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Ashish Khanna, MD, FCCP; Nicholas A. Peters, PharmD, BCPS, BCCCP
The first-line treatment for hypotension remains volume resuscitation, but the addition of vasopressor therapy may be required to achieve hemodynamic goals. Norepinephrine remains the most commonly used vasopressor for the treatment of hypotension in septic shock.1,2 The vasopressor “toolbox” has other potent pharmacologic interventions as well. Other vasopressors, including dopamine, epinephrine, phenylephrine and vasopressin, can be used in combination with, or instead of, norepinephrine based on patient-specific parameters for different clinical indications, mechanism of action or adverse effects. The toolbox also offers some novel drugs such as selepressin and angiotensin II. Though the basic pharmacology of vasopressors is beyond the scope of this article, Table 1 provides a precise summary of the commonly used agents and their sites of receptor action.
Norepinephrine is a catecholamine biosynthetic precursor of epinephrine and mixed adrenergic receptor agonist with potent α-adrenergic receptor stimulation and additional less pronounced β-1 adrenergic agonist activity.3,4 Norepinephrine was previously referred to as “leave ’em dead.” Concerns of potent vasoconstriction limited the use of norepinephrine to second-line treatment for septic shock.4,5
The initial concerns of an increased risk of end-organ ischemia with norepinephrine compared to other vasopressors have been disproven when patients in septic shock are adequately volume resuscitated.6,7
De Backer and the Sepsis Occurrence in Acutely Ill Patients (SOAP II) Investigators compared norepinephrine to dopamine, the previous first-line vasopressor for septic shock, and found that there was no difference in mortality, but patients who received dopamine had an increased incidence of arrhythmias compared to norepinephrine.8–10 In addition, patients with cardiogenic shock appeared to have the worst outcomes with dopamine as a vasopressor agent. No difference was seen with time to goal mean arterial pressure (MAP) when norepinephrine was evaluated against epinephrine in septic shock but there was a higher percentage of patients who withdrew from the study due to adverse metabolic effects of epinephrine, including lactic acidosis and tachycardia.11 Norepinephrine is dosed in µg/min or µg/kg/ min (weight-based). Both strategies have been utilized in major randomized clinical trials in septic shock.8,12 There is little clinical information and no recommendation on the preferred dosing strategy of vasopressors in critically ill patients. Obese patients who receive weight-based dosing are at risk of increased norepinephrine exposure potentially leading to increased adverse effects at the cost of increased efficacy. In obese patients with septic shock, there was no difference in time to goal MAP comparing weight-based-dosed norepinephrine to non-weight-based-dosed norepinephrine.13 Current evidence supports the recommendation from the 2016 Surviving Sepsis Campaign Guidelines, which support norepinephrine as the first-choice vasopressor.14
Vasopressin, also known as antidiuretic hormone, is released within the body in response to hypotension or hypovolemia.15 In septic shock, vasopressin levels are elevated, then become depleted by 96 hours, with one study identifying 32% of patients having relative vasopressin deficiency (≤ 3.6 pg/mL).16 Vasopressin causes vascular smooth muscle constriction through binding to V1 receptors, it has no catecholamine receptor activity, and it increases clinical response to other vasopressors.15 Doses greater than 0.06 units/min, when used for septic shock, have been associated with the risk of developing ischemic skin lesions.17 The question of whether norepinephrine or vasopressin should be our primary tool for defending blood pressure in septic shock has been an ongoing debate.
The 2008 Vasopressin and Septic Shock Trial (VASST) randomized patients with septic shock to norepinephrine versus norepinephrine plus low-dose vasopressin (0.01 to 0.03 units/min). No difference in mortality or safety was seen, but a slightly surprising secondary analysis showed a statistically significant reduction in mortality with vasopressin in patients with a predefined stratum of less severe septic shock.18 Another VASST analysis looked for evidence of an interaction between vasopressin and corticosteroid treatment.19 The combination of vasopressin and corticosteroids led to a lower mortality compared with norepinephrine plus corticosteroids. Further, patients who received vasopressin without corticosteroids had an increased mortality compared with patients who received norepinephrine and no corticosteroids.
Importantly, a post hoc analysis of the VASST study showed that vasopressin may reduce progression to renal failure, prompting development of the Vasopressin Versus Noradrenaline as Initial Therapy in Septic Shock (VANISH) study.20 The VANISH study enrolled patients with septic shock and randomized them to one of four treatment arms: (1) vasopressin (0.01 to 0.06 units/min) and hydrocortisone, (2) vasopressin and placebo, (3) norepinephrine and hydrocortisone, and (4) norepinephrine and placebo. No difference was seen in incidence of kidney failure, survivors without kidney failure, median number of kidney failure-free days and mortality at 28 days. However, there was less use of renal replacement therapy with vasopressin.12 Based on the VANISH study, vasopressin has not yet achieved the status of a first-line vasopressor treatment for septic shock.
The Vasopressin Versus Norepinephrine After Cardiac Surgery (VANCS) trial was yet another attempt to assess whether vasopressin had a place as a first-line vasopressor.21 This trial looked at a specific clinical indication (vasoplegia after cardiac surgery, comparable to the vasoplegic syndrome that sets in during high-output septic shock). Vasopressin had a reduction in the primary composite end point compared to norepinephrine. The composite end point included mortality or severe complications (stroke, requirement for mechanical ventilation for longer than 48hours, deep sternal wound infection, reoperation or acute renal failure) within 30 days, and on closer analysis it is clear that this composite outcome is largely driven by severe complications, namely acute renal failure and atrial fibrillation, and not a mortality difference at all.
All in all, vasopressin has been shown to be as safe as norepinephrine at lower doses and remains a key component of the vasopressor toolbox. Vasopressin is not titrated to clinical effect as are other vasopressors and could be thought of more as a replacement therapy and treatment of relative vasopressin deficiency. The 2016 Surviving Sepsis Campaign Guidelines suggest adding vasopressin (doses up to 0.03 units/min) to norepinephrine to help achieve MAP target or decrease norepinephrine dosage.14
Selepressin, a selective V1a agonist, offers the benefits of vasopressin with fewer undesirable side effects such as oxytocin and V2 receptor activation (seen with vasopressin) that may worsen fluid overload and microvascular thrombosis. The superiority of selepressin over vasopressin has already been proven in the ovine model of septic shock.22 The Selepressin Evaluation Program for SepsisInduced Shock – Adaptive Clinical Trial (SEPSIS-ACT) is currently enrolling and aims to answer questions specific to the safety and efficacy of this agent. Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure.
The renin-angiotensin-aldosterone system is operated via the final end product angiotensin II, which further stimulates the release of aldosterone, another hormone, from the adrenal cortex. Pilot information from the Intravenous Angiotensin II for the Treatment of High Output Shock (ATHOS) trial showed promising results.23 Indeed, the data showed a norepinephrine-sparing effect and established the efficacy of angiotensin II, though only as a proof of concept since the data were not adequately powered. The recently concluded ATHOS-3 trial was a multicenter, randomized, double-blind, placebo-controlled phase III clinical study of LJPC-501 (synthetic human angiotensin II) in patients with catecholamine-resistant hypotension.24 The preliminary results from ATHOS-3 show a highly significant outcome in the percentage of patients achieving the primary efficacy end point of a prespecified target blood pressure (MAP of >75mmhg or an increase of >10mmhg from baseline). In addition, a trend to improved survival has been seen. It thus appears that angiotensin II may be an integral part of the vasopressor toolbox in the years to come.
The most common adverse effects of vasopressors as a class include arrhythmias, extravasation and ischemia. Patients who are not adequately fluid resuscitated are at increased risk of arrhythmias. Clinicians should try to avoid using epinephrine and dopamine in patients who are at risk of, or who have experienced, arrhythmias with other vasopressors. It is recommended that vasopressors be administered a through central venous catheters to reduce the incidence of extravasation and local tissue ischemia.25 Recent clinical evidence suggests that shortterm and low-dose peripheral administration of vasopressors may be safe, but this has largely not translated to widespread use in clinical practice.25–27 Peripheral tissue ischemia secondary to prolonged hypotension or highdose vasopressor therapy can occur.28 Routine clinical monitoring in addition to using the lowest effective vasopressor dose can help prevent tissue ischemia. These agents are titrated to clinical endpoints but should not be titrated faster than every 5 to 15 minutes to avoid potentially overshooting hemodynamic targets.29
In clinical practice, vasopressin is commonly administered as a fixed dose with no bedside nurse titration. Vasopressin titration parameters are adapted from the VASST study, in which infusions were down-titrated by 0.005 units/min every hour.18 There is little guidance on which vasopressor to titrate off first in patients requiring multiple vasopressors to maintain hemodynamics. A small study showed an increase in hypotensive events when vasopressin was discontinued before norepinephrine.30 Clinicians can consider weaning norepinephrine before vasopressin in septic shock, but vasopressors should be weaned based on patient-specific factors, including adverse effects and effect on hemodynamics.
The message for the bedside clinician and practicing intensivist is simple. When faced with a hypotensive and septic patient, while doing everything else, treat the hypotension and defend a target MAP. There is strong evidence from the intraoperative world suggesting that MAPs of less than 65 mm Hg are associated with myocardial injury after noncardiac surgery, acute kidney injury and mortality.31–33 This target is no different from a drop in blood pressure from a higher baseline and therefore, simplistically, we are closer to an empirical definition of hypotension in the intraoperative period.32 Though the septic hypotensive patient may have a complex interplay of factors that make defining a blood pressure a particularly difficult challenge, there is room and interest for an optimal blood pressure finding study in this population as well.
How should this target MAP be defended? There is a reason that evolution provided us with multiple mechanisms of defending our blood pressure. The vasopressor toolbox approach is precisely this concept of a multimodal approach to vasopressor management in shock. This may not be any different from using multiple antihypertensive medications for higher blood pressure and a simple, rather logical approach of targeting multiple physiologic mechanisms to help a hypotensive patient. Indeed, the consequences of excessive norepinephrine (catecholamine) use in terms of tachyphyllaxis and the burden on the myocardium has been well-documented in the shape of Takotsubo, or stress-induced, cardiomyopathy.34 Whether there is a precise dose response to catecholamine overdose is not yet known. The vasopressor toolbox is available to the bedside intensivist. This means an early consideration for transitioning to vasopressin and consideration of a multiple vasopressor approach that includes other agents as well, some of which are old and time tested, and some of which are new and still need to be proven via robust clinical trials.
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2. Lamontagne F, Cook DJ, Adhikari NK, et al. Vasopressor administration and sepsis: a survey of Canadian intensivists. J Crit Care. 2011 Oct;26(5):532.e1-e7.
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8. De Backer D, Biston P, Devriendt J, et al; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-789.
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10. Sakr Y, Reinhart K, Vincent JL, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006 Mar;23(3):589-597.
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17. Dünser MW, Mayr AJ, Tür A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med. 2003 May;31(5):1394-1398.
18. Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-887.
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20. Gordon AC, Russell JA, Walley KR, et al. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83-91.
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22. He X, Su F, Taccone FS, et al. A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock. Crit Care Med. 2016 Jan;44(1):23-31.
23. Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5)5:534.
24. Chawla LS, Russell JA, Bagshaw SM, et al. Angiotensin II for the treatment of high-output shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial. Crit Care Resusc. 2017 Mar;19(1):43-49.
25. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015 Jun;30(3):653.e9-e17.
26. Cardenas-Garcia J, Schaub KF, Belchikov YG, Narasimhan M, Koenig SJ, Mayo PH. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015 Sep;10(9):581-585.
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28. Bockenstedt TL, Baker SN, Weant KA, Mason MA. Review of vasopressor therapy in the setting of vasodilatory shock. Adv Em Nurs J. 2012 Jan-Mar;34(1):16-23.
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31. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013 Sep;119(3)3:507-515.
32. Salmasi V, Maheshwari K, Yang D, et al. Relationship between intraoperative hypotension, defined by either reduction from baseline or absolute thresholds, and acute kidney and myocardial injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology. 2017 Jan;126(1):47-65.
33. Mascha EJ, Yang D, Weiss S, Sessler DI. Intraoperative mean arterial pressure variability and 30-day mortality in patients having noncardiac surgery. Anesthesiology. 2015 Jul;123(1):79-91.
34. Veillet-Chowdhury M, Hassan SF, Stergiopoulos K. Takotsubo cardiomyopathy: a review. Acute Card Care. 2014 Mar;16(1):15-22.