Some New Perspectives on Vasopressors for Septic Shock
Written By: Nathalie Briones, MD
Edited by: Sunny Elagandala, MD
Septic shock, a type of distributive shock, is a process by which an abnormal redistribution of blood flow occurs in the peripheral vessels due to the vasodilatory effects of sepsis, causing damage to end organs secondary to hypoperfusion. Sepsis affects approximately 1.7 million adults per year in the USA, [1] and septic shock is noted to be the leading cause of death in ICUs, with a mortality rate as high as 30-60% [11]. Because of this, early identification and proper management in the early hours of the recognition of sepsis is critical, and numerous guidelines have been instituted throughout the years to help guide our management, with the most notable being the Surviving Sepsis Campaign. [2] Despite these known guidelines, current literature continues to evolve on the treatment of sepsis, including ongoing discussions about vasopressors.
The preferred vasopressor for the initial management of septic shock has remained to be norepinephrine, with vasopressin and epinephrine as notable second-line agents. Further, current guidelines have soft recommendations for dopamine in highly select cases (such as patients with low risk of tachyarrhythmias, and absolute or relative bradycardia), [2] as well as dobutamine in cases of shock refractory to these measures, [2] however recent literature has also suggested additional approaches to vasopressors in sepsis that may also be of potential benefit. These new studies include suggestions for initiating vasopressors even earlier in the course of sepsis, the addition of angiotensin II for refractory shock, as well as the potential role for early adjunctive vasopressin in reducing mortality and norepinephrine requirements.
Vasopressor choice
Norepinephrine, the first-line pressor in septic shock, has partial alpha-1 and alpha-2 effects with a small amount of beta-1 agonism, therefore is considered as a “balanced inopressor,” because it acts as a venous and arterial vasoconstrictor as well as a mild inotrope. Although previous guidelines suggested that epinephrine was a suitable alternative as a first-line agent, the most recent guidelines recommend norepinephrine as the preferred first-line agent. [2]
Epinephrine, a beta-1 and beta-2 agonist with moderate alpha-1 effects, increases cardiac output with an additional increase in peripheral vascular resistance. However, it is now considered second-line given its association with an increased risk of tachycardia and lactic acidosis, with potential deleterious effects. [4] Vasopressin, another second-line agent, causes vascular smooth muscle vasoconstriction by working in a separate mechanism from the catecholamine pathway. It has noted to be a useful adjunct to norepinephrine and other vasopressors, however is not recommended as a single agent. [2]
Dopamine, which has effects at the dopaminergic receptors as well as beta-1 and alpha-1 effects at higher doses, has largely fallen out of favor given a number of studies that have demonstrated potential harm associated with its use, including dysrhythmias, increased morbidity and mortality. [4] Because of this, it is now considered only as a rescue agent in highly select cases (e.g. those with low risk for tachydysrhythmias and with relative bradycardia) when shock is refractory to other medications. [2] Dobutamine, on the other hand, is a pure inotrope that increases cardiac output, and may be used as an adjunct to norepinephrine if cardiogenic shock is also suspected as a contributor to hypoperfusion. [2]
Early Initiation of Pressors?
Although standard practice on sepsis management includes source control, early antibiotics, IV fluids until optimal intravascular volume is achieved (usually initiated as a 30cc/kg IV fluids), and to initiate vasopressors only after MAPs remain refractory to these measures, a recent study from 2019, the CENSER trial, evaluated the benefit of initiating norepinephrine even earlier. This single-center, randomized, double blind, placebo-controlled trial randomized patients to either receive standard treatment plus norepinephrine at an untitrated fixed rate of 0.05mcg/kg/min via either central or peripheral access or receive standard treatment plus a placebo infusion.
Interestingly, there was found to be a significant benefit in the control of shock by 6 hours and a decreased 28-day mortality rate, with a decreased incidence of cardiogenic pulmonary edema as well as decreased incidence of new onset arrhythmias. [3] The study still remains to be externally validated, however this new take on the early initiation of vasopressors shows some promise and may lead us to a new path on the management of sepsis.
As an interesting aside, the norepinephrine was initiated peripherally in the CENSER trial if no central access was available (as was the case in 60% of the patients), with no difference in rates of skin necrosis between groups (1 case per group). [3] This adds to the prior evidence that it is relatively safe to use norepinephrine through a peripheral IV. [13] Per a 2015 systematic review by Loubani et al, extravasation events were mostly associated with IV placement distal to the antecubital fossa, and the average length of infusion before extravasation was 35 hours. [14] Therefore, lack of central access should NOT be a barrier to the early initiation of pressors in septic shock.
Angiotensin II for Refractory Shock?
In 2017, the FDA approved angiotensin II as an intravenous infusion to improve MAP in patients with septic or other distributive shock [5] following the promising results of the ATHOS-3 trial. The trial was a multi-center, prospective, double blind, randomized-controlled trial that assessed the benefit of adding angiotensin II in severe vasodilatory shock that was resistant to catecholamines, and it showed a 40% improvement in MAP response compared to placebo. [6]
Angiotensin II is a non-catecholamine vasopressor that is naturally secreted as part of the renin-angiotensin system and causes systemic vasoconstriction. [6] When added to catecholamine vasopressors in Catecholamine-Resistant Hypotension (CRH, defined as greater than 0.2 ug/kg/min of Norepinephrine), there was found to be a significant reduction in catecholamine doses, an improvement in SOFA scores at 48 hours, with a lower adverse event rate compared to placebo and a trend toward reduced mortality at 30 days (46% vs 54% in placebo). Although further studies are needed, ATHOS-3 provides compelling evidence that the addition of angiotensin II could be safe and effective at optimizing hemodynamics in CRH.
Should Vasopressin Be Initiated Early in Septic Shock?
Vasopressin (also known as antidiuretic hormone) is an endogenous peptide hormone secreted from the hypothalamus and released from the posterior pituitary, and it uniquely has distinct roles during states of health versus states of shock. [8] In healthy states, its main role is in controlling osmolarity with very little effect on blood pressure, whereas in shock states, vasopressin binds to V1 receptors on vascular smooth muscle, which increases blood pressure through vasoconstriction. [7,8] Recognizing its relative deficiency during septic shock sparked its use as a vasopressor [1,7,8,9], and while it is not recommended for use as a single initial agent [1], it is a common adjunct to norepinephrine in refractory septic shock. [7,8,9]
There has been inquiry into the benefits of initiating vasopressin earlier in the treatment of septic shock, such as in the 2016 VANISH trial, which compared the effect of early initiation of vasopressin vs. norepinephrine in patients with septic shock on kidney failure, with the primary outcome measured as kidney failure-free days. [12] There was no statistically significant improvement in the number of kidney failure-free days in the vasopressin group compared to the norepinephrine group.[12] However, the utility of this study is limited, because while it did evaluate the effects of early initiation of vasopressin in septic shock on kidney failure, it did not compare these results to the effects of later initiation of vasopressin. Additionally, it studied the effect of vasopressin as an alternative to norepinephrine, rather than as an adjunct to it, which is currently the recommended use of vasopressin according to current guidelines. [2]
The 2008 VASST trial was a multi-center randomized, double-blind controlled trial that sought to determine the effect on all-cause mortality when adding low-dose vasopressin as an adjunct to norepinephrine compared to norepinephrine alone in patients with septic shock. [10] However, the study found no significant difference in 28-day mortality rate in the vasopressin + norepinephrine group versus the norepinephrine alone group (35.4% and 39.3%, respectively; p=0.11), and groups also did not differ significantly for multiple secondary outcomes, such as ICU length of stay, hospital stay, or organ dysfunction. [10]
While the jury is still out on whether early vs late use of vasopressin as an adjunct to norepinephrine has an added benefit, a 2019 meta-analysis found that its use in general might result in a reduced mortality in patients with septic shock (RR 0.92; 95% CI 0.84 to 0.99; I2=0%) [11]. The effect size here is small, and there was no significant difference in ICU length of stay, cardiovascular events, CVAs, or other adverse events, except for an increased risk of digital ischemia. [11] Ultimately, more studies are needed to elucidate whether adjunctive vasopressin may have more benefit when initiated earlier versus later, but it still remains a potentially useful non-catecholamine treatment when added to norepinephrine in septic shock. [2,7,8,9,11]
References
1. Rhee, C. et al. (2019). Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals. JAMA Network Open, 2(2), e187571. doi: 10.1001/jamanetworkopen.2018.7571 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2724768
2. Rhodes, A. et al. (2017). Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Medicine, 43(3), 304-377. doi: 10.1007/s00134-017-4683-6 https://www.ncbi.nlm.nih.gov/pubmed/28101605
3. Permpikul, C., et al. (2019). Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. American Journal Of Respiratory And Critical Care Medicine, 199(9), 1097-1105. doi: 10.1164/rccm.201806-1034oc https://www.ncbi.nlm.nih.gov/pubmed/30704260
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5. FDA approves drug to treat dangerously low blood pressure. (2020). Retrieved 10 November 2019, from https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-dangerously-low-blood-pressure
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9. Ahmadi, A. et al. (2017). Vasopressin in septic shock; assessment of sepsis biomarkers: A randomized, controlled trial. Indian Journal Of Critical Care Medicine, 21(9), 578-584. doi: 10.4103/ijccm.ijccm_258_17 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613609/?report=classic
10. Russell, J. et al. (2008). Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. New England Journal Of Medicine, 358(9), 877-887. doi: 10.1056/nejmoa067373 https://www.nejm.org/doi/full/10.1056/NEJMoa067373 \
11. Jiang, L. et al. (2019). The effects and safety of vasopressin receptor agonists in patients with septic shock: a meta-analysis and trial sequential analysis. Critical Care, 23(1). doi: 10.1186/s13054-019-2362-4 https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2362-4
12. Gordon, A. et al. (2016). Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock. JAMA, 316(5), 509. doi: 10.1001/jama.2016.10485 https://jamanetwork.com/journals/jama/fullarticle/2540403
13. Morgenstern, J. (2020). Peripheral vasopressors: the myth and the evidence - First10EM. Retrieved 30 January 2020, from https://first10em.com/peripheralperssors/
14. Loubani, O. et al. (2015). A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Journal Of Critical Care, 30(3), 653.e9-653.e17. doi: 10.1016/j.jcrc.2015.01.014 https://www.sciencedirect.com/science/article/abs/pii/S0883944115000337?via%3Dihub