strategies Aiming at Reducing Catecholamine Exposure in Septic Shock. Critical Care. 2026;30:427.[1]
• The source is a narrative review, not a treatment guideline or a systematic review.
• The review integrates physiology, randomized trials, observational studies, post hoc analyses, preclinical work, and emerging biomarker-guided strategies. These evidence types should not be treated as equivalent.
• Current bedside recommendations in these notes are reconciled with the 2026 Surviving Sepsis Campaign (SSC) adult guideline.[2,3]
• Disclosure context: the corresponding author reported honoraria for presentations and meetings related to DPP3, angiotensin II, and vasopressin outside this work. Emerging interventions should be interpreted with the same evidentiary caution applied to all narrative reviews.

Core Clinical Takeaway

• Norepinephrine remains the first-line vasopressor for septic shock because it restores perfusion pressure rapidly and has a more favorable safety profile than dopamine or epinephrine.
• Catecholamine sparing does not mean withholding norepinephrine from a hypotensive, hypoperfused patient.
• The practical goal is to:
  • Start norepinephrine early when vasoplegia persists.
  • Avoid prolonged severe hypotension.
  • Use the lowest dose that achieves an individualized perfusion goal.
  • Stop unnecessary fluid loading.
  • Reassess cardiac function, venous congestion, fluid responsiveness, and tissue perfusion.
  • Add nonadrenergic or adjunctive treatment when supported by the clinical phenotype and evidence.
• Higher norepinephrine doses are strongly associated with higher mortality, but this relationship is confounded by shock severity. It does not prove that norepinephrine itself is the cause of death.
• Many proposed catecholamine-sparing interventions shorten vasopressor exposure without demonstrating a survival benefit. A reduction in dose or duration is not automatically a patient-centered benefit.

Why Norepinephrine Remains Central

Arterial Tone and Perfusion Pressure

• Septic shock is characterized by profound vasodilation and loss of arterial vascular tone.
• Norepinephrine activates alpha-1 adrenergic receptors and produces dose-dependent increases in systemic vascular resistance and mean arterial pressure (MAP).
• Systemic vascular resistance is a derived global variable. It does not fully describe regional or microcirculatory flow.
• The major pressure drop in the circulation occurs across small arteries and arterioles, not uniformly across the entire vascular system.

The Vascular Waterfall Concept

• Critical closing pressure (Pcrit) is the arterial pressure below which a vessel collapses and flow stops, even if a nominal pressure gradient remains.
• Tissue perfusion pressure can be conceptualized as the gradient between arterial pressure and Pcrit.
• Microcirculatory flow also depends on the vascular waterfall gradient between Pcrit and mean systemic filling pressure (Pmsf).
• In septic vasoplegia:
  • Pcrit may fall toward Pmsf.
  • The vascular waterfall gradient narrows or disappears.
  • Cardiac output may remain normal or high while tissue perfusion remains inadequate.
• Norepinephrine can restore effective flow when it raises Pcrit above Pmsf and raises arterial pressure above the new Pcrit.
• Venous congestion raises Pmsf and can compress the Pcrit-to-Pmsf gradient. A normal MAP therefore does not guarantee adequate tissue perfusion.
• Bedside implication: reassess venous congestion, cardiac function, capillary refill, skin perfusion, urine output, mental status, and lactate kinetics rather than treating MAP as the only target.

Venous Return and Preload

• Alpha-mediated venoconstriction increases stressed venous volume and Pmsf.
• In preload-responsive patients, this may increase venous return and cardiac output.
• In a physiologic study of 25 preload-responsive patients with septic shock and diastolic arterial pressure of 40 mm Hg or lower, increasing norepinephrine raised preload indices and reduced the cardiac index response to a repeat passive leg raise from 19% to 13%.[1]
• Norepinephrine may therefore recruit preload reserve, but this does not replace direct assessment of fluid responsiveness.

Inotropic Effect

• Norepinephrine also stimulates beta-1 receptors.
• In 38 patients with early septic shock and MAP below 65 mm Hg, norepinephrine increased MAP from 56 to 80 mm Hg while left ventricular ejection fraction and Doppler systolic velocities increased.[1]
• This supports a clinically relevant inotropic effect during early shock despite the simultaneous increase in afterload.
• A fall in ejection fraction after restoring vascular tone may unmask previously hidden septic myocardial dysfunction rather than prove that norepinephrine newly injured the heart.

Macro-Microcirculatory Uncoupling

• Septic shock reduces functional capillary density and increases heterogeneity of microvascular flow.
• These abnormalities may persist after MAP and cardiac output normalize.
• Raising MAP from a critically low level can recruit pressure-dependent microvascular beds.
• Beyond that range, the microcirculatory response is heterogeneous because norepinephrine simultaneously restores perfusion pressure and constricts alpha-1 receptor-bearing arterioles.
• This loss of coherence between the macrocirculation and microcirculation explains why a higher MAP does not reliably improve lactate, mottling, or organ function.

Comparative Vasopressor Evidence

Dopamine

• SOAP II found no significant difference in 28-day mortality between dopamine and norepinephrine in patients with shock.
• Arrhythmias were substantially more frequent with dopamine: 24.1% versus 12.4%.
• This safety difference is a major reason dopamine no longer has a routine role in septic shock.

Epinephrine

• Epinephrine can achieve MAP targets but causes more tachyarrhythmia and beta-2 mediated lactate production.
• CAT and CATS did not demonstrate superior clinical outcomes with epinephrine-based treatment.
• An epinephrine-associated lactate increase may be pharmacologic rather than a direct marker of worsening tissue hypoxia, but it complicates interpretation of resuscitation.
• SSC 2026 suggests adding epinephrine when MAP remains inadequate despite norepinephrine and vasopressin, or when vasopressin is unavailable.[2,3]

Norepinephrine Shortage as a Natural Experiment

• During the 2011 United States norepinephrine shortage, substitution with other agents, mainly phenylephrine, was associated with a 3.7% absolute increase in hospital mortality.
• This was an observational natural experiment, not a randomized comparison, but it reinforces the clinical importance of ready access to norepinephrine.

Start Earlier to Use Less

CENSER

• CENSER randomized patients with sepsis and MAP below 65 mm Hg to early low-dose norepinephrine plus fluids or usual care with vasopressors after at least 30 mL/kg of crystalloid.[4]
• Shock control at 6 hours occurred in 76% of the early norepinephrine group and 48% of the usual-care group.
• Cardiogenic pulmonary edema occurred in 14.4% versus 27.7%.
• New-onset arrhythmia occurred in 11% versus 20%.
• Twenty-eight-day mortality did not differ significantly: 15.5% versus 21.9%.
• Interpretation: early norepinephrine improved early shock control and reduced complications, but CENSER did not establish a mortality benefit.

CLOVERS

• CLOVERS randomized 1,563 patients with sepsis-induced hypotension after at least 1 L of crystalloid to a restrictive fluid, vasopressor-prioritized strategy or a liberal fluid strategy.[5]
• Ninety-day mortality was 14.0% versus 14.9%, with no significant difference.
• The restrictive group received a median 2,134 mL less intravenous fluid during the protocol period.
• CLOVERS did not directly randomize immediate versus delayed norepinephrine. It supports the safety of a vasopressor-prioritized, fluid-restrictive strategy after initial fluid administration.
• A post hoc subgroup with advanced chronic kidney disease had lower 90-day death before discharge home with the restrictive strategy, but this exploratory result is not definitive and should not be generalized to all patients with kidney disease.

Bedside Markers of Vasoplegia

• A low diastolic arterial pressure may indicate loss of arterial tone.
• The diastolic shock index is heart rate divided by diastolic arterial pressure.
• A high diastolic shock index in a tachycardic patient may identify a vasoplegic phenotype likely to need early vasopressor support.
• These markers supplement, rather than replace, assessment of infection, preload, cardiac function, obstruction, and tissue perfusion.

Peripheral Norepinephrine

• SSC 2026 suggests starting vasopressors through a peripheral intravenous catheter rather than delaying therapy until central access is secured. Certainty of evidence is very low.[2,3]
• A protocolized prospective cohort of 635 patients used peripheral norepinephrine for a median of 5.8 hours and avoided central venous catheter placement for vasopressor delivery in 51.6% of patients.[1]
• The cohort used a strict protocol and a maximum norepinephrine dose of 15 micrograms/min. Extravasation occurred, but no patient developed tissue necrosis or required surgery.
• In a CLOVERS secondary analysis, peripheral vasopressors were common, with 3 peripheral infusion complications among 490 patients and no tissue necrosis. Central catheter complications occurred in 12 of 322 patients.[6]
• The 15 micrograms/min ceiling from one protocol should not be treated as a universal safety threshold.
• The SSC states that evidence is insufficient to define an optimal catheter size, anatomic site, dose limit, or duration.
• Safe use requires an institutional protocol that addresses:
  • A well-functioning peripheral line.
  • Frequent site assessment.
  • A dedicated infusion line when possible.
  • Prompt recognition of pain, swelling, blanching, leakage, or loss of blood return.
  • Immediate extravasation management.
  • Transition to central access when dose, duration, access quality, or the overall resuscitation plan makes it appropriate.

The Burden of Sustained Adrenergic Exposure

Cardiac Effects

• Early norepinephrine can improve preload, contractility, and perfusion pressure.
• Prolonged or high-dose adrenergic stimulation increases myocardial oxygen demand and wall stress.
• Catecholamine-associated myocardial injury is biologically plausible, with histologic, animal, biomarker, and Takotsubo-like evidence.
• Direct human evidence that norepinephrine independently causes clinically important myocardial injury remains limited.
• Sepsis-induced cardiomyopathy, altered loading conditions, ischemia, inflammation, and treatment exposure often coexist.

Arrhythmias

• Beta-1 stimulation contributes to atrial and ventricular arrhythmias.
• New-onset atrial fibrillation becomes more common as sepsis severity increases and is associated with longer ICU stay and higher mortality.
• A meta-analysis of vasopressin plus catecholamines versus catecholamines alone found a lower atrial fibrillation risk with vasopressin (relative risk 0.77) but no clear survival benefit.
• SEPSISPAM found more atrial fibrillation with a MAP target of 80 to 85 mm Hg than with 65 to 70 mm Hg: 6.7% versus 2.8%.

Metabolic Effects

• Catecholamines increase glycogenolysis, gluconeogenesis, lipolysis, insulin resistance, and substrate turnover.
• Beta-adrenergic stimulation can increase aerobic glycolysis and lactate production without tissue hypoxia, particularly with epinephrine.
• Severe acidosis can reduce myocardial contractility and vasopressor responsiveness.
• Observational data associate vasopressor exposure with ICU-acquired weakness, but residual confounding by severity, immobility, inflammation, corticosteroids, and mechanical ventilation is likely.

Immune Effects

• Catecholamines can suppress tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 while increasing interleukin-10 through beta-2 signaling.
• Experimental studies also suggest impaired neutrophil and macrophage phagocytosis, reduced oxidative burst, altered lymphocyte function, and enhanced bacterial growth or virulence.
• Most mechanistic immune evidence is in vitro or preclinical.
• Higher catecholamine exposure is associated with immunoparalysis, secondary infection, and mortality, but clinical causality remains unproven.

Strategy 1: Do Not Chase an Unnecessarily High MAP

Standard Initial Target

• SSC 2026 recommends an initial MAP target of 65 mm Hg rather than a higher target. This is a strong recommendation with moderate-certainty evidence.[2,3]
• For adults 65 years or older, SSC 2026 suggests an initial MAP range of 60 to 65 mm Hg rather than a higher range. This is a conditional recommendation with low-certainty evidence.
• The target should be treated as a range, not an exact single number.
• MAP should be individualized after considering tissue perfusion, chronic hypertension, neurologic disease, renal perfusion, arterial measurement reliability, and adverse effects of vasopressor escalation.

Evidence Against Routine High Targets

• SEPSISPAM found no mortality benefit from targeting 80 to 85 mm Hg instead of 65 to 70 mm Hg.
• A chronic-hypertension subgroup required less renal replacement therapy at the higher target, but this did not establish a universal survival benefit.
• OPTPRESS randomized 518 patients 65 years or older with septic shock in Japan to MAP 80 to 85 mm Hg or 65 to 70 mm Hg.[7]
• The trial stopped early for a signal of harm.
• Ninety-day mortality was 39.3% with the high target and 28.6% with the standard target, an absolute risk difference of 10.7%.
• The standard-target group also had more catecholamine-free days.
• The mechanism of harm remains uncertain because arrhythmias were not significantly increased.

Lower Targets

• Lower MAP targets may reduce vasopressor exposure in selected patients without active signs of tissue hypoperfusion.
• This does not mean that persistent MAP below 60 mm Hg is routinely safe.
• The risk from hypotension depends on depth, duration, baseline pressure, autoregulation, and organ-specific vulnerability.
• If a higher MAP is considered for chronic hypertension, a time-limited MAP test with simultaneous reassessment of capillary refill, urine output, cognition, lactate, cardiac function, and adverse effects is more defensible than automatically maintaining a high target.

Strategy 2: Resuscitate Perfusion, Not the Monitor Alone

ANDROMEDA-SHOCK

• ANDROMEDA-SHOCK randomized 424 patients to capillary refill time (CRT)-guided or lactate-targeted resuscitation after initial MAP stabilization.[8]
• Twenty-eight-day mortality was 34.9% versus 43.4%, but the difference did not reach conventional statistical significance.
• CRT-guided treatment used 408 mL less fluid during the first 8 hours and produced a 1-point lower Sequential Organ Failure Assessment score at 72 hours.
• A Bayesian reanalysis suggested a high probability of benefit, but it remained exploratory.

ANDROMEDA-SHOCK-2

• ANDROMEDA-SHOCK-2 randomized 1,501 patients with early septic shock, with 1,467 included in the primary analysis across 86 ICUs in 19 countries.[9]
• The intervention used CRT as the perfusion target and integrated pulse pressure, diastolic arterial pressure, fluid responsiveness, and bedside echocardiography to guide fluids, vasopressors, and inotropes.
• The hierarchical composite of mortality, duration of vital support, and hospital stay favored personalized resuscitation (win ratio 1.16; 95% confidence interval 1.02 to 1.33).
• The benefit was driven mainly by shorter duration of vital support, not mortality.
• Ninety-day mortality did not differ significantly: 32.1% versus 33.2%.
• Vasopressor support was approximately 0.95 day shorter with the personalized strategy.
• Interpretation: CRT-centered personalized resuscitation can reduce treatment intensity and organ-support duration, but it has not demonstrated a survival advantage.

Practical Perfusion Reassessment

• After achieving a minimum perfusion pressure, reassess:
  • CRT and mottling.
  • Mental status.
  • Urine output and renal trajectory.
  • Lactate trend and plausible nonhypoxic causes of hyperlactatemia.
  • Pulse pressure and diastolic arterial pressure.
  • Fluid responsiveness before additional boluses.
  • Left and right ventricular function.
  • Venous congestion.
• SSC 2026 suggests using CRT as an adjunct to other perfusion measures, not as a stand-alone target.

Strategy 3: Add Vasopressin to an Escalating Norepinephrine Requirement

Rationale and Evidence

• Relative vasopressin deficiency occurs in a subset of patients with septic shock.
• Vasopressin restores vascular tone through a nonadrenergic pathway and can reduce norepinephrine exposure.
• VASST did not improve its primary mortality outcome overall.[10]
• A prespecified subgroup receiving less than 15 micrograms/min of norepinephrine at randomization had a possible survival benefit, but subgroup results do not prove that earlier vasopressin improves survival.
• VANISH and VANCS II did not establish a mortality benefit. VANISH suggested less renal replacement therapy.
• Vasopressin-containing strategies reduce atrial fibrillation compared with catecholamines alone, but a mortality benefit remains uncertain.

2026 SSC Position

• SSC 2026 conditionally suggests adding vasopressin when norepinephrine doses are escalating, with moderate-certainty evidence.[2,3]
• The review describes a common approach of fixed-dose vasopressin at 0.03 units/min when norepinephrine approaches 0.25 micrograms/kg/min.[1]
• The publicly listed SSC recommendation does not establish 0.25 micrograms/kg/min as a mandatory threshold. Timing should follow the trajectory of shock, local protocols, and the patient's hemodynamic phenotype.
• Vasopressin is usually administered at a fixed low dose rather than titrated as the primary vasopressor.

Phenotype and Cautions

• Vasopressin may be particularly attractive in marked vasoplegia, preserved cardiac output, escalating norepinephrine exposure, or tachyarrhythmia.
• The hypothesis that patients with left ventricular systolic dysfunction may respond less favorably comes from physiologic reasoning and post hoc data. Left ventricular dysfunction is not an established absolute contraindication.
• Monitor for excessive vasoconstriction, digital or mesenteric ischemia, reduced cardiac output, and hyponatremia.
• A reinforcement-learning analysis associated closer agreement with model-recommended vasopressin timing with lower mortality. This was observational model-concordance evidence and requires prospective validation before clinical use.

Strategy 4: Angiotensin II and the Renin-Angiotensin System

Rationale

• Some patients with vasodilatory shock have low angiotensinogen, high renin, reduced angiotensin-converting enzyme activity, increased angiotensin II degradation, or impaired angiotensin II receptor signaling.
• This creates a plausible phenotype of functional angiotensin II deficiency.

ATHOS-3

• ATHOS-3 showed that angiotensin II increased MAP at 3 hours and reduced norepinephrine-equivalent dose in catecholamine-resistant vasodilatory shock.[11]
• Post hoc analyses suggested possible benefit in patients with acute kidney injury requiring renal replacement therapy and in patients with high baseline renin.
• These analyses are hypothesis-generating and have not prospectively validated renin-guided or kidney phenotype-guided treatment.

2026 SSC Position

• SSC 2026 suggests norepinephrine rather than angiotensin II as the first-line vasopressor.
• Angiotensin II is not part of the standard SSC escalation sequence, which moves from norepinephrine to vasopressin and then epinephrine when MAP remains inadequate.
• Angiotensin II may be considered as a rescue option in selected catecholamine-resistant vasodilatory shock according to availability, regulatory status, thrombosis risk, local expertise, and patient phenotype.

DPP3: Biomarker and Experimental Target

• Circulating dipeptidyl peptidase 3 (cDPP3) is released during cellular injury and degrades angiotensin peptides.
• In a multinational cohort of 585 patients with severe sepsis or septic shock, higher cDPP3 was associated with acute kidney injury, renal replacement therapy, and higher 28-day and 90-day mortality.
• Association does not establish that cDPP3 is the cause of organ failure.
• Procizumab, also called invobenitug, is a humanized monoclonal antibody that inhibits cDPP3.
• In a porcine septic shock model, cDPP3 inhibition reduced catecholamine requirements and improved fluid balance.
• A small human pilot study of STC3141 in 26 critically ill patients with sepsis provided early safety, tolerability, and pharmacokinetic information for histone neutralization, not efficacy evidence for cDPP3 inhibition. Human efficacy data for cDPP3 inhibition remain pending.
• SSC 2026 does not address cDPP3 inhibition.

Strategy 5: Corticosteroids

• Corticosteroids improve vascular responsiveness and generally accelerate shock reversal.
• APROCCHSS randomized 1,241 patients with septic shock to hydrocortisone plus fludrocortisone or placebo.[12]
• Ninety-day mortality was 43.0% versus 49.1% (relative risk 0.88).
• Vasopressor-free days through day 28 were 17 versus 15.
• Other major trials, including ADRENAL, did not demonstrate the same mortality effect with hydrocortisone alone but did show faster resolution of shock.
• The survival effect therefore should not be generalized across all steroid regimens and shock severities.
• SSC 2026 conditionally suggests intravenous corticosteroids for septic shock, with low-certainty evidence.
• Steroids should be viewed as an evidence-supported adjunct for ongoing vasopressor-dependent shock, not as a replacement for antibiotics, source control, fluids when indicated, or vasopressors.

Strategy 6: Short-Acting Beta-1 Blockade

Why It Was Studied

• Persistent adrenergic tachycardia increases myocardial oxygen demand and may impair diastolic filling and ventricular-arterial efficiency.
• Esmolol and landiolol can reduce heart rate quickly and can be stopped rapidly if hemodynamics deteriorate.

Conflicting Trial Results

• A single-center trial of 154 patients found lower norepinephrine requirements and lower 28-day mortality with esmolol, but the control mortality of 80.5% and unusually large fluid volumes limit generalizability.
• STRESS-L enrolled patients with established septic shock, tachycardia, and norepinephrine of at least 0.1 micrograms/kg/min for more than 24 hours.
• The trial stopped early for a possible harm signal. Landiolol did not improve the mean 14-day Sequential Organ Failure Assessment score, and 28-day mortality was numerically higher.
• LANDI-SEP improved a hemodynamic composite of heart-rate control without increased vasopressor support, but it did not reduce 28-day mortality.
• A post hoc analysis suggested different responses in sinus tachycardia and atrial fibrillation. This finding is exploratory and should not be used as proof that landiolol benefits atrial fibrillation or harms every patient with sinus tachycardia.
• Meta-analyses remain inconsistent and have low to moderate certainty.

Clinical Position

• SSC 2026 suggests against using beta-blockers as treatment for septic shock. This is a conditional recommendation with very-low-certainty evidence.[2,3]
• Routine beta-blockade for septic sinus tachycardia is not recommended.
• Before considering heart-rate reduction, correct pain, agitation, fever, hypovolemia, hypoxemia, anemia, withdrawal, and excessive beta-agonist exposure, and confirm adequate cardiac output and perfusion.
• Use outside a trial or specialized protocol requires extreme caution and real-time hemodynamic monitoring.

Strategy 7: Methylene Blue

• Excess nitric oxide activates soluble guanylate cyclase and cyclic guanosine monophosphate, contributing to vasoplegia.
• Earlier nonselective nitric oxide synthase inhibition with L-NMMA increased mortality, demonstrating that broad suppression of nitric oxide can be harmful.
• A single-center randomized trial of 91 patients tested methylene blue 100 mg in 500 mL saline over 6 hours daily for 3 days.[13]
• Time to vasopressor discontinuation was 69 hours versus 94 hours.
• Cumulative fluid balance and ICU length of stay were lower.
• Mortality was 33% versus 46%, but the difference was not significant.
• The trial was small and single center, and green urine could have compromised blinding.
• SSC 2026 concludes that evidence is insufficient to recommend intravenous methylene blue for refractory septic shock.
• Clinically important risks include serotonin toxicity with serotonergic drugs, hemolysis in glucose-6-phosphate dehydrogenase deficiency, pulse oximetry interference, and dose-related vascular effects. Safety cannot be inferred from the absence of major events in one small trial.

Emerging Immunomodulation and Blood Purification

Extracellular Histone Neutralization

• Extracellular histones released during cellular injury or NETosis can promote inflammation, endothelial injury, coagulation, and organ dysfunction.
• The histone-neutralizing compound mCBS reduced vasopressor requirement, lactate, interleukin-6, and kidney injury in a sheep model.
• STC3141 was evaluated in a 26-patient human pilot study for safety, tolerability, and pharmacokinetics.
• These findings establish feasibility, not clinical efficacy.
• SSC 2026 does not address extracellular histone neutralization.

Polymyxin B Hemoperfusion

• Unselected randomized trials of polymyxin B hemoperfusion did not improve survival or organ failure.
• A post hoc EUPHRATES analysis restricted to endotoxin activity assay values of 0.60 to 0.89 suggested lower mortality. Because it was post hoc, the result is vulnerable to subgroup-selection bias.
• TIGRIS prospectively enrolled 157 patients with septic shock and endotoxin activity assay values of 0.60 to 0.89.[14]
• Twenty-eight-day mortality was 39% with polymyxin B hemoperfusion and 45% with control.
• The Bayesian posterior probability of benefit was 95.3%, but the 95% credible interval for the adjusted odds ratio crossed 1.
• MAP, vasopressor dose, and vasopressor duration did not differ significantly.
• TIGRIS therefore generated an efficacy signal in a biomarker-selected population but did not demonstrate catecholamine sparing.
• SSC 2026 suggests against blood purification techniques and specifically suggests against polymyxin B hemoperfusion.

2026 SSC: Practical Summary

• Initial MAP:
  • Target approximately 65 mm Hg rather than a higher MAP.
  • For adults 65 years or older, consider an initial range of 60 to 65 mm Hg.
• Perfusion:
  • Use serial lactate in context.
  • Use CRT as an adjunct to other perfusion measures.
  • Use dynamic measures to guide additional fluid.
• Vasopressor access:
  • Start peripherally rather than delaying for central access when immediate support is needed.
• Vasopressor sequence:
  • Norepinephrine first.
  • Add vasopressin when norepinephrine is escalating.
  • Add epinephrine if MAP remains inadequate despite norepinephrine and vasopressin.
• Adjuncts:
  • Intravenous corticosteroids are conditionally suggested.
  • Beta-blockers are conditionally discouraged as treatment for septic shock.
  • Evidence is insufficient for intravenous methylene blue.
  • Blood purification and polymyxin B hemoperfusion are discouraged.
  • Angiotensin II is not preferred as first-line treatment and is not in the standard escalation sequence.
  • cDPP3 inhibition and extracellular histone neutralization remain investigational.

Bedside Catecholamine-Sparing Checklist

First Hour

• Recognize septic shock and begin infection treatment, source-control planning, and hemodynamic resuscitation immediately.
• Evaluate whether hypotension reflects vasoplegia, hypovolemia, myocardial dysfunction, obstruction, or a mixed state.
• Start norepinephrine promptly for persistent hypotension or severe vasoplegia, including through a monitored peripheral line when appropriate.
• Use fluid responsiveness rather than a fixed-volume reflex to guide additional boluses after initial resuscitation.
• Set an initial MAP target near 65 mm Hg, or 60 to 65 mm Hg in many adults 65 years or older, unless a clear patient-specific reason supports another target.

During Escalation

• Confirm that the blood pressure measurement is reliable.
• Reassess CRT, skin temperature, mottling, urine output, mental status, lactate trajectory, and acid-base status.
• Perform bedside echocardiography to assess left ventricular, right ventricular, valvular, and pericardial causes of persistent shock.
• Check for venous congestion and fluid intolerance.
• Add vasopressin when norepinephrine is escalating rather than waiting for extreme catecholamine doses.
• Consider corticosteroids for ongoing vasopressor-dependent septic shock.
• Treat persistent hypoperfusion with cardiac dysfunction using an individualized inotropic strategy rather than simply raising MAP.

Before Calling Shock Refractory

• Reassess source control and adequacy of antimicrobial therapy.
• Exclude occult bleeding, abdominal compartment syndrome, tamponade, tension pneumothorax, massive pulmonary embolism, adrenal crisis, and medication error.
• Confirm adequate but not excessive preload.
• Review arterial and central access, infusion concentration, pump function, and dose calculations.
• Reconsider whether the target MAP is unnecessarily high.
• Reserve angiotensin II, methylene blue, or other rescue therapies for selected cases with clear rationale, awareness of uncertain outcome evidence, and appropriate expertise.

Final Take-Home Points

• Norepinephrine is not the enemy. Untreated hypotension and hypoperfusion are immediately dangerous.
• The correct objective is the lowest effective catecholamine exposure that maintains individualized tissue perfusion.
• Early norepinephrine and monitored peripheral initiation can reduce hypotension and fluid loading without waiting for central access.
• A MAP of approximately 65 mm Hg is the usual starting point. Routine pursuit of 80 to 85 mm Hg adds catecholamine exposure and may harm older patients.
• CRT-centered, phenotype-based resuscitation reduces fluid and vasopressor exposure and shortens organ support, but has not shown a mortality benefit.
• Vasopressin is the best-established nonadrenergic catecholamine-sparing adjunct, although its survival benefit is uncertain and no single norepinephrine threshold fits every patient.
• Corticosteroids accelerate shock reversal. Survival effects vary by regimen and trial.
• Angiotensin II may be useful in selected catecholamine-resistant vasodilatory shock, but high-renin and renal-replacement subgroups remain post hoc hypotheses.
• Beta-blockers should not be used routinely for septic shock. Sinus tachycardia may be compensatory.
• Methylene blue shortens vasopressor duration in one small trial, but survival and safety remain uncertain.
• cDPP3 inhibition, histone neutralization, reinforcement-learning-guided vasopressin, and endotoxin-selected hemoperfusion are research strategies, not routine standards.
• Every apparent catecholamine-sparing intervention should be judged by patient-centered outcomes, not by a lower norepinephrine dose alone.

Selected References

1. Dubech A, Picod A, Pierre A, et al. Current and Future Strategies Aiming at Reducing Catecholamine Exposure in Septic Shock. Crit Care. 2026;30:427. https://doi.org/10.1186/s13054-026-06109-3
2. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Crit Care Med. 2026. https://doi.org/10.1097/CCM.0000000000007075
3. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Intensive Care Med. 2026;52:863-936. https://doi.org/10.1007/s00134-026-08361-1
4. Permpikul C, Tongyoo S, Viarasilpa T, et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). Am J Respir Crit Care Med. 2019;199:1097-1105. https://doi.org/10.1164/rccm.201806-1034OC
5. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023;388:499-510. https://doi.org/10.1056/NEJMoa2212663
6. Fernando SM, et al. Peripheral Vasopressor Use in Early Sepsis-Induced Hypotension. JAMA Netw Open. 2025;8:e2529148. https://doi.org/10.1001/jamanetworkopen.2025.29148
7. Endo A, Yamakawa K, Tagami T, et al. Efficacy of Targeting High Mean Arterial Pressure for Older Patients With Septic Shock (OPTPRESS). Intensive Care Med. 2025;51:883-892. https://doi.org/10.1007/s00134-025-07910-4
8. Hernandez G, Ospina-Tascon GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock. JAMA. 2019;321:654-664. https://doi.org/10.1001/jama.2019.0071
9. Hernandez G, et al. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock. JAMA. 2025. https://doi.org/10.1001/jama.2025.20402
10. Russell JA, Walley KR, Singer J, et al. Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock. N Engl J Med. 2008;358:877-887. https://doi.org/10.1056/NEJMoa067373
11. Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377:419-430. https://doi.org/10.1056/NEJMoa1704154
12. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone Plus Fludrocortisone for Adults With Septic Shock. N Engl J Med. 2018;378:809-818. https://doi.org/10.1056/NEJMoa1705716
13. Ibarra-Estrada M, Kattan E, Aguilera-Gonzalez P, et al. Early Adjunctive Methylene Blue in Patients With Septic Shock. Crit Care. 2023;27:110. https://doi.org/10.1186/s13054-023-04397-7
14. Neyra JA, Legrand M, Tidswell MA, et al. Polymyxin B Haemoadsorption in Endotoxic Septic Shock (TIGRIS). Lancet Respir Med. 2026. https://doi.org/10.1016/S2213-2600(26)00047-0

Apply patient-specific hemodynamic assessment before clinical use.