Today, we discuss a hot-off-the-press sepsis trial, the ANDROMEDA-SHOCK-2 Trial

The Paper

Hernandez, Glenn et al. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock-The ANDROMEDA-SHOCK-2 Randomized Clinical Trial. JAMA [10.1001/jama.2025.20402]

follow-up work from the original Andromeda-Shock Trial [10.1001/jama.2019.0071]

PICO

Patients (P)

Consecutive adult patients (aged ≥18 years) with septic shock were considered eligible. Septic shock was defined as suspected or confirmed infection, plus hyperlactatemia (≥2.0 mmol/L), and requirement of norepinephrine to maintain a MAP of at least 65 mm Hg after an intravenous fluid load of at least 1000 mL^.  Patients could be identified within the intensive care unit, emergency department, operating theater, or hospital wards. Patients were recruited up to 4 hours after inclusion criteria were met.

720 in the intervention group, 747 in the usual care group

86 Sites in 19 countries

Intervention (I)

A personalized hemodynamic resuscitation protocol targeting normalization of capillary refill time (CRT-PHR), using sequential bedside assessments of pulse pressure, diastolic pressure, mandatory fluid-responsiveness testing (e.g., PLR, EEOT, PPV/SVV, mini-fluid challenge, or echo-based indices), and selective echocardiography to guide fluids, vasopressors, and inotropes.

Comparison (C)

Usual care (pragmatic trial) according to local or international sepsis guidelines, where CRT measurement, fluid-responsiveness testing, and bedside echo were permitted but not required. (CRT measurement was performed by study personnel at the 0 and 6 hour mark)

Outcome (O)

Primary: Hierarchical composite of 28-day mortality, duration of vital support (vasoactives, mechanical ventilation, or kidney replacement therapy), and length of hospital stay.
Secondary: 28-day mortality, vital support–free days, and length of hospital stay individually

Statistical Stuff

Planned for a 6% reduction in mortality

Used a stratified hierarchical win ratio analysis (268,069 comparisons. stratified by APACHE score)

Patients at Baseline

Intervention Goals

The CRT-PHR algorithm was based on 4 fundamental pillars:

(1) CRT normalization as the target of hemodynamic resuscitation;

(2) Baseline identification of individual hemodynamic patterns of cardiovascular dysfunction (persistent hypovolemia, vasoplegia, and cardiac dysfunction) by simple clinical tools (pulse pressure and DAP) and basic bedside echocardiography, followed by specific interventions;

(3) Systematic fluid-responsiveness assessment before any fluid resuscitation; and

(4) 2 acute (1-hour) hemodynamic tests: a trial of a higher MAP target and a trial of a fixed low-dose dobutamine.

6 hour protocol

Monitored CRT at baseline and every hour afterwards.

Abnormal CRTs were treated as per the flow diagram

During the 6-hour study period, a higher percentage of patients normalized CRT in the CRT-PHR group compared with usual care (85.9% vs 61.7%)

Only 35% of patients had to advance to tier 2

Intervention Components

Monitoring Capillary Refill Time

Monitored at trial entry and if normal, every hour afterwards

CRT was assessed by applying firm pressure to the ventral surface (fingertip) of the distal phalanx of a finger, using a glass microscope slide. The pressure was increased until the skin was blank, maintained for 10 seconds, and then released. The time required to return to the normal skin color was measured with a chronometer and a refill time longer than 3 seconds was defined as abnormal.

Tier 1 – DBP Push

If CRT abnormal, and pulse pressure >=40 (inotropy believed to be good) then ask if DBP<50

If so, push DBP >50 with NorEPI up-titration

If it didn't normalize the CRT, go back to original BP goals

Tier 1 – Fluid Responsiveness

If pulse pressure < 40, assess fluid responsiveness

If FR+, give 500 mls of crystalloid or 5% albumin over 30 minutes and reassess CRT

If still abnormal, may repeat x 1 with still FR+

Fluid Responsiveness Methods

Like Andromeda Shock 1:

Permitted fluid responsiveness assessments from Prior ANDROMEDA

Pulse Pressure Variation

Measurable in mechanically ventilated patients, with no spontaneous breathing efforts, tidal volume equal or higher than 8 ml/kg of ideal body weight, with cardiac sinus rhythm, and no cause of low respiratory compliance. Measured through a respiratory cycle, with the formula: (PPmax-PPmin)/((PPmax+PPmin)/2).  Value > 13% considered significant.  If TV less than 8ml/kg, perform a tidal volume challenge, transiently elevating TV to 8 ml/kg [33,36].

Stroke Volume Variation

Measurable in mechanically ventilated patients, with no spontaneous breathing efforts, tidal volume equal or higher than 8 ml/kg of ideal body weight, with cardiac sinus rhythm, and no cause of low respiratory compliance.  Output measured with minimally invasive direct cardiac output monitors, which use proprietary formula of pulse-contour analysis.  Value > 10% considered significant. If TV less than 8ml/kg, perform a tidal volume challenge, transiently elevating TV to 8 ml/kg. [33,36]

Passive Leg Raising VTI

Measurable in spontaneously breathing or mechanically ventilated patients.  Patient must be quickly changed from semi-recumbent position to a reverse-Trendelenburg position with legs in 45°. Changes in VTI must be registered before 1 minute of position change. Use the formula: (VTImax-VTImin)/ (VTImax+VTImin)/2).     Value > 15% considered significant. Use with caution in patients with abdominal or inferior extremity surgical interventions and in abdominal hypertension. [14]

IVC Variation

With a transthoracic echocardiographic probe, subcostal longitudinal view of IVC is obtained. With M-Mode, maximal and minimal diameter are registered.  Value are obtained with the formula (Dmax-Dmin)/Dmin). Values > 15% are considered significant during mechanical ventilation [34]. Collapsibility of IVC during spontaneous breathing has also been used satisfactorily to predict fluid responsiveness, with suggested values of >40% [17].

End-Expiratory Occlusion Test

Measurable in mechanically ventilated patients. Output measured with a direct cardiac output monitor. A 15 seconds or higher end expiratory pause is performed (with no patient-induced effort). Value > 5% increase of CO is considered significant. [13]

Less Desirable

Pasive Leg Raise with Pulse Pressure

Measurable in spontaneously breathing or mechanically ventilated patients.  Patient must be quickly elevated from semi-recumbent position to a reverse-trendelemburg position with legs in 45°. Changes in pulse pressure must be registered before 1 minute of position change.   with the formula: (PPmax-PPmin)/((PPmax+PPmin)/2).   Value > 12% considered significant. Use with caution in patients with abdominal or inferior extremity surgical interventions and in abdominal hypertension. [14]

I couldn't discover whether they allowed mini-fluid challenges (100 ml) for changes in PP or CO measures

from Kattan, E., Ospina-Tascón, G.A., Teboul, JL. et al. Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial. Crit Care 24, 23 (2020). https://doi.org/10.1186/s13054-020-2732-y

Tier 2 – Cardiac Dysfunction

Signs of Dysfunction

Tier 2 Fluid Responsiveness

Perform successive fluid challenges until CRT normalizes, fluid responsiveness becomes negative, or safety limits are met.

• After echo ruled out major cardiac dysfunction, if the patient was still fluid responsive, additional 500 mL boluses (crystalloid or colloid) could be given, each over 30 minutes, until one of three stop-conditions was met:
  1. CRT normalized (<= 3 s)
  2. The patient became fluid-unresponsive on repeat testing (PLR, mini-fluid challenge, etc.)
  3. A predefined safety limit was reached

Those safety limits were the same as in ANDROMEDA-1 and were spelled out explicitly in the AS-2 supplemental protocol:

• Central venous pressure > 15 mm Hg
• Worsening oxygenation (≥ 3-point rise in FiO₂ requirement or ≥ 5 cm H₂O increase in PEEP to maintain same saturation)
• New pulmonary rales or B-lines suggesting overload
• PaO₂/FiO₂ < 150 mm Hg, or
• Clinical concern for pulmonary edema or rising ventilatory pressures

Tier 2 – MAP Push if Prior Hypertension History

Only patients with a known history of chronic hypertension, as defined in the baseline data.

When:
After all Tier-2 prerequisites were met—so:

• Cardiac dysfunction ruled out or treated,
• Fluid responsiveness exhausted or negative,
• CRT still > 3 s.

Procedure:

• Temporarily raise norepinephrine to reach a MAP of 80–85 mm Hg for one hour.
• If CRT normalized during that hour, the higher MAP target was maintained for the remainder of the 6-hour protocol.
• If CRT did not improve, norepinephrine was reduced back to the prior dose and the patient proceeded to the dobutamine test.

Micro-circulatory opening was the proposed mechanism

Yes — there are studies that look at higher mean arterial pressure (MAP) targets (~80-85 mmHg) in patients with septic shock and pre-existing hypertension, but the evidence does not clearly support benefit, and in some cases suggests risk. Below is a summary you (as critical-care doctor) would find useful (yes, I dragged myself out of bed for this).

Key Trials / Studies

1. SEPSISPAM (High vs Low MAP in Septic Shock) [N Engl J Med. 2014;370:1583-93]
   • RCT in France: patients with septic shock randomized to MAP target 80-85 mmHg vs 65-70 mmHg.
   • For the overall population: no statistically significant difference in 28-day or 90-day mortality (28-day ~37% vs ~34%; HR ~1.07, 95% CI 0.84–1.38) in high vs low MAP.
   • In the subgroup with chronic hypertension, there was a reduction in doubling of creatinine / need for renal-replacement therapy in the high-target group (52.0% vs 38.9%; p=0.02) though no mortality benefit.
   • Noted adverse effect: higher incidence of new-onset atrial fibrillation in high-MAP group (6.7% vs 2.8%).
2. OPTPRESS (Older Patients with Septic Shock, Japan) [10.1007/s00134-025-07910-4]
   • Recent multicenter RCT in Japan: patients ≥65 yrs with septic shock randomized to MAP target 80-85 mmHg vs 65-70 mmHg.
   • Trial was stopped early for harm. At 90 days, mortality was 39.3% in the high‐target group vs 28.6% in the control group (risk difference ~10.7%, 95% CI 2.6-18.9%).
   • No subgroup (including those with known hypertension) showed benefit.

Tier 2 – Dobutamine Test

• If CRT remained abnormal after fluids (for responders), norepinephrine adjustment, and the MAP test (temporary increase to 80–85 mm Hg in chronic hypertensives), clinicians performed a dobutamine test.
• The test consisted of a fixed low-dose dobutamine infusion of 5 µg/kg/min for one hour.
• No titration, no hemodynamic endpoints other than CRT.

Interpretation:

• If CRT normalized during that hour, it implied low cardiac output or contractile impairment was limiting perfusion.
  → Dobutamine was continued at that same dose.
• If CRT stayed abnormal, the test was deemed negative.
  → The dobutamine was stopped, and management reverted to standard care or “rescue therapies.”

Tier 2 – Rescue Therapies

Once CRT remained abnormal after all Tier 2 interventions, further management left the structured protocol and reverted to clinician judgment.

Results

At 28 days after randomization, we observed 131 131 wins (48.9%) for the CRT-PHR group over 112 787 (42.1%) in the usual care group, yielding a stratified win ratio of 1.16 (95% CI, 1.02-1.33; P = .04)

I don't know how to calculate a fragility index on this time of statistical analysis, but the best I can tell is if <10% of the patients changed from win, results would be non-significant

These results were mainly driven by a shorter duration of vital support

Intervention patients got less fluids, more dobutamine

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Scott Weingart, MD FCCM

Editor-in-Chief, at EMCrit.org

An ED Intensivist from NY.
Professor
Nassau University Medical Center
No conflicts of interest (coi).

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