June - 2017
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The Septic Shock 3.0 Definition and Trials: A Vasopressin and Septic Shock Trial Experience
Crit Care Med, 2017, 45:940-948
How will the new Sepsis/Septic Shock 3.0 definitions affect enrolment and management of sepsis RCTs? This study applies the new requirement for a lactate of 2 mmol/L or greater to the VASST trial.
In VASST patients were included if they met the criteria of sepsis plus hypotension (MAP < 65 mmHg) plus norepinephrine (>5 ug/min for at least 6 hour after >500 ml fluid resuscitation. This study retrospectively applied the Septic Shock 3.0 definition by dividing the cohort to lactate greater than 2.0 mol/L or less than equal to 2 mol/L and comparing 28-day and 90-day mortality rates.
Overall when the new Septic Shock 3.0 definition was applied to a previously collected sepsis RCT population, the effect was a large decrease in sample size, an increase in mortality, and no difference in mortality effect in the vasopressin vs norepinephrine group. However a significantly decreased mortality was observed in the vasopressin group the low severity stratum (lactate <2.0 mmol/L), consistent with the post-hoc analysis of the original trial.
This tells us the new definition will affect sample size calculations and recruitment rates in future sepsis trials.
Objectives: The Septic Shock 3.0 definition could alter treatment comparisons in randomized controlled trials in septic shock. Our first hypothesis was that the vasopressin versus norepinephrine comparison and 28-day mortality of patients with Septic Shock 3.0 definition (lactate > 2 mmol/L) differ from vasopressin versus norepinephrine and mortality in Vasopressin and Septic Shock Trial. Our second hypothesis was that there are differences in plasma cytokine levels in Vasopressin and Septic Shock Trial for lactate less than or equal to 2 versus greater than 2 mmol/L.
Design: Retrospective analysis of randomized controlled trial.
Setting: Multicenter ICUs.
Methods: We compared vasopressin-to-norepinephrine group 28- and 90-day mortality in Vasopressin and Septic Shock Trial in lactate subgroups. We measured 39 cytokines to compare patients with lactate less than or equal to 2 versus greater than 2 mmol/L.
Patients: Patients with septic shock with lactate greater than 2 mmol/L or less than or equal to 2 mmol/L, randomized to vasopressin or norepinephrine.
Interventions: Concealed vasopressin (0.03 U/min.) or norepinephrine infusions.
Measurements and Main Results: The Septic Shock 3.0 definition would have decreased sample size by about half. The 28- and 90-day mortality rates were 10–12 % higher than the original Vasopressin and Septic Shock Trial mortality. There was a significantly (p = 0.028) lower mortality with vasopressin versus norepinephrine in lactate less than or equal to 2 mmol/L but no difference between treatment groups in lactate greater than 2 mmol/L. Nearly all cytokine levels were significantly higher in patients with lactate greater than 2 versus less than or equal to 2 mmol/L.
Conclusions: The Septic Shock 3.0 definition decreased sample size by half and increased 28-day mortality rates by about 10%. Vasopressin lowered mortality versus norepinephrine if lactate was less than or equal to 2 mmol/L. Patients had higher plasma cytokines in lactate greater than 2 versus less than or equal to 2 mmol/L, a brisker cytokine response to infection. The Septic Shock 3.0 definition and our findings have important implications for trial design in septic shock.
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