ANDROMEDA-SHOCK2 – Personalized Hemodynamic Resuscitation

Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock

ANDROMEDA SHOCK 2 Investigators @ShockAndromeda2. JAMA 2025. doi:10.1001/jama.2025.20402

Clinical Question

In adult patients with early septic shock, does a personalised haemodynamic resuscitation protocol targeting capillary refill time (CRT) normalisation improve outcomes compared to usual care?

Background

In septic shock, the pathophysiological mechanisms contributing to the development of a shocked state are diverse
Capillary refill time (CRT) is an simple, reproducible method of measuring peripheral perfusion; and there are a number of other physiological signs are easily observable at the bedside for clinicians to use
The ANDROMEDA-SHOCK trial demonstrated CRT as a valid resuscitation target in septic shock when compared to lactate
- The CRT group received less intravenous fluids, earlier resolution of organ dysfunction, alongside a signal towards lower mortality
Incorporating some of these additional assessments alongside CRT in a tiered approach has not previously been studied
The CRT-PHR algorithm was based on 4 pillars:
- CRT normalization as the target of hemodynamic resuscitation
- baseline identification of individual patterns of dysfunction (persistent hypovolemia, vasoplegia, and cardiac dysfunction) by simple clinical tools (pulse pressure and diastolic blood pressure) and basic bedside echocardiography, followed by specific interventions
- systematic fluid-responsiveness assessment before any fluid resuscitation
- use of short hemodynamic tests (a trial of a higher MAP target +/- a trial of a fixed low-dose dobutamine) if needed

Design

Multicentre, investigator-initiated, open-label, parallel group randomised control trial with concealed allocation
Central randomisation (1:1) via web-based system to CRT-PHR or usual care group stratified by centre using permuted blocks of variable size
Mandatory training for participating clinicians at each site with weekly case-by-case protocol adherence audit of recruited patients in CRT-PHR group by dedicated team
Hierarchical composite outcome used as primary outcome (analysed as a win ratio):
- Stratified by APACHE II score
- Early tie if both participants died in each group
- Hierarchy: (1) all cause mortality at day 28, (2) duration of vital support including vasoactives, mechanical ventilation and CRRT truncated day 28 (3) Hospital LOS at day 28
Power calculation:
- Study assumed 28-day mortality of 39%, mean number of days needing life support 5.6 days, and length of hospital stay 15.6 days in survivors, whereby CRT-PHR group would reduce mortality by 6%, shorten mean days on vital support by 1.3 days, and shorten length of stay by 1.6 days
- Sample size estimated 1500 patients required for power of 88% to show superiority in the hierarchical composite outcome for a 2-sided α of .05 after considering several scenarios

Setting

86 ICU across 19 countries – Americas, Europe, Asia
March 2022 – April 2025

Population

Inclusion:
- Adult patients (age ≥18 years) with septic shock (Sepsis-3 criteria)
  - Defined as suspected or confirmed infection, plus hyperlactataemia (≥2mmol/L), and requirement of norepinephrine to maintain MAP ≥ 65mmHg after at least 1L IV fluid bolus in 1hr
- Patients could be from emergency department, intensive care, operating theatre, or hospital wards
Exclusion
- Pregnancy
- Anticipated surgery or dialysis procedure during the first 8h after septic shock diagnosis
- Do-not-resuscitate status
- Child B or C liver cirrhosis
- Active bleeding
- Acute haematological malignancy
- Severe concomitant acute respiratory distress syndrome
- More than 4 hours after officially meeting septic shock criteria
Participant Flow
- 4553 assessed for eligibility of which 1501 randomised (largely due to exclusion criteria)
- 1467 patients included in analysis
  - Americas = 816, Europe = 609, Asia = 76
  - 720 patients allocated to CRT-PHR group and 747 to usual care
Baseline characteristics were similar between groups: (CRT-PHR vs usual care):
- Age: 66 vs 65
- Female: 42 vs 45%
- APACHE II: 70 vs 70
- SOFA : 8 vs 8
- Site of Infection:
  - Abdominal: 49 vs 46 %
  - Respiratory: 18 vs 21 %
  - Urinary: 21 vs 18 %
- Microbiologically confirmed infection: 64 vs 63%
- Time to enrolment: 2 vs 2 hrs
- Organ Support at Baseline:
  - IMV: 47 vs 49%
  - Vasopressin: 24 vs 21% (note: 100% on noradrenaline)
- Fluid: 1.5 vs 1.5L
- HR 102 vs 105
- Lactate: 3.7 vs 3.6
- CRT: 4 vs 4
- Veno-arterial CO2 gradient: 6.8 vs 6.3
- Central Venous Saturations: 74 vs 73

Intervention

CRT-PHR
- Tiered approach aimed at normalising CRT during 6 hr study period
  - CRT assessed using glass slide, and time taken to return to normal skin colour measured (> 3 seconds abnormal)
- Tier 1:
  - Entry measurement of CRT:
  - if normal then periodic monitoring
  - if abnormal then pulse pressure and diastolic blood pressure assessed with the use of fluid challenges (max 1L) following fluid responsiveness test and noradrenaline
  - If CRT normalised then periodic monitoring required
  - If CRT remained abnormal then proceed to Tier 2
- Tier 2:
  - Bedside echo conducted to rule out cardiac dysfunction and need for specific therapy
  - If no cardiac dysfunction fluid responsiveness assessed again with fluid challenges if responsive
  - If not fluid responsive and prior hypertension a MAP test conducted
    - MAP 80-85 for 1hr > If CRT goal met, then maintain MAP throughout 6h study period
  - If not hypertensive or failed response to MAP test then a dobutamine test conducted
    - 5mcg/kg/min dobutamine for 1 hour > continued if CRT goal met
  - If all these failed then rescue therapies allowed (steroids, high volume filtration, extracorporeal adsorption)
- Hourly reassessment of CRT required

Control

Usual care treated according to local and/or international guidelines. CRT only measured at baseline and at 6 hours (fluid responsiveness test and echocardiography were allowed)

Other Management:

At 6 hours:
- Similar dose of noradrenaline (0.28 vs 0.27 mcg/kg/min), use of vasopressin (37 vs 33%)
- Higher rates of dobutamine use in CRT-PHR group (12 vs 5%)
- Lower volume of fluid (600mls vs 850mls) and fluid balance (0.9 vs 1.2L) in CRT-PHR group
- CVP, MAP similar
- Lactate lower (3.2 vs 3.5) and CRT shorter (2.8 vs 3.4 secs) in CRT-PHR group

Outcome

Primary outcome: Hierarchical composite of mortality, vital support free days and hospital LOS
- 131,131 (48.9%) wins in CRT PHR group vs 112787 (42.1%) in usual care
  - Stratified Win Ratio 1.16 (95% CI 1.02 – 1.33)
  - Driven by effect in group with higher (> 19) APACHE II scores
Secondary outcomes:
Comparing CRT-PHR vs usual care group
- No significant difference in
  - 28 d all-cause mortality
    - 26.5 vs 26.6%, HR 0.99 (95% CI 0.81 – 1.21)
  - Mean Hospital LOS (to day 28)
    - 15.3 vs 16.2, MD -0.85 (95% CI -1.80 – 0.1)
- Significantly greater in intervention group
  - Mean vital support-free days: 16.5 vs 15.4, pOR = 1.28 (95% CI 1.06-1.54)

Authors’ Conclusions

Among patients with early septic shock, personalised haemodynamic resuscitation protocol targeting capillary refill time was superior to usual care for the primary composite outcome of mortality, duration of vital support, and length of hospital stay at day 28, primarily due to shorter duration of organ support

Strengths

Multicentre, multinational randomized controlled trial with allocation concealment
The team should be applauded for leading a global collaboration among different intensive care networks adopting a complex multifaceted intervention
Building on prior high quality, randomised work
Patient-centred outcomes
Short time to randomisation (median 2 hours from meeting criteria)
Mandatory training on trial procedures and protocol implementation
Pre-published statistical analysis plan
Use of win ratio analysis prioritises outcome by importance and mitigates some of the issues with composite outcomes
Generally good adherence (44 protocol violations, 111 protocol deviations reported, eTable 7) for a trial with a complex intervention
Minimal loss to follow-up (14 in CRT-PHR, 6 in usual care)
Similar use of rescue therapies between groups (eTable 15)

Weaknesses

Bias:
- Unblinded study
- CRT measurement is subject to inter-observer variability, and fluid responsiveness not standardised across sites
- Decisions regarding cessation of vital support and initiation of renal replacement were made by attending intensivists according to local practices and not adjudicated
Primary difference in effect largely due differences in non/less patient-important outcomes:
- Whether shortening organ support and/or hospital LOS by <1 day is meaningful enough to justify the complexity of the intervention is debatable
Bundle effect:
- Difficult to isolate which component is beneficial
- The trial may be demonstrating the benefit of dedicated expert-driven resuscitation rather than specifically a CRT-targeted strategy
- Whether regular periodic assessment (1-hourly), and associated increased attention (Hawthorn effect) could have influenced the outcomes in a condition where early recognition (and intervention) is known to improve outcomes?
Feasibility and reproducibility:
- Executing complicated protocolised interventions and assessments requiring serial CRT measurements, pulse pressure measurements, fluid responsiveness testing, echocardiography in less-resourced settings may not be feasible.
- Whether the difference in outcome is time-sensitive is unknown and the short time to enrolment/intervention seen in the trial may not be reproducible in all settings
- Similarly, high protocol adherence rates may not be reproducible in more resource-limited settings.
Generalisability
- Recruitment sites were overwhelmingly from Spain and Latin America (there does appear to be some site effect in the post-hoc analysis (eFigure 5)
- May not be generalisable to local populations, resources, practices, and outcomes. Especially in Australia where mortality from septic shock is significantly lower than the predicted 39%.

The Bottom Line

This study together with ANDROMEDA-SHOCK supports the potential role of CRT as a useful resuscitation target for sepsis
In practice, I favour a multimodal approach integrating bedside assessment and CRT alongside lactate clearance, MAP, and urine output
Further studies may be required to tease out the contribution of CRT normalisation vs the protocol as a whole before altering current practice.

External Links

Metadata

Summary author: Tim Law
Summary date: 24 November 2025
Peer-review editor: George Walker

Picture by: Magda Ehlers / Pexels