52 in 52 – #8: The “ANDROMEDA-SHOCK” Trial

Welcome back to the “52 in 52” series. This collection of posts features recently published must-know articles. Our eighth post looks at the ANDROMEDA-SHOCK trial.

Author: Brannon Inman (Chief Resident, Emergency Medicine Physician, San Antonio, TX) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

In patients with septic shock, does peripheral perfusion guided resuscitation improve 28 day all cause mortality compared to lactate guided resuscitation

Study design:

• Multicenter randomized controlled, superiority trial

PICO:

Population:

• Included patents in 28 hospitals in Central and South America (Argentina, Chile, Colombia, Ecuador, Uruguay)
• Included patients > 18 years
• Admitted to the ICU with early (< 4 hours) septic shock defined by the Sepsis-3 criteria
  • Lactate >2
  • Suspected/confirmed infection
  • Vasopressors to maintain map ≥65 despite 20mL/kg over 60 minutes
• Exclusion criteria included:
  • Bleeding
  • Severe acute respiratory distress syndrome
  • Do-not-resuscitate status (DNR)

Intervention:

• Use of capillary refill time (CRT)
  • CRT was measured every 30 min until normalization then hourly for the subsequent 8 hours
  • Resuscitation targeted to CRT < 3 seconds
  • “CRT was measured by applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure was increased until the skin was blank and then maintained for 10 seconds. The time for return of the normal skin color was registered with a chronometer, and a refill time greater than 3 seconds was defined as abnormal.” – excerpt from text

Comparator:

• Lactate guided resuscitation
  • Lactate measured every 2 hours for 8 hours with goal of 20% reduction in 2 hours

Both groups were resuscitated in a similar fashion according to the following treatment protocol:

In the event patients were not meeting treatment arm requirements, the following actions were taken:

1. Patients were first assessed for fluid responsiveness (blue box above)
   1. Stroke volume variation or passive leg raise
   2. 500 cc IVF boluses given until target met or no longer fluid responsive
2. Vasopressor test (green box above)
   1. Patients with history of HTN had trial of MAP 80-85 mmHg using a steadily increasing norepinephrine infusion, followed by reassessment
3. Inotrope challenge (red box above)
   1. If patient not responsive to the above interventions, they had a trial of dobutamine or milrinone

Outcome:

• 424 patients randomized, with 416 completing the trial
• Day 28 mortality
  • 34.9% in the CRT group
  • 43.4% in the lactate group
  • Hazard ratio 0.75 (95% CI 0.55-1.02)
• No difference in secondary outcomes: organ dysfunction at 72 hours after randomization, death within 90 days, mechanical ventilation free days, renal replacement therapy, vasopressor-free days within 28 days, ICU/hospital LOS

Take away:

• Negative trial
• Overall, both groups were well balanced with good protocol adherence (violations in 13.7% CRT patients and 10.8% lactate patients). There was a trend but no statistically significant reduction in mortality with use of peripheral perfusion compared to measurement of serum lactate. There was an 8.5% mortality difference which is nothing to laugh at.
• This trial was set up as a superiority trial. It would be interesting to see how the results would be had the trial been conducted as a non-inferiority trial.
• The trial was underpowered. The original calculations were to detect a mortality difference of 15%.  They likely set the study’s mortality difference too high to be feasible. This set the trial up for a high chance of Type II error (falsely accept the null).
• It was also non-blinded, which may result in provider bias.
• Overall, CRT-guided resuscitation is probably at least as good as resuscitation based on lactate.

My take:

I practice in a country where measurement of serum lactate is mandated for reimbursement. Therefore, I will continue to measure serum lactate. However, this trial suggests the use of peripheral perfusion markers such as capillary refill is a potentially viable and useful bedside assessment I can use in the ED and ICU to quickly gauge how my resuscitation is going for critically ill septic patients.

Reference:

1. Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-664. doi:10.1001/jama.2019.0071