Publication

• Title: Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest: A Randomized Clinical Trial
• Acronym: VSE-2
• Year: 2013
• Journal published in: JAMA
• Citation: Mentzelopoulos SD, Malachias S, Chamos C, Konstantopoulos D, Ntaidou T, Papastylianou A, et al. Vasopressin, Steroids, and Epinephrine and Neurologically Favorable Survival After In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2013;310(3):270-279.

Context & Rationale

• Background

  • Survival with good neurological function after in-hospital cardiac arrest (IHCA) remains poor, particularly when postresuscitation shock and post-arrest brain injury develop.
  • Epinephrine improves coronary perfusion pressure and return of spontaneous circulation (ROSC), but its net effect on long-term, patient-centred outcomes has been uncertain and biologically contested (macrohaemodynamics vs microcirculatory injury).
  • Vasopressin (V1-mediated vasoconstriction) can be effective in acidotic states and may augment coronary/cerebral perfusion during CPR; earlier vasopressin-alone trials did not demonstrate consistent survival benefit, prompting interest in combination strategies.
  • Cardiac arrest physiology resembles a severe stress state with inflammatory activation and potential relative adrenal insufficiency; corticosteroids may enhance catecholamine responsiveness, stabilise vasomotor tone, and modulate post-arrest inflammation.
  • Preliminary clinical data suggested that a combined “vasopressin–steroids–epinephrine” (VSE) approach might improve ROSC and survival, motivating a multicentre, neurologically focused confirmatory trial.
• Research Question/Hypothesis

  • In adults with vasopressor-requiring IHCA, does vasopressin plus epinephrine during CPR with methylprednisolone during CPR, and stress-dose hydrocortisone for postresuscitation shock, improve ROSC and survival to discharge with favourable neurological outcome versus epinephrine-based standard care with placebo?
• Why This Matters

  • The intervention uses inexpensive, widely available drugs; even a modest increase in neurologically favourable survival would be clinically important at population scale.
  • Demonstrating benefit would challenge contemporary assumptions about resuscitation pharmacology and could reshape intra-arrest and immediate post-arrest care pathways.
  • The strategy is a bundled intervention spanning arrest and post-arrest phases, providing a test case for “cardiac arrest bundle” trial design and implementation.

Design & Methods

• Research Question: Among adults with vasopressor-requiring IHCA, does VSE during CPR plus stress-dose hydrocortisone for postresuscitation shock improve ROSC and survival to discharge with CPC 1–2 versus standard epinephrine-based care with placebo?
• Study Type: Multicentre (3-hospital), randomised, double-blind, placebo-controlled, parallel-group trial in Greece; enrolment 2008–2010; settings included ICU/CCU, emergency department, wards, and operating theatre.
• Population:
  • Adults (≥18 years) with in-hospital cardiac arrest requiring vasopressor administration during CPR (contemporary 2005 algorithm context).
  • Randomisation performed during CPR when vasopressor requirement was identified.
  • Key exclusions included: terminal illness with life expectancy <6 weeks or do-not-resuscitate order; exsanguination; arrest before hospital admission; intravenous corticosteroids before arrest (including hydrocortisone for septic shock); previous enrolment.
  • Patients randomised but achieving ROSC before study-drug administration (i.e., ultimately not “vasopressor-requiring”) were excluded from the primary analysis set (16 per group).
• Intervention:
  • During CPR (first 5 CPR cycles; ~3 minutes per cycle): vasopressin 20 IU per cycle plus epinephrine 1 mg per cycle.
  • During the first CPR cycle: methylprednisolone 40 mg IV once.
  • Postresuscitation shock (sustained >4 hours): hydrocortisone 300 mg/day continuous IV infusion for up to 7 days, then taper (200 mg on day 8, 100 mg on day 9, then stop).
  • Stress-dose hydrocortisone was limited to ≤3 days if there was evidence of acute myocardial infarction.
• Comparison:
  • During CPR (first 5 cycles): epinephrine 1 mg per cycle plus saline placebo (in place of vasopressin).
  • During the first CPR cycle: saline placebo (in place of methylprednisolone).
  • Postresuscitation shock: placebo saline infusion (in place of hydrocortisone); open-label hydrocortisone was permitted clinically, and its prescription cancelled study infusion.
• Blinding: Double-blind for intra-arrest study drugs and post-arrest hydrocortisone/placebo infusion; study syringes were prepared by a pharmacist; clinicians, investigators, patients, and outcome assessors were intended to remain blinded.
• Statistics: Power calculation assumed survival to discharge with CPC 1–2 of 4% (control) vs 15% (VSE); alpha 0.05; power 80%; required sample size 244; 300 planned to account for exclusions; analyses were intention-to-treat among vasopressor-requiring patients (modified ITT) using logistic regression for binary outcomes and Cox regression for time-to-event outcomes.
• Follow-Up Period: Daily assessment through days 1–10; clinical outcomes through day 60; neurological outcome at hospital discharge; additional post hoc 1-year follow-up reported in the supplement.

Key Results

This trial was not stopped early. Enrolment was completed (300 randomised); primary analysis included 268 vasopressor-requiring patients (VSE n=130; control n=138).

Outcome	VSE (n=130)	Control (n=138)	Effect	p value / 95% CI	Notes
ROSC ≥20 minutes (co-primary)	109/130 (83.9%)	91/138 (65.9%)	OR 2.98	95% CI 1.39 to 6.40; P=0.005	Reported OR from logistic regression.
Survival to discharge with CPC 1–2 (co-primary)	18/130 (13.9%)	7/138 (5.1%)	OR 3.28	95% CI 1.17 to 9.20; P=0.02	CPC assessed at hospital discharge.
Poor outcome during follow-up to day 60 (death or CPC 3–5)	Not reported	Not reported	HR 0.70	95% CI 0.54 to 0.92; P=0.009	Time-to-event analysis.
Postresuscitation shock subgroup: survival to discharge with CPC 1–2	16/76 (21.1%)	6/73 (8.2%)	OR 3.74	95% CI 1.20 to 11.62; P=0.02	Pre-specified subgroup.
Postresuscitation shock subgroup: poor outcome to day 60	Not reported	Not reported	HR 0.61	95% CI 0.43 to 0.89; P=0.009	Pre-specified subgroup; time-to-event analysis.
Duration of advanced life support	13 min (6 to 20)	19 min (9 to 30)	Not reported	P=0.01	Median (IQR).
Epinephrine dose during advanced life support	4 mg (2 to 5)	5 mg (3 to 9)	Not reported	P=0.002	Median (IQR).
Mean arterial pressure during CPR (arterial line subgroup)	75.6 mm Hg (26.9)	52.2 mm Hg (16.9)	Not reported	P<0.001	Mean (SD).
Mean arterial pressure ~20 min after ROSC (arterial line subgroup)	93.7 mm Hg (31.3)	69.1 mm Hg (20.4)	Not reported	P<0.001	Mean (SD).
Postresuscitation shock subgroup: neurologic failure-free days (days 1–60)	0 (0 to 18); max 58	0 (0 to 0); max 58	Not reported	P=0.005	Median (IQR).
Postresuscitation shock subgroup: renal failure-free days (days 1–60)	2 (0 to 40); max 60	0 (0 to 2); max 60	Not reported	P=0.009	Median (IQR).
Patient-days requiring insulin (target glucose ≤180 mg/dL)	249/494 (50.4%)	130/361 (36.0%)	Not reported	P<0.001	Higher insulin exposure in the steroid pathway.
Post hoc: 1-year survival with CPC 1–2	11/130 (8.5%)	5/138 (3.6%)	OR 2.46	95% CI 0.76 to 7.99; P=0.13	Post hoc; limited power for long-term functional outcome.

• Across the analysed cohort, VSE was associated with higher ROSC and higher survival to discharge with CPC 1–2, but the absolute number of neurologically favourable survivors was small (18 vs 7).
• The benefit signal was more pronounced in the pre-specified postresuscitation shock subgroup (CPC 1–2: 21.1% vs 8.2%), aligning with the biological rationale for post-arrest steroid support.
• Marked haemodynamic separation was achieved during CPR and early after ROSC (MAP during CPR 75.6 vs 52.2 mm Hg; MAP ~20 min after ROSC 93.7 vs 69.1 mm Hg), alongside lower epinephrine exposure and shorter ALS duration.

Internal Validity

• Randomisation and allocation concealment
  • Randomisation used a computer-generated sequence (Research Randomizer v4) and pharmacy-prepared, identical syringes.
  • Allocation was concealed from bedside clinicians and investigators; the pharmacist alone knew the allocation rule.
• Dropout and post-randomisation exclusions
  • 300 patients were randomised; 32 (16 per group) were excluded from the primary analysis because ROSC occurred before study-drug administration (not ultimately vasopressor-requiring).
  • This constitutes a modified ITT approach and may introduce selection bias despite symmetric exclusions.
• Performance and detection bias
  • Double-blinding reduces differential co-interventions; CPR study-drug delivery was separated from the core resuscitation team by design.
  • Primary outcomes are relatively objective (ROSC; survival); CPC at discharge has some subjectivity and is potentially sensitive to discharge practices and withdrawal decisions.
• Protocol adherence and separation of the variable of interest
  • Intra-arrest separation: epinephrine dose during ALS 4 mg (2 to 5) vs 5 mg (3 to 9); P=0.002.
  • System-level separation: ALS duration 13 min (6 to 20) vs 19 min (9 to 30); P=0.01.
  • Physiological separation (arterial line subgroup): MAP during CPR 75.6 (26.9) vs 52.2 (16.9) mm Hg; P<0.001; MAP ~20 min after ROSC 93.7 (31.3) vs 69.1 (20.4) mm Hg; P<0.001.
  • Post-arrest steroid separation was imperfect due to deviations and crossovers: in postresuscitation shock survivors ≥4 hours, stress-dose hydrocortisone was administered to 58/76 in the VSE group, while 15/73 control patients received open-label hydrocortisone; additional patients received neither study infusion nor open-label hydrocortisone.
• Baseline characteristics and illness severity
  • Key baseline variables were broadly comparable; mean age was 65.5 (14.2) vs 68.2 (13.6) years.
  • Arrest population was high-risk and predominantly non-shockable (asystole was the most common initial rhythm), consistent with a “vasopressor-requiring” IHCA cohort.
• Heterogeneity
  • Only three centres contributed patients; statistical heterogeneity across centres was reported as low for primary endpoints (ROSC I²=0.16; neurologically favourable survival I²=0).
• Timing and dose
  • Methylprednisolone was delivered during the first CPR cycle, maximising biological plausibility for early haemodynamic effects.
  • Hydrocortisone was initiated at 4 hours after ROSC for postresuscitation shock, targeting the early vasoplegic/inflammatory phase; dose was stress-dose (300 mg/day) with taper.
• Outcome assessment and follow-up completeness
  • Short-term outcomes were ascertained during admission; follow-up was reported to day 60, with additional post hoc 1-year functional survival.
• Statistical rigour
  • Sample size was based on the neurological primary endpoint, and the observed effect estimates were directionally consistent with planning assumptions.
  • Two co-primary endpoints were tested; the analysis plan used regression modelling for primary outcomes and time-to-event methods for follow-up outcomes.

Conclusion on Internal Validity: Overall, internal validity appears moderate: randomisation and blinding were robust and physiological separation was substantial, but the modified ITT population, post-arrest treatment crossovers, and small number of neurologically favourable survivors limit certainty about the magnitude and durability of benefit.

External Validity

• Population representativeness
  • Includes typical in-hospital settings (ICU/CCU, wards, ED, operating theatre), but restricted to vasopressor-requiring arrests (excluding arrests rapidly reversed without vasopressors).
  • High prevalence of non-shockable rhythms and postresuscitation shock suggests applicability to a high-severity IHCA phenotype rather than all-comers (including promptly defibrillated VF/VT).
• Intervention feasibility
  • Requires availability of vasopressin, corticosteroids, and pharmacy/logistics for blinded preparation (for trial replication) or standardised resuscitation packs (for real-world implementation).
  • Because the intervention spans intra-arrest and ICU phases, implementation fidelity depends on both code-team practice and post-arrest critical care pathways.
• Contemporary relevance
  • Conducted under older resuscitation algorithm context; contemporary practice (timing of vasopressors, removal of atropine from non-shockable algorithms, evolved post-arrest care) may modify effects.

Conclusion on External Validity: Generalisability is limited-to-moderate, most applicable to adult, high-severity, vasopressor-requiring IHCA with postresuscitation shock in systems able to deliver protocolised post-arrest shock management; transferability to contemporary algorithms and broader IHCA phenotypes remains uncertain.

Strengths & Limitations

• Strengths:
  • Randomised, double-blind, placebo-controlled design across three hospitals.
  • Patient-centred co-primary endpoint (survival to discharge with CPC 1–2), not merely ROSC.
  • Detailed physiological and organ dysfunction secondary outcomes supporting mechanistic plausibility (MAP differences; failure-free days).
  • Pre-specified subgroup analysis in postresuscitation shock, aligned with the hydrocortisone component.
• Limitations:
  • Multicomponent bundle (vasopressin, epinephrine exposure differences, methylprednisolone, and post-arrest hydrocortisone), preventing attribution to any single element.
  • Modified ITT analysis with post-randomisation exclusions (ROSC before study-drug delivery).
  • Post-arrest hydrocortisone delivery had protocol deviations and crossovers (open-label hydrocortisone use in controls; incomplete stress-dose hydrocortisone in some VSE patients).
  • Neurological outcome assessed at discharge; longer-term functional outcomes were post hoc and underpowered (1-year CPC 1–2 not statistically significant).
  • Three-centre setting and older resuscitation algorithm context may limit transportability to other systems and current practice.

Interpretation & Why It Matters

• Clinical signal

  • VSE was associated with higher ROSC and higher survival to discharge with CPC 1–2 in a vasopressor-requiring IHCA cohort, with a stronger signal in postresuscitation shock.
  • The magnitude of benefit is clinically meaningful if reproducible, but is based on a small number of neurologically favourable survivors and requires replication.
• Mechanistic coherence

  • Large intra-arrest and early post-ROSC MAP differences support a haemodynamic mechanism (improved coronary/cerebral perfusion during CPR and stabilised early post-arrest circulation).
  • Increased insulin exposure suggests a measurable systemic steroid effect in the post-arrest phase, consistent with the intervention’s intended biological activity.
• Bundle implications

  • This is not purely a “CPR drug” trial; it tests an integrated arrest-to-ICU bundle, implying that future confirmatory work should preserve (or explicitly test) the post-arrest hydrocortisone component.

Controversies & Subsequent Evidence

• Precedent evidence and motivation: The trial was preceded by a smaller RCT using a similar VSE plus post-arrest hydrocortisone strategy, generating an initial signal for improved outcomes and underpinning the rationale for multicentre testing.¹
• Interpretation in the contemporaneous literature: Published commentaries highlighted (i) the clinically important neurological endpoint, (ii) the small absolute number of favourable survivors and wide confidence intervals, and (iii) uncertainty about which component(s) (vasopressin vs corticosteroids vs reduced epinephrine exposure vs post-ROSC shock therapy) drove the observed effect.²³⁴
• Independent RCT evidence (VAM-IHCA): A later, larger multicentre trial tested vasopressin plus methylprednisolone during IHCA resuscitation (without routine post-arrest hydrocortisone) and increased ROSC, but did not demonstrate a statistically significant improvement in longer-term, patient-centred survival outcomes, tempering enthusiasm for routine adoption of VSE-type strategies.⁵
• Durability of effect: Longer-term follow-up from VAM-IHCA participants did not show improved longer-term functional outcomes, reinforcing uncertainty about durable neurological benefit beyond discharge-based measures.⁶
• Synthesis of evidence: Individual participant data meta-analysis and subsequent systematic reviews generally support improved ROSC with vasopressin–steroid strategies, while the certainty for survival with favourable neurological outcome remains limited by few trials, imprecision, and variation in inclusion of post-arrest hydrocortisone; hyperglycaemia management signals (e.g., insulin exposure) are consistently relevant in steroid-inclusive protocols.⁷⁸⁹
• Key unresolved debate: Whether the VSE-2 signal reflects (i) a true synergistic bundle effect spanning CPR and post-arrest shock, (ii) benefit confined to postresuscitation shock phenotypes, or (iii) context-specific practice effects that did not reproduce in later pragmatic multicentre work remains the central interpretive fault line.

Summary

• In 268 vasopressor-requiring IHCA patients, VSE increased ROSC ≥20 minutes (83.9% vs 65.9%; OR 2.98; 95% CI 1.39 to 6.40; P=0.005).
• VSE increased survival to discharge with CPC 1–2 (13.9% vs 5.1%; OR 3.28; 95% CI 1.17 to 9.20; P=0.02).
• Benefit signal was stronger in the pre-specified postresuscitation shock subgroup (CPC 1–2: 21.1% vs 8.2%; OR 3.74; 95% CI 1.20 to 11.62; P=0.02).
• Physiological separation was substantial (MAP during CPR 75.6 vs 52.2 mm Hg; MAP ~20 min after ROSC 93.7 vs 69.1 mm Hg; both P<0.001), supporting mechanistic plausibility.
• Post hoc 1-year CPC 1–2 survival did not reach conventional statistical significance (8.5% vs 3.6%; OR 2.46; 95% CI 0.76 to 7.99; P=0.13), underscoring uncertainty about durability.

Further Reading

Other Trials

• 2009Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169(1):15-24. DOI
• 2021Andersen LW, Isbye D, Kjaergaard J, et al. Effect of vasopressin and methylprednisolone vs placebo on return of spontaneous circulation in patients with in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2021. DOI
• 2022Granfeldt A, Andersen LW, Søholm H, et al. Long-term outcomes following vasopressin and methylprednisolone in in-hospital cardiac arrest. Resuscitation. 2022. DOI
• 2011Ducros L, Vicaut E, Soleil C, et al. Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans. J Emerg Med. 2011;41(5):453-459. DOI
• 2007Tsai MS, Huang CH, Chang WT, et al. The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study. Am J Emerg Med. 2007;25(3):318-325. DOI

Systematic Review & Meta Analysis

• 2022Holmberg MJ, Fernando SM, Anothaisintawee T, et al. Vasopressin and glucocorticoids for in-hospital cardiac arrest: an individual participant data meta-analysis. Resuscitation. 2022. DOI
• 2022Saghafi F, Fahimi F, Roshani S, et al. Efficacy of combination triple therapy with vasopressin, steroid, and epinephrine protocol for cardiac arrest: a systematic review and meta-analysis. J Intensive Care. 2022. DOI
• 2023Penn J, Costantini TW, Tran A, et al. Efficacy and safety of corticosteroids in cardiac arrest patients: a systematic review and meta-analysis with trial sequential analysis. Crit Care. 2023. DOI
• 2020Li Y, Liu L, Zhang D, et al. Efficacy and safety of corticosteroid therapy in patients with cardiac arrest: a systematic review of randomized controlled trials. Eur J Clin Pharmacol. 2020. DOI
• 2022Satti DI, Monda V, Abbas A, et al. Efficacy of vasopressin–steroids–epinephrine protocol for in-hospital cardiac arrest: systematic review and meta-analysis with trial sequential analysis. J Geriatr Cardiol. 2022. DOI

Observational Studies

• 2005Pene F, Hyvernat H, Mallet V, et al. Prognostic value of relative adrenal insufficiency after out-of-hospital cardiac arrest. Intensive Care Med. 2005;31(5):627-633. DOI
• 2006Kim JJ, Lim YS, Shin JH, et al. Relative adrenal insufficiency after cardiac arrest: impact on postresuscitation disease outcome. Am J Emerg Med. 2006;24(6):684-688. DOI
• 2008de Jong MF, Beishuizen A, de Jong MJ, et al. The pituitary-adrenal axis is activated more in non-survivors than in survivors of cardiac arrest, irrespective of therapeutic hypothermia. Resuscitation. 2008;78(3):281-288. DOI
• 2020Liu B, Zhang R, Wang Y, et al. Steroid use after cardiac arrest and outcomes in critically ill patients. J Int Med Res. 2020. DOI
• 2014Donnino MW, Salciccioli JD, Howell MD, et al. Time to administration of epinephrine and outcome after in-hospital cardiac arrest with non-shockable rhythms: retrospective analysis. BMJ. 2014;348:g3028. DOI

Guidelines

• 2025Wigginton JG, et al. Part 9: Adult Advanced Life Support: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025. DOI
• 2025Hirsch KG, et al. Part 11: Post–Cardiac Arrest Care: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025. DOI
• 2025Drennan IR, et al. Advanced Life Support: 2025 International Liaison Committee on Resuscitation Consensus on Science with Treatment Recommendations. Circulation. 2025. DOI
• 2025Soar J, et al. European Resuscitation Council Guidelines 2025: Adult Advanced Life Support. Resuscitation. 2025. DOI
• 2020Panchal AR, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020. DOI

Notes

• VSE-2 tests an arrest-to-ICU bundle (vasopressin + methylprednisolone during CPR, plus hydrocortisone for postresuscitation shock), which is central to interpretation and to replication attempts that omit the post-arrest steroid component.
• The key patient-centred endpoint is CPC 1–2 at discharge; longer-term functional outcomes were reported post hoc and were underpowered.

Overall Takeaway

VSE-2 is a landmark IHCA pharmacotherapy trial because it tested a biologically coherent, low-cost arrest-to-ICU drug bundle against patient-centred neurological survival and demonstrated substantial haemodynamic separation with improved discharge neurological outcomes. However, crossovers, modified ITT analysis, and limited long-term data mean the magnitude and durability of benefit remain uncertain, particularly given later multicentre evidence and meta-analytic synthesis that confirm ROSC benefit but leave neurologically intact survival less secure.

Bibliography

• 1.Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169(1):15-24. DOI
• 2.Ballew KA. Vasopressin plus epinephrine plus corticosteroids improved neurologically favorable survival after in-hospital cardiac arrest. Ann Intern Med. 2013;159:JC3. DOI
• 3.Buddineni JP, Bilkovski R. Epinephrine, vasopressin and steroids for in-hospital cardiac arrest: the right cocktail therapy? Crit Care. 2014. DOI
• 4.McLean J. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest. J Emerg Med. 2013. DOI
• 5.Andersen LW, Isbye D, Kjaergaard J, et al. Effect of vasopressin and methylprednisolone vs placebo on return of spontaneous circulation in patients with in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2021. DOI
• 6.Granfeldt A, Andersen LW, Søholm H, et al. Long-term outcomes following vasopressin and methylprednisolone in in-hospital cardiac arrest. Resuscitation. 2022. DOI
• 7.Holmberg MJ, Fernando SM, Anothaisintawee T, et al. Vasopressin and glucocorticoids for in-hospital cardiac arrest: an individual participant data meta-analysis. Resuscitation. 2022. DOI
• 8.Penn J, Costantini TW, Tran A, et al. Efficacy and safety of corticosteroids in cardiac arrest patients: a systematic review and meta-analysis with trial sequential analysis. Crit Care. 2023. DOI
• 9.Saghafi F, Fahimi F, Roshani S, et al. Efficacy of combination triple therapy with vasopressin, steroid, and epinephrine protocol for cardiac arrest: a systematic review and meta-analysis. J Intensive Care. 2022. DOI