Published online Dec 9, 2025. doi: 10.5492/wjccm.v14.i4.111164
Revised: August 5, 2025
Accepted: August 27, 2025
Published online: December 9, 2025
Processing time: 144 Days and 20.5 Hours
Refractory septic shock is a critical and multifaceted condition that continues to pose significant challenges in critical care.
To systematically review randomized trials on emerging interventions for refractory septic shock, assessing mortality, vasopressor use, intensive care unit (ICU) length of stay, and organ dysfunction.
A systematic search was conducted in PubMed, EMBASE, Cochrane CENTRAL Library, and Web of Science for studies published between 2000 and 2024. Inclusion criteria encompassed randomized controlled trials (RCT) evaluating innovative therapies for refractory septic shock. Variables of interest: The primary outcome was all-cause mortality among patients treated with novel interventions. Secondary outcomes included length of stay in the ICU, total hospital length of stay, and use of vasoactive drugs. Methodological rigor was assessed using the Cochrane Risk of Bias tool.
From 850 records, 24 RCTs met the inclusion criteria, evaluating therapies such as methylene blue, vasopressin, terlipressin, and combinations of hydrocortisone, vitamin C, and thiamine. Mortality rates ranged from 28.6% to 56.8%. Methylene blue reduced vasopressor dependency in patients requiring high norepinephrine doses by 1.0 vasopressor-free day, and terlipressin improved renal perfusion by 13.1%. Combination therapies enhanced secondary outcomes, including reductions in Sequential Organ Failure Assessment score. However, no single intervention consistently demonstrated significant survival benefits.
Adjunctive therapies for refractory septic shock may improve hemodynamics and organ function, however, they have not been shown to consistently reduce mortality. Larger trials are needed to confirm these findings. Multimodal approaches targeting inflammation are critical.
Core Tip: This systematic review of 24 randomized controlled trials evaluates novel therapies for refractory septic shock, including methylene blue, vasopressin, terlipressin, and hydrocortisone-vitamin C-thiamine combinations. While these interventions improve hemodynamics and organ function, no consistent mortality reduction was observed. Methylene blue reduced vasopressor dependency, and terlipressin enhanced renal perfusion. Larger, standardized trials are needed to validate findings and guide multimodal treatment strategies.