Sepsis Journal Club Roundup

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The management of patients with sepsis can be exceptionally complex. As with many patient’s with complex critical illnesses, often times attention to seemingly minor aspects of the patient’s management can have significant impacts on the patient’s course of illness. In this recap of our most recent journal club, we review 3 such aspects of the care of patients with sepsis. Does the type of IV fluids really make a difference? Are steroids a friend or foe in the care of these patients? And can the simple bedside assessment of capillary refill replace serial measurements of lactate?

Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018;378(9):829–39. 

The SALT-ED trial was a pragmatic, unblinded, cluster-randomized, multiple-crossover, single center trial evaluating non critically ill patients in the emergency department comparing balanced crystalloid (LR/plasma-lyte) to normal saline. The primary outcome was hospital-free days at day 28. Fluid was the only aspect of care controlled by the protocol. All other aspects of care determined by treating clinicians (including need for crystalloid and volume). Fluid type administered was only given in the emergency department and was based on calendar month. Patients were excluded if they received less than 500 mL of fluid in the emergency department or if they were admitted to an ICU. Ultimately this study included 13,347 patients (6,708 balanced crystalloids, 6,639 NS) with 88.3% of the patients receiving only the assigned fluids. No difference was found in the primary outcome, hospital-free days at day 28 [25 vs. 25 (OR 0.98; 95% CI 0.92-1.04; P=0.41)], however a difference was found in a composite of major adverse kidney events within 30 days [4.7% vs. 5.6% (OR 0.82; 95% CI 0.70-0.95; P=0.01)]. This composite included death, new renal-replacement therapy, and final serum creatinine increase ≥200% baseline creatinine. No individual component was significant. There were several limitations to this study including being a single-center, non-blinded study limits without separate analysis of LR and Plasma-Lyte.

Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018;378(9):797–808. 

Why we chose this article

  • Using steroids in the setting of septic shock has been a controversial topic.

  • Studies in the past couple of decade have shown both survival benefit and no survival benefit.

Why it is important

  • Septic shock has high mortality and the management for hemodynamic control is currently fluid resuscitation followed by vasopressors.

  • Steroids are currently an option after initial resuscitation, but we do not have a definitive answer if they provide a mortality benefit or cause harm.

  • ADRENAL was a very large study that aimed to give us an answer to the steroid question.

Study details

  • Multicenter, double blinded, parallel group, randomized, controlled trial

  • Infusions of hydrocortisone versus placebo (note: we typically give boluses in our practice setting)

  • Multinational: Australia, UK, New Zealand, Saudi Arabia, Denmark

  • N = 3658 patients in septic shock, on ventilators, and on pressors. Both medical and surgical ICU settings

  • Primary outcome: 90 day mortality

  • Secondary outcomes: shock reversal, recurrence of shock, time to discharge, duration of ventilation, days alive and free of ventilation, frequency of renal replacement therapy, days alive and free of renal replacement therapy, new bacterial or fungal infection, blood transfusions

Results

  • Primary outcome: no difference in mortality, also did subgroup analysis with no difference in all subgroups

  • Secondary outcome: steroid group had quicker shock reversal, shorter time in ICU, shorter time on ventilator, and fewer blood transfusions

  • Adverse events: 21 (hydrocortisone) vs 6 (placebo), significantly greater in steroid group

Limitations

  • Patients who received etomidate were excluded

  • Antibiotic choice was not analyzed

  • Unclear how much fluids patients received

  • No cost benefit analysis

Take home points

  • There was no mortality difference in steroid vs placebo groups

  • However, there are significant secondary outcomes which could have clinical significance (less time on ventilator, less time in ICU, faster shock reversal)

  • There was significantly more adverse events with steroids, but a relatively small number overall

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. JAMA 2019;321(7):654–11. 

Why we chose this article

ANDROMEDA-SHOCK was a novel study as it challenged the common practice of trending lactates in septic shock and provided a foundation for future studies to determine more reliable markers for septic shock

Why is it important?

Although the abstract states that no significant difference was found in mortality between the capillary refill time (CRT) group versus the lactate group, this study demonstrated a trend towards improved 28 day mortality without the use of serial lactates and also demonstrated a faster way to assess response to resuscitation. 

Study Details

  • Multi-centered, randomized, superiority trial (non-blinded) that was conducted at 28 intensive care units in 5 different countries (Argentina, Chile, Colombia, Ecuador, and Uruguay)

  • Inclusion criteria: Adult patients greater than 18 years old that were admitted to the ICU with septic shock (suspected/confirmed infection, lactate > 2.0 mMol, and vasopressor use to maintain >65) after an IV fluid load of at least 20mL/kg over 60 minutes

  • Exclusion criteria: Bleeding, ARDS, DNR Status

  • 424 patients were randomized to an 8 hour intervention period in which 212 were assigned to CRT group and remaining 212 were assigned to lactate group

    • Lactate levels assessed every 2 hours in lactate group

    • CRT evaluated every 30 minutes due to faster rate of recovery

    • Goal for each intervention was to normalize CRT or decrease lactate levels by 20% every 2 hours

  • Primary outcome: All-Cause Mortality at 28 days

  • Secondary Outcomes:

    • Death within 90 days

    • Organ Dysfunction during the first 72 hours (assessed by SOFA)

    • Mechanical Ventilation-Free Days in 28 days

    • Vasopressor Free Days (28 days)

    • CRRT Free Days 

Study Protocol

For the following protocol, if the goal of normalization of CRT or decrease in lactate levels by 20% every 2 hours was not met, patient would progress down the protocol. 

  1. Assessment of fluid responsiveness with pulse pressure variation, end-expiratory occlusion time with measurement of velocity time interval on ultrasound, or passive leg raise; if fluid responsive, bolus would be given

  2. Assess if patient has chronic hypertension; if present, vasopressor test in which levophed increased until MAP 80-85 and then lactate levels and CRT reassessed

  3. If target not reached, low dose dobutamine or milrinone was added

Results

  • No significant difference in 28-day mortality based on power of study (34.9% mortality in the CRT group compared to 43.4% in lactate group; p=0.06)

  • 242 patients were fluid responsive (57%) and 106 patients (25%) were not; unable to tell in the remainder

  • Only 28.8% of CRT groups required a vasopressor test when compared to lactate group (40.1%(; p = .02)

  • In regards to secondary outcomes, SOFA score was approximately less by 1 in CRT group compared to lactate group at 72 hours (p=.045)

Take Home Points

  • Although there was a trend towards decreased mortality in CRT group, the sample size was calculated on absolute risk reduction of 15%, making a difference not statistically significant

  • Clinicians were non-blinded which may have led to changes in the management of patients

  • 90-day mortality as primary outcome is considered to be a better primary outcome when compared to 28 day mortality in sepsis studies

  • Future studies are required in order to determine if a CRT based resuscitation strategy is superior to lactate based resuscitation strategy

References

  1. Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med 2018;378(9):829–39. 

  2. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med 2018;378(9):797–808. 

  3. 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. JAMA 2019;321(7):654–11. 

Authorship

  • Selmer et al - Adam Gottula, MD, PGY-3 University of Cincinnati Department of Emergency Medicine

  • Venkatesh, et al - James Li, MD, PGY-3 University of Cincinnati Department of Emergency Medicine

  • Hernandez, et al - Shan Modi, MD, PGY-3 University of Cincinnati Department of Emergency Medicine

  • Editing, Peer Review, and Posting, Jeffery Hill, MD MEd