In this episode I’ll:
1. Discuss an article about corticosteroids in septic shock.
2. Answer the drug information question “Which dose of vasopressin should be used in septic patients?”
3. Share a resource for residency and job interviews.
Article
Adjunctive Glucocorticoid Therapy in Patients with Septic Shock
Authored by: The ADRENAL trial investigators.
Published in New England Journal of Medicine in January 2018
Background
Steroids have been in and out of favor for use in septic shock over the past several decades. The ADRENAL investigators sought to definitively answer the question of whether steroids improve mortality in septic shock with a large, multi-center, randomized controlled trial.
Methods
The authors randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.
Results
Over 1800 patients in each group were enrolled and analyzed. At 90 days, there was no difference in mortality between the steroid and placebo groups. There were also six pre-specified subgroups in which the primary endpoint was analyzed:
- Medical vs Surgical admission type
- High vs low dose of catecholamine infusions
- Pulmonary vs. nonpulmonary source of infection
- Male vs. female gender
- APACHE II score above or below 25 (≥25 has been used as a cutoff point to identify patients at a higher risk for death)
- The duration of shock according to four intervals of 6 hours each between 0 and 24 hours before randomization
There was no difference in mortality between the steroid and placebo groups for any of the pre-specified subgroups.
The only secondary endpoint that revealed a difference was that fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion.
Conclusion
The authors concluded:
Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.
Discussion
The design and scope of this trial are truly impressive. Unfortunately, in the eyes of many clinicians, it would have only been considered a definitive trial if it had found a clear benefit or harm associated with steroid use in septic shock and mortality.
With a finding of “no difference,” secondary endpoints or previous trials will likely be relied upon in clinical practice. Between days 1 and 7, patients in the hydrocortisone group had a higher mean arterial pressure than did those in the placebo group. Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than did those in the placebo group. These differences are not clinically meaningful but they present a potential for seeing immediate effect while the patient is in the middle of a critical illness.
While I expect the position of steroids in septic shock to be changed in the sepsis guidelines, I would not predict that this trial will have an immediate effect on the frequency of use of steroids in patients with septic shock.
Drug information question
Q: Should vasopressin be dosed at 0.03 or 0.04 units/min for patients with septic shock?
A: Updated sepsis guidelines now recommend using a fixed vasopressin dose of 0.03 units/min.
The guidelines have some stronger wording about dosing in the most recent edition:
would advocate caution when using it in patients who are not euvolemic or at doses higher than 0.03 U/min.
We suggest adding either vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to norepinephrine with the intent of raising MAP to target, or adding vasopressin (up to 0.03 U/min) (weak recommendation, moderate quality of evidence) to decrease norepinephrine dosage.
It may seem like splitting hairs when talking about the difference between 0.03 and 0.04 units/min, and can be challenging to get providers to agree to change the dose in a patient on 0.04 units/min that finally appears stable. For this reason getting your institution’s protocol changed to a fixed vasopressin dose of 0.03 units/min probably represents the best way to ensure that vasopressin is routinely used at the recommended dose.
Resource
The resource for this episode is the website tldrpharmacy.com and their mock residency interview information. Pharmacist Brandon Dyson shares valuable pearls for understanding what the common interview questions are really getting at, and how to answer them successfully. Brandon also has put together a guide on how to master the interview process. These interview tips can be used not just for residency interviews but for any job interview.
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.
One other interesting outcome is that the group getting hydrocortisone spent less time in the ICU. When you combine the less time in the ICU and likely less time on the vent (at least initially), that can equate to patient satisfaction and cost savings.