The Pathophysiology and Management of Refractory Septic Shock: When Standard Protocols Fail

A Review for Postgraduate Medical Education

Dr Neeraj Manikath , claude.ai

Abstract

Refractory septic shock represents a critical juncture where evidence-based guidelines meet their limits and clinicians must navigate the treacherous waters of salvage therapies. This condition, affecting 10-20% of septic shock patients, carries mortality rates of 60-90% and challenges our understanding of cardiovascular physiology, endocrine function, and cellular metabolism. This comprehensive review explores the pathophysiological mechanisms underlying therapeutic resistance, evaluates emerging salvage interventions, and provides practical guidance for managing these critically ill patients when protocolized bundles fail.

Introduction

Refractory septic shock represents one of the most formidable challenges in critical care medicine. Despite adherence to the Surviving Sepsis Campaign guidelines and implementation of early goal-directed therapy, approximately 10-20% of patients with septic shock fail to respond to conventional interventions. These patients, despite aggressive fluid resuscitation and high-dose vasopressor support, continue to exhibit persistent hypotension and progressive multi-organ dysfunction. Mortality rates range from 60% to as high as 80-90% in those requiring norepinephrine doses exceeding 1 μg/kg/min, making this condition one of the most lethal scenarios encountered in intensive care units.

This review article explores the underlying pathophysiology of refractory septic shock and examines the evolving landscape of salvage therapies, bridging the gap between protocolized care and the desperate interventions required when conventional approaches fail.

Defining Refractory Septic Shock

The 2021 Surviving Sepsis Campaign defines refractory shock as persistent shock despite norepinephrine or epinephrine administration at doses ≥0.25 μg/kg/min for at least 4 hours. However, the literature reveals significant heterogeneity in defining this condition, with some authors characterizing it as requiring norepinephrine doses ≥1 μg/kg/min.

The lack of consensus reflects the complexity of the syndrome—refractory shock is not merely a number on a vasopressor infusion but rather a constellation of findings:

• Persistent hypotension (MAP <65 mmHg) despite high-dose catecholamines
• Progressive lactic acidosis or rising lactate despite resuscitation
• Worsening organ dysfunction scores (increasing SOFA)
• Evidence of tissue hypoperfusion (decreased urine output, altered mentation, cool extremities)

Clinical Pearl: Don't wait for the textbook definition. Consider escalating therapy when norepinephrine requirements exceed 0.5 μg/kg/min and continue to rise despite adequate volume status.

The Pathophysiological Cascade: Why Standard Treatment Fails

1. Persistent Microcirculatory Dysfunction: The Hidden Catastrophe

The cornerstone of refractory septic shock lies in the dissociation between macrocirculation and microcirculation—a phenomenon termed "loss of hemodynamic coherence." Despite achieving target mean arterial pressures through vasopressor escalation, tissue perfusion at the capillary level remains profoundly impaired.

Understanding the Microcirculation

Bedside visualization using sidestream dark field (SDF) imaging technology has revolutionized our understanding of septic microcirculation. These handheld videomicroscopes use green light (530 nm wavelength) absorbed by hemoglobin to create real-time images of flowing erythrocytes through sublingual capillaries—a non-invasive window into the microcirculation.

Studies using this technology demonstrate that microvascular alterations in septic shock are characterized by:

• Decreased functional capillary density
• Increased proportion of capillaries with stopped or intermittent flow
• Heterogeneous perfusion patterns (well-perfused areas adjacent to non-perfused regions)
• Loss of capillary recruitment during resuscitation

The severity of these microvascular disturbances correlates with organ dysfunction and mortality. Importantly, these alterations persist even when systemic hemodynamic parameters (cardiac output, blood pressure) have been normalized—explaining why some patients continue to deteriorate despite "adequate" resuscitation.

Pathophysiological Mechanisms

Multiple interconnected mechanisms drive microcirculatory failure:

1. Endothelial Dysfunction and Glycocalyx Degradation: The endothelial glycocalyx, a gel-like layer coating the vascular endothelium, acts as a mechanosensor and barrier regulator. In sepsis, inflammatory mediators, reactive oxygen species, and enzymes degrade this protective layer, leading to:

   • Increased vascular permeability and edema formation
   • Enhanced leukocyte and platelet adhesion
   • Loss of nitric oxide bioavailability

2. Microthrombosis and Coagulopathy: Sepsis-induced coagulopathy creates microthrombi that occlude small vessels while simultaneously causing consumptive coagulopathy, creating the paradox of bleeding and clotting.

3. Altered Red Blood Cell Deformability: Sepsis reduces erythrocyte deformability, impairing their ability to navigate through narrow capillaries (3-4 μm diameter). This mechanical obstruction further compromises oxygen delivery.

4. Shunting and Heterogeneous Flow: Pathological arteriovenous shunting diverts blood away from nutritive capillaries, creating areas of profound hypoxia adjacent to relatively well-oxygenated tissue.

Clinical Implications

The practical challenge is that we cannot easily assess microcirculation at the bedside in most ICUs. SDF imaging remains largely a research tool. Therefore, clinicians must rely on indirect markers:

• Persistent lactic acidosis despite normal/elevated cardiac output
• Prolonged capillary refill time (>4.5 seconds)
• Mottled skin (Livedo reticularis)
• Rising lactate-to-pyruvate ratio (when available)

Oyster: When MAP is "adequate" but lactate continues to rise or fails to clear, suspect persistent microcirculatory dysfunction rather than inadequate macrocirculatory resuscitation. Consider shifting from a pure MAP-targeting strategy to assessing peripheral perfusion markers.

2. Adrenal Insufficiency and Corticosteroid Resistance

The hypothalamic-pituitary-adrenal (HPA) axis undergoes profound disruption during severe sepsis, leading to a spectrum of dysfunction ranging from absolute adrenal insufficiency to corticosteroid receptor resistance.

Pathophysiology of HPA Axis Dysfunction in Sepsis

Multiple mechanisms contribute:

1. Impaired cortisol synthesis: Inflammatory mediators directly inhibit 11β-hydroxylase and other steroidogenic enzymes
2. Increased tissue cortisol metabolism: Upregulation of 11β-hydroxysteroid dehydrogenase type 2 increases cortisol catabolism
3. Glucocorticoid receptor resistance: Decreased receptor expression and impaired nuclear translocation reduce end-organ responsiveness
4. Relative deficiency: While absolute cortisol levels may be elevated, they are inadequate for the magnitude of physiological stress

The Controversy: Evidence and Guidelines

The role of corticosteroids in refractory septic shock remains one of the most debated topics in critical care. Recent meta-analyses suggest corticosteroids likely reduce short-term mortality and increase shock reversal at seven days, though they increase hyperglycemia risk. However, the landmark ADRENAL trial (2018) found no mortality benefit at 90 days from hydrocortisone 200 mg daily in mechanically ventilated septic shock patients.

Current 2024 focused guidelines suggest:

• Consider hydrocortisone 200 mg/day (as continuous infusion or divided doses) for refractory septic shock
• Do not perform ACTH stimulation testing to guide therapy
• Avoid corticosteroids in septic shock responsive to fluid and vasopressor resuscitation

Practical Approach

In patients requiring norepinephrine >0.5 μg/kg/min who remain hemodynamically unstable:

• Initiate hydrocortisone 50 mg IV every 6 hours or 200 mg/day continuous infusion
• Continue until shock resolves (vasopressors discontinued)
• Taper over 2-3 days to avoid rebound hypotension
• Monitor for hyperglycemia and treat aggressively

Teaching Hack: The ACTH stimulation test is dead—don't order it! Cortisol levels (basal or stimulated) do not predict who will benefit from corticosteroid therapy. The decision should be based on hemodynamic status, not biochemistry.

3. Vasopressin Deficiency and Beyond Norepinephrine

Vasopressin, also known as antidiuretic hormone (ADH), plays a crucial but underappreciated role in cardiovascular homeostasis during critical illness.

Vasopressin Physiology in Septic Shock

In early septic shock, circulating vasopressin levels are appropriately elevated (100-200 pg/mL). However, as shock progresses beyond 24-48 hours, levels paradoxically decrease to near-normal or subnormal ranges (3-20 pg/mL) despite ongoing hypotension—a phenomenon termed "relative vasopressin deficiency."

Mechanisms include:

• Depletion of neurohypophyseal stores
• Decreased synthesis due to hypotension-induced hypoperfusion of the posterior pituitary
• Autonomic dysfunction
• Desensitization of baroreceptors

Vasopressin as Adjunct Therapy

Vasopressin acts through V1A receptors on vascular smooth muscle to cause vasoconstriction via:

• Activation of phospholipase C
• Increased intracellular calcium
• Sensitization of contractile proteins to calcium

Advantages over catecholamines:

• Maintains efficacy in acidotic environment (pH <7.2)
• No tachyphylaxis with prolonged use
• Reduces norepinephrine requirements
• May improve renal perfusion through afferent arteriolar vasodilation

The VASST trial demonstrated that adding low-dose vasopressin (0.03 units/min) to norepinephrine in septic shock reduced mortality in patients with less severe shock but showed no overall survival benefit.

Current Recommendations: Add vasopressin 0.03-0.04 units/min when norepinephrine requirements exceed 0.25-0.5 μg/kg/min. Do not titrate—use fixed dose.

Selepressin: The Selective V1A Agonist

Selepressin represented a promising advance—a selective V1A receptor agonist without V2 activity, theoretically avoiding:

• V2-mediated water retention
• von Willebrand factor release (reduced thrombosis risk)
• Dilutional hyponatremia

Animal studies showed selepressin superior to both vasopressin and norepinephrine, with improved hemodynamics, reduced inflammation, and decreased vascular leak. Early phase 2A human trials showed selepressin could effectively replace norepinephrine with potential benefits in fluid balance and ventilation duration.

However, the phase 2B SEPSIS-ACT trial was stopped for futility. There were no differences in:

• Ventilator-free days (primary outcome)
• 90-day mortality
• RRT-free days
• ICU-free days

Selepressin is no longer marketed—a cautionary tale about the translational gap between promising preclinical data and clinical efficacy.

Angiotensin II: The New Kid on the Block

Synthetic angiotensin II (Giapreza®) was approved in 2017 for vasodilatory shock. The ATHOS-3 trial showed that angiotensin II significantly increased MAP in patients with catecholamine-resistant vasodilatory shock. Post-hoc analyses suggest potential benefit in patients with:

• Acute kidney injury
• High renin levels
• Right ventricular dysfunction

Concerns include:

• Thromboembolism risk (higher D-dimer levels)
• High cost ($600-1,000 per day)
• Limited long-term outcome data

Consider angiotensin II as a third-line agent (after norepinephrine + vasopressin) in catecholamine-resistant shock, particularly with concurrent AKI.

4. Mitochondrial Dysfunction: Cytopathic Hypoxia

Beyond inadequate oxygen delivery lies a more insidious problem—cells' inability to utilize delivered oxygen for ATP generation. This phenomenon, termed "cytopathic hypoxia," represents the final common pathway of cellular dysfunction in sepsis.

Mechanisms of Mitochondrial Dysfunction

1. Direct mitochondrial damage: Reactive oxygen/nitrogen species, damage-associated molecular patterns (DAMPs), and inflammatory mediators directly injure mitochondrial DNA and respiratory chain complexes

2. Impaired oxidative phosphorylation: Dysfunction of complexes I, III, and IV reduces electron transport efficiency and ATP generation

3. Mitochondrial biogenesis impairment: Sepsis suppresses PGC-1α, the master regulator of mitochondrial biogenesis, preventing repair and replacement of damaged mitochondria

4. Mitochondrial quality control disruption: Impaired mitophagy allows accumulation of dysfunctional mitochondria

Clinical Manifestations

Patients with cytopathic hypoxia present with:

• Normal or elevated venous oxygen saturation (ScvO2 >70%) despite tissue hypoperfusion
• Persistent lactic acidosis with adequate cardiac output
• Reduced arteriovenous oxygen difference
• Progressive organ failure despite hemodynamic optimization

This explains the paradox of patients with "supranormal" oxygen delivery who continue to deteriorate.

Metabolic Resuscitation: The HAT Therapy Controversy

The Rationale: Biological Plausibility

The combination of Hydrocortisone, Ascorbic acid (vitamin C), and Thiamine (HAT therapy) was proposed based on compelling physiological rationale:

Vitamin C (Ascorbic Acid)

• Antioxidant properties: Scavenges reactive oxygen species
• Endothelial protection: Preserves endothelial barrier function
• Catecholamine synthesis: Required cofactor for dopamine β-hydroxylase
• Vasopressor synthesis: Enhances endogenous vasopressin and catecholamine production
• Immunomodulation: Modulates neutrophil function and cytokine production

Thiamine (Vitamin B1)

• Cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase
• Essential for aerobic metabolism and ATP generation
• Often deficient in critically ill patients
• Deficiency exacerbates lactic acidosis
• May prevent vitamin C-induced oxalate nephropathy

Hydrocortisone

• Synergistic with vitamin C in restoring vascular tone
• Reduces inflammation
• Enhances vasopressor responsiveness

The Rise: Marik's Observation

The 2017 retrospective study by Marik et al. reported dramatic results in 47 patients with severe sepsis/septic shock treated with:

• Vitamin C 1.5 g IV every 6 hours
• Thiamine 200 mg IV every 12 hours
• Hydrocortisone 50 mg IV every 6 hours

Results showed:

• 8.5% mortality in HAT group vs. 40.4% in controls (p=0.001)
• Faster resolution of organ dysfunction
• No treatment-related adverse events

These striking results sparked global interest and widespread adoption despite being a single-center, before-after study with significant potential for bias.

The Fall: Negative RCTs

Subsequent randomized controlled trials have consistently failed to replicate these benefits:

CITRIS-ALI (2019): No difference in SOFA scores or mortality VITAMINS (2020): No difference in mortality or vasopressor duration ACTS (2020): Higher mortality with vitamin C LOVIT (2022): Increased mortality and persistent organ dysfunction with high-dose vitamin C

Current Evidence and Recommendations

Meta-analyses of HAT therapy show:

• No mortality benefit
• No reduction in organ failure
• Potential harm with high-dose vitamin C (≥6 g/day)
• No benefit from combination therapy over steroids alone

2024 Guidelines recommend AGAINST routine use of high-dose vitamin C in septic shock.

Clinical Bottom Line: HAT therapy is not supported by current evidence and should not be used routinely. If hydrocortisone is indicated for refractory shock, use it alone rather than in combination.

Oyster: The HAT therapy story exemplifies the importance of rigorous trial design. Single-center observational studies, no matter how striking, require validation in properly powered RCTs before changing practice. Biological plausibility ≠ clinical efficacy.

Rescue Therapies: When Nothing Else Works

Veno-Arterial ECMO for Septic Cardiomyopathy

Septic cardiomyopathy, characterized by reversible biventricular dysfunction, occurs in 10-70% of septic shock patients. When severe, it contributes to refractory shock despite maximal medical therapy.

Pathophysiology

• Direct myocardial depression from inflammatory mediators (TNF-α, IL-1β)
• Mitochondrial dysfunction in cardiomyocytes
• β-adrenergic receptor downregulation
• Myocardial edema from increased capillary permeability

Indications for VA-ECMO in Septic Shock

Consider VA-ECMO in highly selected patients with:

1. Severe septic cardiomyopathy (EF <30%) refractory to inotropes
2. Reversible cause of sepsis with source control achieved
3. Age <65 years with limited comorbidities
4. Short duration of shock (<48 hours of high-dose pressors)
5. SOFA score <15

Evidence and Outcomes

Mortality in septic shock patients on VA-ECMO is high (60-85%), significantly worse than other ECMO indications. Risk factors for mortality include:

• SOFA score >15 at ECMO initiation
• Prolonged shock-to-ECMO interval (>24 hours)
• Multiple organ failure
• Acute kidney injury requiring dialysis
• Lactate >10 mmol/L

Practical Approach

VA-ECMO for septic shock should only be considered in highly selected patients at experienced centers. Key principles:

• Early recognition and rapid initiation (within 24 hours of refractory shock)
• Peripheral cannulation (femoral arterial and venous access)
• Aggressive source control and antimicrobial therapy
• Daily reassessment for recovery or futility
• Consideration of distal perfusion catheter for leg ischemia

Therapeutic Plasma Exchange (TPE)

TPE, also known as plasmapheresis, removes and replaces patient plasma to eliminate pathologic substances including cytokines, endotoxins, and activated complement factors.

Rationale

• Removes pro-inflammatory cytokines (cytokine storm)
• Eliminates circulating endotoxin
• Replaces consumed coagulation factors
• Provides fresh albumin and immunoglobulins

Evidence

The evidence is mixed:

• Several small RCTs show faster shock reversal and improved hemodynamics
• Meta-analyses suggest potential mortality benefit
• No definitive large-scale RCT demonstrating survival benefit

The EUPHRATES trial of polymyxin B hemoperfusion (targeting endotoxin removal) was negative for overall population but suggested benefit in patients with high endotoxin activity levels.

When to Consider TPE

Consider in highly selected cases of:

• Refractory septic shock with suspected high cytokine/endotoxin burden
• Toxin-mediated shock (Streptococcal toxic shock, Clostridial sepsis)
• As adjunct to source control in severe necrotizing infections

Typical protocol:

• 1-1.5 plasma volumes exchanged per session
• Daily sessions for 3-5 days
• Replacement with fresh frozen plasma or albumin

Polymyxin B Hemoperfusion

Polymyxin B hemoperfusion uses a cartridge containing immobilized polymyxin B to bind and remove endotoxin from blood during hemofiltration.

Mechanism: Polymyxin B binds lipid A (the toxic component of lipopolysaccharide), neutralizing endotoxin and reducing systemic inflammation.

Evidence

The EUPHRATES trial (2018) was neutral overall but post-hoc analysis suggested benefit in patients with:

• Multiple organ failure assessment (MOFA) score >2
• Endotoxin activity assay (EAA) 0.60-0.89
• MAP <65 mmHg despite >0.1 μg/kg/min norepinephrine

Current recommendations:

• Not routinely recommended
• May consider in severe gram-negative septic shock with high endotoxin burden
• Requires specialized equipment and expertise
• Primarily used in Japan and some European centers

Methylene Blue

Methylene blue inhibits nitric oxide synthase and guanylate cyclase, reducing excessive vasodilation in distributive shock.

Mechanism: By blocking cGMP production, methylene blue reduces vascular smooth muscle relaxation, potentially improving vasopressor responsiveness.

Evidence: Limited to small case series and uncontrolled studies. May cause:

• Transient increase in blood pressure
• Pulmonary hypertension
• Serotonin syndrome (with SSRIs)
• Interference with pulse oximetry
• Blue-green discoloration of urine

Consider as last-resort therapy in catecholamine-resistant vasodilatory shock, but evidence is insufficient for routine use.

A Pragmatic Approach: Putting It All Together

The Refractory Shock Algorithm

Step 1: Confirm True Refractoriness

• Re-evaluate volume status (dynamic indices, echocardiography)
• Reassess source control adequacy
• Verify appropriate antimicrobial therapy
• Rule out alternative diagnoses (adrenal crisis, cardiac tamponade, tension pneumothorax)

Step 2: Optimize Conventional Therapy

• Target MAP 65-70 mmHg (unless chronic hypertension suggests higher target)
• Add vasopressin 0.03-0.04 units/min when NE >0.25-0.5 μg/kg/min
• Consider low-dose epinephrine (0.01-0.05 μg/kg/min) if cardiac output low
• Initiate hydrocortisone 200 mg/day if persistently requiring high vasopressors

Step 3: Assess for Treatable Complications

• Echocardiography: Septic cardiomyopathy? Consider inotrope
• Evaluate microcirculation clinically: Mottling, prolonged CRT
• Check cortisol, thyroid function if not already done
• Review drug levels (antibiotics, sedatives) for appropriate dosing

Step 4: Consider Third-Line Vasopressors

• Angiotensin II 20 ng/kg/min starting dose (if available and AKI present)
• Consider methylene blue 1-2 mg/kg in extreme circumstances

Step 5: Evaluate for Rescue Therapies

• Young patient (<65) with reversible cause and severe septic cardiomyopathy → Consider VA-ECMO at experienced center
• Toxin-mediated septic shock (Strep TSS, Clostridial) → Consider TPE
• Gram-negative septic shock with high endotoxin burden → Consider polymyxin B hemoperfusion (if available)

Step 6: Family Discussion and Goals of Care When mortality exceeds 80-90% based on illness severity, have honest discussions about:

• Realistic expectations
• Time-limited trials of intensive therapy
• Transition to comfort measures if no improvement

Clinical Pearls and Teaching Points

Pearls for Practice

1. The "Vasopressor Ceiling": When NE exceeds 1 μg/kg/min, mortality approaches 90%. This is not a hard cutoff but a trigger for:

   • Critical reassessment
   • Senior clinician involvement
   • Family discussion
   • Consideration of salvage therapies

2. Hemodynamic Coherence: A patient with MAP 70 mmHg but lactate 8 mmol/L, mottled extremities, and anuric kidneys does NOT have adequate resuscitation. Focus on perfusion markers, not just MAP.

3. The Lactate Paradox: Rising lactate with supranormal ScvO2 suggests:

   • Cytopathic hypoxia (mitochondrial dysfunction)
   • Arteriovenous shunting
   • Impaired lactate clearance (liver dysfunction)
   • Consider shifting to alternative perfusion endpoints

4. Source Control is King: The best "rescue therapy" is removing the source. Revisit need for:

   • Surgical exploration
   • Percutaneous drainage
   • Device removal
   • Debridement

5. Steroid Timing Matters: If considering steroids, initiate within first 12-24 hours of shock onset. Late initiation (>48 hours) less likely to benefit.

Common Pitfalls

1. Over-reliance on MAP: MAP is a necessary but not sufficient target. Assess global perfusion.

2. Fluid Neglect: In patients not responding to pressors, ensure they're actually euvolemic first. Reassess volume status.

3. Premature Escalation: Don't jump to rescue therapies without optimizing basics first.

4. Ignoring Antimicrobial Review: Is spectrum adequate? Levels therapeutic? Source controlled?

5. Failure to Set Limits: Establish goals and time-limited trials rather than escalating indefinitely.

Hacks for Teaching

The "Why Are We Failing?" Checklist

1. Wrong bug? (inadequate spectrum)
2. Wrong drug? (subtherapeutic levels, resistance)
3. Wrong site? (occult source not controlled)
4. Wrong diagnosis? (not septic shock at all)
5. Wrong hemodynamics? (cardiogenic component, tamponade)
6. Wrong everything? (too sick to survive despite perfect care)

The Septic Shock Timeline

• 0-6 hours: Fluid resuscitation + antibiotics + source control
• 6-24 hours: Vasopressor optimization, add vasopressin
• 24-48 hours: Consider steroids if persistently refractory

• 48 hours: Reassess everything; consider salvage therapies or transition to palliative care

Conclusion

Refractory septic shock represents the convergence of multiple pathophysiological derangements—microcirculatory failure, adrenal axis dysfunction, mitochondrial collapse, and progressive organ failure—that conspire to create a syndrome resistant to our best interventions. The evidence supporting salvage therapies remains frustratingly weak, with most interventions based on physiological rationale rather than definitive outcome trials.

The key to managing these desperately ill patients lies not in the uncritical application of increasingly exotic therapies, but in:

1. Meticulous attention to fundamentals (source control, appropriate antibiotics, adequate resuscitation)
2. Serial reassessment for reversible causes
3. Recognition that some patients are too sick to save despite optimal care
4. Honest discussions with families about realistic expectations

As intensivists, we must balance therapeutic nihilism with appropriate hope. Some patients will survive with aggressive interventions. Many will not. Our challenge is discerning between the two and ensuring that our interventions—even when unsuccessful—respect the dignity and wishes of our patients and their families.

Key References

1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021;47(11):1181-1247.

2. Ince C, Boerma EC, Cecconi M, et al. Second consensus on the assessment of sublingual microcirculation in critically ill patients. Intensive Care Med. 2018;44(3):281-299.

3. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL). N Engl J Med. 2018;378(9):797-808.

4. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients with Septic Shock (VANISH). JAMA. 2016;316(5):509-518.

5. Russell JA, Vincent JL, Kjølbye AL, et al. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in septic shock. Crit Care. 2017;21:201.

6. Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3). N Engl J Med. 2017;377(5):419-430.

7. Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support (VITAMINS). JAMA. 2020;323(5):423-431.

8. Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit (LOVIT). N Engl J Med. 2022;386(25):2387-2398.

9. Combes A, Fanelli V, Pham T, Ranieri VM; European Society of Intensive Care Medicine Trials Group and the "Strategy of Ultra-Protective lung ventilation with Extracorporeal CO2 Removal for New-Onset moderate to severe ARDS" (SUPERNOVA) investigators. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in ARDS. Crit Care. 2019;23(1):7.

10. Honoré PM, Hoste E, Molnár Z, et al. Cytokine removal in human septic shock: Where are we and where are we going? Ann Intensive Care. 2019;9(1):56.

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Author's Note: This review represents current evidence as of 2024-2025. The field of septic shock management continues to evolve rapidly. Clinicians should consult the most recent guidelines and literature when making clinical decisions. Remember: evidence-based medicine means integrating best available evidence with clinical expertise and patient values—particularly crucial when evidence is weak or absent in refractory shock.