Persistent tissue hypoperfusion improves risk stratification beyond vasopressor dose in refractory septic shock: a secondary analysis of the ANDROMEDA-SHOCK-2 trial

Intensive Care Medicine: Published: 15 July 2026

Purpose

A recent Delphi consensus highlighted elements for defining refractory septic shock. We assessed whether integrating persistent tissue hypoperfusion with vasopressor dose after protocolized resuscitation improves mortality risk stratification compared with vasopressor dose alone.

Methods

We performed an exploratory secondary analysis of the ANDROMEDA-SHOCK-2 trial. After 6 h of hemodynamic resuscitation, refractoriness was operationalized as a norepinephrine equivalent dose (NEE) > 0.5 µg/kg/min plus an abnormal capillary refill time (> 3 s) and non-decreasing lactate (two-hypoperfusion criteria). A complementary analysis included NEE > 0.5 µg/kg/min combined with either of the tissue perfusion criteria. The primary outcome was 28-day mortality.

Results

Among 1363 patients with complete data, 188 (13.8%) had NEE > 0.5 µg/kg/min at 6-h, with 47.9% mortality. Fifty-three patients (3.9%) were classified as refractory septic shock under the two-hypoperfusion criteria and 124 (9.1%) under the ≥ 1-hypoperfusion criterion. Mortality was 73.6% (39/53) among patients meeting two-hypoperfusion criteria, compared with 23.7% (310/1310) among those classified as non-refractory according to these criteria. (aHR, 4.68; 95% CI 3.31–6.64;p < 0.001). Under ≥ 1-hypoperfusion criterion, mortality was 55.0% (68/124), compared with 22.7% (281/1239) among those classified as non-refractory under this approach (aHR, 2.62; 95% CI 1.90–3.46;p < 0.001). Refractory patients under either approach required had fewer life-support free days. Compared with NEE > 0.5 µg/kg/min alone, the two-hypoperfusion construct yielded superior prognostic enrichment for 28-day mortality (LR + , 8.12; 95% CI 4.70–14.03 vs. 2.71; 95% CI 2.10–3.50;p < 0.001).

Conclusion

In early septic shock, combining persistent tissue hypoperfusion with vasopressor dose improves risk stratification beyond vasopressor dose alone and identifies a subgroup with markedly increased mortality. These hypothesis-generating findings require validation in future studies.

 

Circulating biomarkers of vasoplegia: a systematic review

Annals of Intensive Care volume 15, Article number: 150 (2025) Published: 30 September 2025

 

Background

Vasoplegia is characterised by persistent hypotension and reduced systemic vascular resistance despite preserved cardiac output, commonly arising in sepsis, following major surgery, and within systemic inflammatory responses. Despite its clinical significance and association with poor outcomes, there is no universally accepted definition or standardised biomarker, impeding early diagnosis, stratification, and targeted therapy. While individual studies have examined biomarkers within specific clinical contexts such as septic shock or cardiac surgery, no comprehensive synthesis across all aetiologies of vasoplegia has previously been undertaken.

Objectives

To systematically evaluate and synthesise the current evidence regarding circulating biomarkers associated with the incidence, severity, prediction, and progression of vasoplegia across diverse critical care and perioperative populations. As well as review definitions used across literature.

Methods

This systematic review was conducted in accordance with PRISMA 2020 guidelines and registered on PROSPERO (CRD42024438786). Studies were included if they investigated adult patients in critical care or perioperative settings with vasoplegia defined by reduced vascular resistance and hypotension requiring vasopressors.

Results

A total of 43 studies met inclusion criteria. The included studies examined 39 unique biomarkers, with renin and adrenomedullin being the most frequently studied. Heterogeneity in definitions of vasoplegia, outcome measures, and comparator populations precluded meta-analysis. However, several biomarkers demonstrated potential clinical utility: elevated renin levels correlated with vasopressor requirements and haemodynamic instability, while adrenomedullin levels were predictive of vasoplegia development and duration.

Conclusions

The lack of standardisation in biomarker assay methods and vasoplegia definitions remains a significant barrier to comparative analysis. Whilst this review highlights renin and adrenomedullin as promising candidate biomarkers for vasoplegia, the heterogeneity in study design, biomarker measurement, and diagnostic criteria underscores the urgent need for a consensus definition of vasoplegia, standardised sampling protocols, and unified outcome measures. Future research should focus on biomarker-guided risk stratification and personalised therapies, with an emphasis on validating predictive and mechanistic roles across diverse vasoplegic phenotypes.

 

 

Vasopressin and its analogues in patients with septic shock: holy Grail or unfulfilled promise?

Critical Care volume 29, Article number: 333, Published: 29 July 2025

Abstract

The Surviving Sepsis Campaign (SSC) recommends norepinephrine as first-line vasopressor in patients with septic shock. For many years, there has been growing evidence that high doses of norepinephrine might have cardiac and immunological adverse effects and be associated with poorer outcomes. Current SSC guidelines therefore suggest adding vasopressin, a non-catecholaminergic vasopressor, as a second-line vasopressor rather than increasing the norepinephrine dose in patients requiring doses of norepinephrine base > 0.25–0.50 µg/kg/min, after excluding persistent hypovolemia and cardiac dysfunction. Vasopressin is a peptide hormone that causes vasoconstriction through its specific receptor, the arginine vasopressin receptor V1. Up to one-third of patients with septic shock may have vasopressin deficiency, which contributes to refractory septic shock. Vasopressin use is associated with a norepinephrine-sparing effect, which may in turn reduce the complications induced by high-doses of norepinephrine, by decreasing the vasopressor load: this is the concept of decatecholaminization. Nevertheless, the use of vasopressin in patients with septic shock has not yet demonstrated clear benefits in terms of patient outcomes, such as less cardiotoxicity, reduced use of renal replacement therapy or decreased mortality. The heterogeneity in the use of vasopressin and the definition of early vasopressin administration between different studies as well as many unresolved issues regarding the use of vasopressin in patients with septic shock could explain the absence of clear and relevant clinical benefits. Thus, the identification of subgroups of patients likely to benefit the most from vasopressin, the management of vasopressin administration (time to initiation, optimal doses, weaning strategy) and a better understanding of the interactions between vasopressin and corticosteroids represent major areas of research for future studies.

 

Improving vasopressor use in cardiac arrest

by Gavin D. Perkins and Keith Couper 

Critical Care volume 27, Article number: 81 (2023) Published: 02 March 2023

Abstract

The Chain of Survival highlights the effectiveness of early recognition of cardiac arrest and call for help, early cardiopulmonary resuscitation and early defibrillation. Most patients, however, remain in cardiac arrest despite these interventions. Drug treatments, particularly the use of vasopressors, have been included in resuscitation algorithms since their inception. This narrative review describes the current evidence base for vasopressors and reports that adrenaline (1 mg) is highly effective at achieving return of spontaneous circulation (number needed to treat 4) but is less effective on long-term outcomes (survival to 30 days, number needed to treat 111) with uncertain effects on survival with a favourable neurological outcome. Randomised trials evaluating vasopressin, either as an alternative to or in addition to adrenaline, and high-dose adrenaline have failed to find evidence of improved long-term outcomes. There is a need for future trials to evaluate the interaction between steroids and vasopressin. Evidence for other vasopressors (e.g. noradrenaline, phenylephedrine) is insufficient to support or refute their use. The use of intravenous calcium chloride as a routine intervention in out of hospital cardiac arrest is not associated with benefit and may cause harm. The optimal route for vascular access between peripheral intravenous versus intraosseous routes is currently the subject of two large randomised trials. Intracardiac, endobronchial, and intramuscular routes are not recommended. Central venous administration should be limited to patients where an existing central venous catheter is in situ and patent.

Renal Outcomes of Vasopressin and Its Analogs in Distributive Shock: A Systematic Review and Meta-Analysis of Randomized Trials

Renal Outcomes of Vasopressin and Its Analogs in Distributive Shock: A Systematic Review and Meta-Analysis of Randomized Trials

by Nedel, Wagner L.; Rech, Tatiana H.; Ribeiro, Rodrigo A.; Pellegrini, José Augusto S.; Moraes, Rafael B.  

Critical Care Medicine: January 2019 - Volume 47 - Issue 1 - p e44–e51

Objectives: To systematically review the literature and synthesize evidence concerning the effects of vasopressin and its analogs compared with other vasopressors in distributive shock, focusing on renal outcomes. Data Sources: We performed a systematic review in MEDLINE, Embase, Cochrane Central, and Clinicaltrials.gov databases.

Study Selection: Randomized clinical trials that compared vasopressin and its analogs with other vasopressors and reported renal outcomes in adult patients with distributive shock.

Data Extraction: Paired reviewers independently screened citations, conducted data extraction and assessed risk of bias. Three prespecified subgroup analyses were conducted. Three main outcomes related to acute renal failure were analyzed: the need for renal replacement therapy, acute kidney injury incidence, and acute kidney injury-free days. I2 test was used to evaluate heterogeneity between studies. Substantial heterogeneity was defined as I2 greater than 50%. A random-effects model with Mantel-Haenszel weighting was used for all analyses. Heterogeneity was explored using subgroup analysis. The quality of evidence for intervention effects was summarized using Grading of Recommendations Assessment, Development, and Evaluation methodology. This study was registered in the PROSPERO database (CRD42017054324).

Data Synthesis: Three-thousand twenty-six potentially relevant studies were identified, and 30 articles were reviewed in full. Seventeen studies met the inclusion criteria, including a total of 2,833 individuals. Of these, 11 studies (2,691 individuals) were suitable for quantitative meta-analysis. Overall, the evidence was of low to moderate quality. Patients who received vasopressin and its analogs had a reduced need for renal replacement therapy (odds ratio, 0.59 [0.37–0.92]; p = 0.02; I2 = 49%) and a lower acute kidney injury incidence (odds ratio, 0.58 [0.37–0.92]; p = 0.02; I2 = 63%). These results should be interpreted with caution, due to excessive heterogeneity. Acute kidney injury-free data was not pooled, since the small number of studies and extreme heterogeneity. Conclusions: In patients with distributive shock, vasopressin and its analogs use is associated with a reduced need for renal replacement therapy and lower acute kidney injury incidence. These results are supported by high risk of bias evidence.