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Early Norepinephrine for Septic Shock

September 3, 2020

Written by Sam Parnell

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Early initiation of norepinephrine for patients with septic shock was associated with decreased short-term mortality, reduced time to achieve target MAP, and lower volume of IV fluid administered within 6 hours.

Why does this matter?
There have been several advances in management of sepsis, but septic shock continues to be a leading cause of morbidity and mortality. The 2018 Surviving Sepsis Campaign Bundle recommends administering broad-spectrum antibiotics, rapidly administering 30 ml/kg crystalloid for hypotension or lactate ≥ 4 mmol/L, and applying vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain MAP ≥ 65 mmHg. Recent guidelines have also recommended norepinephrine as the first-line vasopressor for septic shock. CENSER showed improved shock control with early norepinephrine and was included in this meta-analysis. However, optimal timing of vasopressors, especially in relation to IV fluid administration, is unknown.

Norepinephrine for septic shock – use early and often
This was a systematic review and meta-analysis of 5 studies with 929 patients comparing early vs late norepinephrine initiation for patients with septic shock. Patients receiving early norepinephrine had lower short-term mortality (21.6% vs. 37%; OR = 0.45, 95%CI 0.34 to 0.61), shorter time to achieve target MAP (mean difference = − 1.39 hour; 95%CI, − 1.81 to − 0.96), and less IV fluids within 6 hours (mean difference = − 0.50L; 95%CI − 0.68 to − 0.32). There was no statistically significant difference in ICU length of stay.

Unfortunately, there was not a standard definition of “early” vs “late” norepinephrine initiation between the included studies. The classification of “early” norepinephrine initiation ranged from within 1 hour to within 6 hours. However, regardless of the exact timing of the “early” groups, this review suggests that early and aggressive initiation of norepinephrine can improve outcomes for patients in septic shock.

Of note, peripheral IV norepinephrine infusion, which is safe when administered with proximal large bore IVs at low doses for short time periods, can help facilitate more rapid administration of vasopressors for patients with septic shock.  

We may have to wait for the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) study for the definitive answer about early IV fluids vs early vasopressors for septic shock. But in the meantime, consider early initiation of norepinephrine for patients with septic shock, especially when their blood pressure does not rapidly improve with initial IV fluid administration.

Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis. Crit Care. 2020 Aug 6;24(1):488. doi: 10.1186/s13054-020-03204-x.

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