SEPSIS-ACT: Selepressin in Septic Shock

Background: Septic shock is the most severe form of sepsis. It is characterized by vasodilation and increased capillary permeability leading to hypotension and tissue hypoxia.  The initial treatment of septic shock includes early identification, intravenous fluids when necessary, appropriate broad-spectrum antibiotics, source control and organ support. Vasopressor therapy is often required to maintain adequate perfusion to support end organs.  Norepinephrine is the accepted first-line vasopressor for patients in septic shock, but it is not always effective in patients with extreme vasoplegia due to sepsis. Selepressin, a selective vasopressin V1a receptor agonist, is a non-catecholaminergic vasopressor that may assist in these patients.  It works by mitigating vasodilatation, vascular leakage, and tissue edema, but without V1b- or V2-mediated effects seen with vasopressin, which result in increased procoagulant factors, salt/water retention, nitric oxide release, and corticosteroid stimulation.

What They Did:

• Blinded, phase 2b/3 randomized clinical trial of adult patients with septic shock requiring more than 5 mcg/min of norepinephrine.
• Study took place in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the US
• 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, or 3.5 ng/kg/min; n = 585) vs placebo (n = 283) all given as continuous infusions titrated to hemodynamic parameters
• Study was broken up into two parts:
  • Part 1: Identify the best selepressin dosing regimen and to trigger transition to part 2
  • Part 2: Comparison of the best-performing regimen with placebo

Outcomes:

• Primary: Ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drugs
• Key Secondary:
  • 90d mortality
  • Kidney replacement therapy-free days
  • ICU-free days
• Safety:
  • Ischemic events
  • Hypotension
  • Unanticipated changes in vital signs and laboratory values

Inclusion:

• ≥18 years of age
• Proven or suspected infection
• Septic shock (Defined as hypotension = SBP <90mmHg or MAP <65mmHg requiring > 5ug/min of norepinephrine for > 1hr despite more than 1L of IVFs)

Exclusion:

• Receiving vasopressin or terlipressin
• Unable to start study drug within 12hrs of the onset of any use of vasopressor treatment (not counting use during surgery or other procedures if the vasopressor was completely weaned before use for sepsis-induced hypotension)
• Sepsis not the primary cause of hypotension

Results:

• 868 patients enrolled
  • 585 received 1 of 3 selepressin regimens
  • 283 received placebo
• 828 patients included in the final analysis
  • 562 in the selepressin group
  • 266 in the placebo group
• Median study drug duration = 37.8hrs

Strengths:

• 98.7% of patients completed the trial
• Doses of selepressin were chosen based on an analysis of a prior feasibility study
• Weaning from the vent was based on daily spontaneous breathing trials
• Investigators, study personnel, and clinical team were all blinded to allocation
• Used an intention-to-treat analysis which models itself toward real world practice
• Groups were well-balanced at baseline in terms of severity of illness and comorbid conditions
• Addresses an important question of whether adding a second vasopressor with differing action improves outcomes
• Randomization and blinding were appropriately performed 

Limitations:

• Study stopped early due to futility
• Primary outcome was a combined composite outcome
• Patient received norepinephrine for a median of 8 hours before enrollment, which limits the ability to determine the consequences of avoiding catecholamine-based vasopressor support earlier in septic shock
• Due to small numbers it is not possible to assess overall effects in subgroups as sepsis is a heterogenous condition
• Study was not powered to detect differences in adverse effects
• Would have been nice to see comparison to vasopressin instead of placebo as this is a commonly used second line agent in refractory septic shock

Discussion:

• During infusion of Selepressin there were several significant differences in the course of shock and patient care, but remember these are hypothesis generating as the study was not powered for these results:
  • Over the 1^st 6hrs, the selepressin group had a higher MAP (mean 74 vs 70mmHg) and lower norepinephrine requirement (mean 0.29 vs 0.48 ug/kg/min)
  • Patients receiving Selepressin had higher urine output (100 vs 86mL/hr) and lower net fluid balance (81 vs 107mL/hr) in the 1^st 24hrs

Author Conclusion: “Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days.  Further research would be needed to evaluate the potential role of selepressin for another patient-centered outcomes in septic shock.”

Clinical Take Home Point: The administration of selepressin did not result in improvement in any patient oriented or surrogate outcomes and cannot be recommended based on this data.

References:

1. Pierre-Francois L et al. Effect of Selepressin vs Placebo on Ventilator-and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial. JAMA 2019. PMID: 31577035

 Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)