Does Norepinephrine Exhibit a Time-Dose Relationship in Septic Shock?

To the Editor:

We read with great interest the recent VariatiOn in fLUids adMinistEred in shock-CHaracterizAtion of vaSoprEssor Requirements in Shock (VOLUME-CHASERS) study by Roberts et al (1), recently published in Critical Care Medicine, addressing a relatively unexplored aspect of septic shock management: the effect of early vasopressor exposure during resuscitation. The study by Roberts et al (1) observed that while an association exists between increasing vasopressor doses and increasing mortality through both the first 6 and 24 hours, this association was lost when at least 2,000 mL of fluid was administered. In particular, higher doses (≥ 15 μg/min of norepinephrine equivalents) in the first 6 hours followed by lower doses (< 15 μg/min) was associated with lower mortality compared with the use of high doses or the use of low doses in the first 6 hours followed by higher doses. As such, the VOLUME-CHASERS study begins essential work integrating vasopressor timing and dose intensity with mortality outcomes. The study by Roberts et al (1) lends further support that the first 6 hours of resuscitation are critical but lacks the hour-by-hour detail necessary to guide clinicians in real-time.

The benefits from early-high and late-low vasopressor dosing complement recent data supporting early norepinephrine in septic shock. Bai et al (2) reported higher mortality for every hour delay in administering initial norepinephrine through 6 hours and lower overall norepinephrine requirements with earlier initiation. The Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) trial showed norepinephrine within 70 minutes of shock onset improved 28-day mortality (15.5% vs 21.9%; p = 0.15), and Colon Hidalgo et al (3) reported an association between increased mortality and starting vasopressors after 6 hours (4). Finally, Ospina-Tascón et al (5) found vasopressors started within 1 hour of initial fluids were associated with less cumulative fluids through 24 hours and lower mortality.

Taken together, early shock control with fluid and vasopressors may reduce the need for more of either intervention later in shock resuscitation. These data suggest benefits from early norepinephrine in septic shock. Even though differences in reporting limit true hour-by-hour comparisons of norepinephrine dosing, higher upfront norepinephrine doses (i.e., during the first 1 to 2 hr) appears promising for future studies. The intensely debated landscape of sepsis resuscitation should consider this nontraditional strategy of early norepinephrine, as it may prevent hemodynamic decompensation and prevent chasing blood pressures with escalating vasopressors.