Background: Septic shock causes life threatening organ dysfunction needing vasopressor despite adequate fluid resuscitation. Numerous studies and meta-analysis have proven norepinephrine as the initial vasopressor of choice in septic shock with vasopressin as add-on. Although guidelines have established the goal monitoring response in septic shock, optimal approach in discontinuation of the vasopressors in the recovery phase of septic shock remains limited.

Methods: A systematic review and meta-analysis was performed on randomized controlled trials (RCTs) and non-randomized studies comparing incidence of hypotension within 24 hours of discontinuing norepinephrine first versus vasopressin. Three reviewers independently selected studies, assessed their quality, and extracted the following data: the number and characteristics of patients enrolled, inclusion and exclusion criteria for each study, the description of interventions (discontinuing norepinephrine first versus discontinuing vasopressin first) and outcomes (incidence of hypotension within 24 hours).

Results: Seven retrospective cohort studies and one prospective randomized control trial were included. Compared with norepinephrine, risk of hypotension is higher when vasopressin is discontinued first among patients in the recovery phase of septic shock (RR 2.06; 95% CI [1.11,3.82]; I2 91%). Results were consistent in the subgroup analysis after excluding abstract-only and poor-quality studies (RR 1.73; 95% CI [0.74, 4.03]; I2 93%). There is no difference in ICU (RR 0.97; 95% CI [0.71, 1.32]; I2 38%) and in-hospital mortality (RR 0.88; 95% CI [0.66, 1.16]; I2 41%) between the two vasopressor weaning strategies. Finally ICU length of stay was reported on 5 studies with no significant difference between the two strategies.

Conclusion: Based on the results, there is increased risk of hypotension when vasopressin is discontinued first versus norepinephrine.

Keywords: systematic review and meta-analysis, vasopressor, discontinuation, septic shock, norepinephrine, vasopressin

1. Elixhauser A, Friedman B, Stranges E; Septicemia in U.S. Hospitals, 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb122.pdf
2. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC; The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb;315(8):801-10.
3. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: Intensive Care Med. 2017; 43:304–77.
4. Hollenberg SM. Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med. 2011; 183:847–55.
5. Nguyen HD, Lu S, Possagnoli I, Stokes P. Comparative Effectiveness of Second Vasoactive Agents in Septic Shock refractory to Norepinephrine. J Intensive Care Med. 2017; 32(7):451. Epub 2016 May 6.
6. Jeon K, Song J, Chung C, Yang J, Suh G. Incidence of Hypotension According to Discontinuation Order of Vasopressors in the Management of Septic Shock: A Prospective Randomized Control Trial (DOVVS). Critical Care. 2018; 22:131.
7. Musallam N, Altshuler D, Merchan C, Zakhary B, Aberle C, Papadopoulos J. Evaluating Vasopressor Discontinuation Strategies in Patients with Septic Shock on Concomitant Norepinephrine and Vasopressin Infusions. Annals of Pharmacotherapy. 2018.
8. Sacha G, Lam S, Duggal A, Torbic H, Reddy A, Bauer S. Hypotension Risk Based on Vasoactive Agent Discontinuation Order in Patients in the Recovery Phase of Septic Shock. 2018.
9. Hammond D, McCain K, Painter J, Clem O, Cullen J, Brotherton A, Chopra D, Meena N. Discontinuation of Vasopressin Before Norepinephrine in the Recovery Phase of Septic Shock. Journal of Intensive Care Medicine. 2018.
10. Bisell B, Magee C, Moran P, Bastin M, Flannery A. Hemodynamic Instability Secondary to Vasopressin Withdrawal in Septic Shock Journal of Intensive Care Medicine. 2017.
11. Bauer S, Aloi J, Ahrens C, Yeh J, Culver D, Reddy A. Discontinuation of Vasopressin Before Norepinephrine Increases the Incidence of Hypotension in Patients Recovering from Septic Shock: A Retrospective Cohort Study. Journal of Critical Care. 2010.
12. Curtis J. Discontinuation of vasopressors in septic shock patients weaning from Norepinephrine and vasopressin. Crit Care Med (2016) 44:12
13. Bredhold B, Winters S, Allen L, Callison J, Heidel E, Hamilton L. Impact of the sequence of norepinephrine and vasopressin discontinuation post-septic shock. Crit Care Med (2017) 46:1