In this episode, I’ll discuss early vs delayed norepinephrine use in patients with septic shock.
The optimal timing of when to start a vasopressor in patients with septic shock is unknown. While early norepinephrine makes intuitive sense, there are many reasons why a clinician may wish to see if a patient first responds to IV fluids – including that vasopressor use is often seen as committing the patient to a central line and an ICU admission – two things that come with their own inherent risks.
In an attempt to improve the knowledge in this area a group of authors conducted a systematic review and meta-analysis with trial sequential analysis looking at early norepinephrine use in septic shock and published the results in the journal Critical Care.
Ten studies with nearly 5000 patients were analyzed. The primary outcome was mortality in the ICU. Secondary outcomes included ICU length of stay, total fluid volume received at 6 hours, norepinephrine dose, mechanical ventilation-free days, renal replacement therapy-free days, and time to achieve a targeted mean arterial pressure (MAP).
Early norepinephrine significantly reduced mortality, whether looking at just randomized trials or when including propensity score matching and observational studies. The odds ratio for mortality in favor of early norepinephrine ranged from 0.49 to 0.71.
Unfortunately, there was considerable variability in the design of the included studies as to what was considered early administration of norepinephrine. One study had early administration begin in the pre-hospital phase of care, the largest study considered early to be within 3 hours, and the others ranged from considering early to be within 25 to 360 minutes.
When trial sequential analysis was applied to the data regarding mortality, the authors found a trend towards a benefit with early norepinephrine administration; however, the result was ultimately inconclusive due to insufficient evidence.
In the secondary outcomes, early norepinephrine administration was associated with about half a liter less fluid administered, a quicker achievement of the target MAP by 1.3 hours, and about 4 more ventilator-free days.
The authors concluded:
In conclusion, early initiation of norepinephrine may improve some clinical outcomes in septic shock without increasing adverse events. These results may suggest that this attitude is reasonable. Nevertheless, high-quality, adequately powered RCTs are still needed to confirm the relevance of this strategy, and to better define which patients with septic shock may benefit from it.
Ultimately, while this analysis does provide support for clinicians who lean towards early vasopressor administration, more data will be required before a definitive, practice-changing recommendation can be made in favor of routine early norepinephrine administration.
The article in this episode is a selection from my Hospital Pharmacy Academy’s weekly literature digest. Have you ever felt like your physician colleagues are one step ahead of you with new literature developments? Every week, Academy members are provided a summary curated and explained by me of the top hospital pharmacy-related articles published that week from over 20 major journals and sources to save you time and keep you up to date with the literature. To get immediate access, go to pharmacyjoe.com/academy.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
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