Introduction
Shock is characterized by the failure of circulation to deliver adequate oxygen and nutrients to the tissues. Pharmacological support is often required to stabilize the hemodynamic status; a wide array of agents is employed by clinicians in this scenario. Although controlled trials have compared agents used for hemodynamic support, there is no robust evidence favoring a specific agent in heterogeneous situations often encountered in clinical practice.
In 1953, Livesay and Chapman from the Baylor College of Medicine, Houston, first reported on the efficacy of norepinephrine in patients with “acute hypotensive states”. They administered norepinephrine as an intravenous infusion in 22 patients with circulatory shock of varying etiology, including myocardial infarction, pulmonary emboli, massive hemorrhage, and barbiturate intoxication. Norepinephrine could sustain blood pressure in all but two of these patients. Seven patients survived, seemingly from the verge of death, with norepinephrine being the ostensible lifesaver (1). This seminal study proved to be the stepping stone for detailed investigation and the widespread use of norepinephrine among shocked patients.
Mechanism of action of vasopressors
Vasopressors are natural hormones or their derivatives that regulate blood pressure by binding to specific receptors. They activate intracellular signaling systems through receptor-specific effects.
Alpha-1 Receptor
Alpha-1 receptor stimulation leads to the activation of phospholipase C and the formation of inositol triphosphate and diacylglycerol. The intracellular calcium level rises, leading to vasoconstriction.
Alpha-2 Receptor
Alpha-2 receptor stimulation causes the inactivation of adenylate cyclase with resultant decrease in the intracellular cyclic adenosine monophosphate. The effects include reduced sympathetic outflow and feedback inhibition of norepinephrine.
Beta-1 Receptor
Stimulation of beta-1 receptors activates adenylate cyclase with an increase in the intracellular cAMP levels. Effects include increased heart rate, myocardial contractility, and conduction velocity.
Beta-2 Receptor
Beta-2 receptor stimulation also results in the activation of adenylate cyclase and an increase in the intracellular cAMP, mediating vasodilatation.
Which vasopressor to choose: the evidence
Several landmark trials have evaluated the use of vasopressors in patients with circulatory shock in the recent past (Table 1). Although they do not provide us with definitive answers regarding the optimal vasopressor in specific clinical situations, head-to-head comparisons do offer guidance on the relative impact on clinical outcomes, and possible adverse effects. Besides, they have rebutted many tradition-borne misconceptions, including the renal-protective effect of dopamine.
Table 1. Pivotal studies that have evaluated the efficacy of vasopressors in shock
| Study/year | Population | Group 1 | Group 2 | Outcomes |
| De Backer et al.7(SOAP II, 2010) | Patients on vasopressor for shock | Dopamine as first-line vasopressor | Norepinephrine as first-line vasopressor | 28-d mortality similar. More arrhythmias with dopamine. Higher mortality with dopamine in cardiogenic shock |
| Annane et al.8 (2007) | Septic shock | Norepinephrine combined with dobutamine | Epinephrine | No difference in the 28-d, ICU, and hospital mortality. Similar duration of vasopressor support; similar rates of improvement in SOFA scores |
| Myburgh et al. (2008)9 | Vasopressor requirement for any cause | Epinephrine | Norepinephrine | No difference in the time to achieve MAP target. Higher heart rate and lactate levels with epinephrine, only in the first 4 h. No difference in the 28- or 90-d mortality |
| Russel et al.10 (VASST, 2008) | Septic shock, on norepinephrine ≥5mcg/min | Vasopressin | Norepinephrine | No difference in the 28- or 90-d mortality. Lower 28-d mortality with vasopressin in the pre-defined subgroup of less severe septic shock |
| Gordon et al.12 (VANISH, 2016) | Septic shock, requiring vasopressors despite fluid resuscitation | 2 × trial; four groups with norepinephrine or vasopressin alone or in combination with hydrocortisone | No difference in the incidence of renal failure (AKIN 3) between groups. No difference in the 28-d, ICU, and hospital mortality. Duration of mechanical ventilation, ICU and hospital length of stay, similar | |
| Khanna et al.15 (ATHOS 3, 2017) | Vasodilatory shock, refractory to conventional vasopressors | Angiotensin II | Placebo | Increase in MAP by ≥10 mm Hg of baseline or ≥75 mm Hg achieved by more patients on angiotensin II. Greater improvement in the cardiovascular SOFA at 48 h with angiotensin II. 28-d mortality similar |
Norepinephrine vs. dopamine
Considering the multifactorial origin of circulatory shock, what does the available evidence suggest regarding the optimal vasopressor? Recommended by many guidelines and favored by most clinicians, norepinephrine is by far the most commonly used agent. A survey was conducted among 839 physicians from 82 countries to evaluate their preferred vasopressor in patients with septic shock. The overwhelming majority of physicians (97%) preferred norepinephrine as the agent of choice (2). The Surviving Sepsis Guidelines also recommend norepinephrine as the first-line vasopressor in septic shock (3).
Although more popular among clinicians from a bygone era, dopamine is still widely used for circulatory support, especially during the early phase of shock. It is traditionally considered safe for peripheral venous administration compared to other vasopressors, although there is no suggestion that it may be any safer than norepinephrine by this route. Besides, dopamine, by virtue of dopaminergic receptor stimulation, is considered to increase splanchnic and renal perfusion and reduce fluid accumulation in the lung (4). The purported “renal protective” effect of dopamine was refuted more than two decades ago by the ANZICS low-dose dopamine trial (5). What is the evidence from more recent trials that compare clinical outcomes between dopamine and norepinephrine in patients with circulatory shock?
The efficacy of dopamine as a vasopressor was evaluated in the SOAP study. In this multicenter observational study, dopamine administration was associated with significantly higher ICU and hospital mortality. On multivariate analysis, dopamine remained one of the independent risk factors for ICU mortality among patients with shock (6).
Against this background, the SOAP II randomized controlled trial (RCT) compared dopamine with norepinephrine as the first-line vasopressor in patients with shock (7). Shock was defined as persisting hypotension with a mean arterial pressure (MAP) <70 mm Hg or systolic pressure <100 mm Hg despite adequate fluid resuscitation with signs of tissue hypoperfusion. In this blinded trial, a total of 1679 patients were included, with 858 randomized to receive dopamine and 821 to norepinephrine. Open-label norepinephrine, epinephrine, or vasopressin could be commenced if the blood pressure could not be maintained with 20 mcg/kg/h of dopamine, or 0.19 mcg/kg/min of norepinephrine. Mortality at 28 days, the primary outcome, was not significantly different between the dopamine and norepinephrine groups (52.5% vs. 48.5%, p = 0.10). There was no difference between groups in the number of days without organ support. Death due to refractory shock was more common in dopamine-treated patients. Besides, the incidence of cardiac arrhythmias, especially atrial fibrillation, was significantly greater with dopamine compared to norepinephrine. Contrary to conventional wisdom, on subgroup analysis, the use of dopamine was associated with significantly higher 28-d mortality among patients with cardiogenic shock. This RCT clearly established that the putative beneficial effect of dopamine on dopaminergic receptors does not translate to improved clinical outcomes; indeed, mortality was higher among patients with cardiogenic shock treated with dopamine compared to norepinephrine.
Norepinephrine-dobutamine combination to fine-tune the circulation
How does the judicious titration of the vasoconstrictor effect of norepinephrine and the cardiogenic effects of dobutamine in combination compare with epinephrine alone in patients with septic shock? These two strategies were compared in a double-blind RCT among 330 patients with septic shock across 19 ICUs in France (8). The increase in blood pressure occurred at a similar rate among both groups of patients. There was no difference in the 28-d mortality between groups. ICU and hospital mortality were also similar between the two groups. The arterial pH levels were significantly lower and the lactate levels higher among epinephrine-treated patients compared to those who received the dobutamine-norepinephrine combination. This RCT suggested that there is no likely advantage with the use of a combination of norepinephrine and dobutamine compared with epinephrine alone in patients with septic shock.
Epinephrine vs. norepinephrine
How does epinephrine compare with norepinephrine in patients with septic shock?
The CAT study investigators compared epinephrine with norepinephrine among patients requiring vasopressor support for any cause across four ICUs in Australia (9). Blinded infusions of either drug were administered to maintain a MAP ≥70 mm Hg. A total of 280 patients were randomized, 140 to each arm. The median time to achieve the target MAP, the primary outcome, was similar between patients treated with epinephrine compared with norepinephrine (35.1 vs. 40 h; p = 0.26). The time to target MAP was similar in subgroups of patients with sepsis and other causes of acute circulatory failure. A significant increase in heart rate and lactate levels was observed during the first 4 h of commencement of therapy with epinephrine; there was no difference between the two groups after this period. More patients were withdrawn from the epinephrine group by the treating physician (12.9% vs. 2.8%); high lactate levels and tachycardia were the most common reasons attributed to withdrawal. No significant difference was observed in the 28 or 90-day mortality between the two groups.
Considering its association with worse clinical outcomes in observational studies, epinephrine was compared with other agents in patients requiring hemodynamic support in a meta-analysis (10). Among the twelve RCTs included, the most common use was in septic shock, and the most common comparator was a combination of norepinephrine and dobutamine. There was no difference in mortality at the longest duration of follow-up between epinephrine compared with other vasoactive agents. The incidence of myocardial ischemia and the requirement for renal replacement therapy were also comparable. A trend towards a more rapid heart rate and ventricular arrhythmias was observed with the use of epinephrine although the difference was not statistically significant.
Vasopressin
The VASST trial evaluated the use of vasopressin in combination with norepinephrine compared to norepinephrine alone in patients with septic shock (11). No difference was observed between the two groups in the 28- and 90-d mortality. Besides, there was no difference in the number of days alive without organ dysfunction and the requirement for renal replacement therapy. A trend towards improved renal function in vasopressin-treated patients with septic shock was noted in other studies (12,13). Against this background, the VANISH multicenter RCT was conducted to specifically evaluate a likely beneficial impact of the early use of vasopressin on renal function in patients with septic shock (13). In this 2×2 factorial trial, patients with septic shock, requiring vasopressor support were enrolled within 6 hours of shock onset. The four study groups included patients with norepinephrine and vasopressin alone or in combination with hydrocortisone. There was no difference in the incidence in the incidence of renal failure (AKIN stage 3) between groups. This study did not demonstrate any beneficial effect on renal function with early vasopressin compared to norepinephrine support among patients with septic shock
Vasopressin may be associated with a lower incidence of atrial fibrillation compared with norepinephrine. The incidence of atrial fibrillation was lower with vasopressin compared with norepinephrine in patients with vasoplegic syndrome and hypotension following cardiac surgery (14). An individual patient meta-analysis of patients in septic shock that compared vasopressin with any comparator vasoactive agent echoed these findings. Although there was no difference in the 28-d mortality with vasopressin compared to other vasoactive drugs, the authors noted a significantly lower incidence of arrhythmias with vasopressin (15). These studies suggest that vasopressin use may be associated with a lower incidence of cardiac arrhythmias, particularly atrial fibrillation. However, these findings remain hypothesis-generating and need further evaluation.
Angiotensin II
Pharmacological support of the circulation shock has revolved around different types of catecholamines and vasopressin. Under physiological conditions, a drop in blood pressure leads to the release of renin by the juxtaglomerular cells in the kidney; two amino acids are split from renin to form angiotensin I. Angiotensin I is converted to angiotensin II, a potent vasoconstrictor, by the angiotensin-converting enzyme, resulting in an increase in blood pressure.
The ATHOS-3 trial aimed to evaluate whether adjuvant angiotensin II administration would increase blood pressure in patients with vasodilatory shock, refractory to conventional doses of vasopressors (16). Patients on >0.2 mcg/kg/min of norepinephrine or an equivalent dose of other vasopressors were randomized to receive angiotensin II or placebo. Angiotensin II was commenced at 20 ng/kg/min per minute and titrated over 3 hours to achieve a target MAP ≥75 mm Hg, with the dose of other vasopressors maintained at a constant dose. The primary endpoint of an increase in the MAP of ≥10 mm Hg from baseline or to ≥75 mm Hg, was achieved by more patients in the angiotensin II group compared to placebo (69.9% vs. 23.4%; p<0.001). Furthermore, angiotensin II also resulted in a greater improvement in the cardiovascular SOFA score at 48 hours. Serious adverse events were similar between the two groups of patients; digital, myocardial and gut ischemia, and arrhythmias were of concern with angiotensin II. The 28-d mortality was similar between the two groups.
In a subsequent retrospective study of patients in shock, 67% of patients responded to angiotensin II administration with an increase in the MAP and reduced dose of other vasopressors. A favorable hemodynamic response was observed more often with lower serum lactate levels and concomitant use of vasopressin. On adjusted analysis, response to angiotensin II was associated with a lower likelihood of 30-d mortality (17).
Based on the current level of evidence, angiotensin II may be a therapeutic option in patients with vasodilatory shock refractory to conventional vasopressors. Although it has been shown to increase blood pressure, no large RCT has yet been carried out to evaluate clinical outcomes compared to conventional vasopressors, including norepinephrine. The safety and efficacy of angiotensin II in patients with burns, myocardial ischemia, and liver dysfunction remain unknown. Besides, the question of whether it should be used in combination with conventional vasopressors or as the sole agent also remains unanswered.
Other agents
The effects of vasopressin are mediated through three types of receptors; AVPR1a receptor stimulation leads to vasoconstriction, AVPR1b stimulation results in ACTH release, and AVPR2 receptors mediate the antidiuretic effect. Selective stimulation of AVPR1a receptors may reduce capillary permeability in septic shock with less fluid accumulation in the lungs in an animal model (18). However, in the SEPSIS-ACT trial, selepressin, a novel, selective AVPR1a receptor agonist, did not reveal any difference in the ventilator-free or vasopressor-free days among patients with septic shock (19).
Methylene blue antagonizes nitric oxide-mediated vasodilatation by the inhibition of guanylate cyclase activation. This property has spurred its use in vasoplegic shock following cardiopulmonary bypass, resulting in a catecholamine-sparing effect (20). However, no RCTs have been conducted to test its efficacy in septic shock (21).
Summary
Vasodilatory shock usually requires support with vasopressor agents in addition to intravenous fluid resuscitation. Norepinephrine is currently favored by most guidelines and commonly used as the preferred agent by most clinicians. However, there is a lack of robust evidence regarding its superiority compared to other vasopressors. Epinephrine may also offer effective circulatory support, with no significant difference in clinical outcomes. However, tachycardia may be a concern; besides, lactate levels may rise during the early phase of resuscitation, and may obfuscate the clinical picture. Combining dobutamine with norepinephrine may not be routinely required to balance the cardiogenic and vasoconstrictive effects of these agents. Although dopamine is commonly used for its purported salutary effect on the kidneys, no renal-protective effect has been demonstrated in large RCTs. Besides, dopamine use in cardiogenic shock has been associated with increased mortality compared with other vasopressors. A trend towards improved clinical outcomes was observed with vasopressin compared to norepinephrine in less severe septic shock in the VASST trial; however, this effect remains unconfirmed. Specifically, vasopressin use has not been associated with improved renal function. Angiotensin II improves blood pressure in vasodilatory shock refractory to conventional vasopressors; however, the impact on clinical outcomes needs further investigation.
References
1. Livesay WR, Chapman DW. The treatment of acute hypotensive states with 1-norepinephrine. Am J Med Sci. 1953 Feb;225(2):159–71.
2. Scheeren TWL, Bakker J, De Backer D, Annane D, Asfar P, Boerma EC, et al. Current use of vasopressors in septic shock. Ann Intensive Care. 2019 Jan 30;9(1):20.
3. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021 Nov;47(11):1181–247.
4. Bertorello AM, Sznajder JI. The dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks. Am J Respir Cell Mol Biol. 2005 Nov;33(5):432–7.
5. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet Lond Engl. 2000 Dec 23;356(9248):2139–43.
6. Sakr Y, Reinhart K, Vincent JL, Sprung CL, Moreno R, Ranieri VM, 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;34(3):589–97.
7. Daniel DB, Patrick B, Jacques D, Christian M, Didier C, Cesar A, et al. Comparison of Dopamine and Norepinephrine in the Treatment of Shock. N Engl J Med. 2010;11.
8. Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. The Lancet. 2007 Aug;370(9588):676–84.
9. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J, et al. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2226–34.
10. Belletti A, Nagy A, Sartorelli M, Mucchetti M, Putzu A, Sartini C, et al. Effect of Continuous Epinephrine Infusion on Survival in Critically Ill Patients: A Meta-Analysis of Randomized Trials. Crit Care Med. 2020 Mar;48(3):398–405.
11. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877–87.
12. Lauzier F, Lévy B, Lamarre P, Lesur O. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Intensive Care Med. 2006 Nov;32(11):1782–9.
13. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509–18.
14. Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, Rhodes A, Landoni G, Osawa EA, et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology. 2017 Jan;126(1):85–93.
15. Nagendran M, Russell JA, Walley KR, Brett SJ, Perkins GD, Hajjar L, et al. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019 Jun;45(6):844–55.
16. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419–30.
17. Wieruszewski PM, Wittwer ED, Kashani KB, Brown DR, Butler SO, Clark AM, et al. Angiotensin II Infusion for Shock. Chest. 2021 Feb;159(2):596–605.
18. He X, Su F, Taccone FS, Laporte R, Kjølbye AL, Zhang J, 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.
19. Laterre PF, Berry SM, Blemings A, Carlsen JE, François B, Graves T, et al. Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock. JAMA. 2019 Oct 15;322(15):1476–85.
20. Mehaffey JH, Johnston LE, Hawkins RB, Charles EJ, Yarboro L, Kern JA, et al. Methylene Blue for Vasoplegic Syndrome after Cardiac Surgery: Early Administration Improves Survival. Ann Thorac Surg. 2017 Jul;104(1):36.
21. Russell JA. Vasopressor therapy in critically ill patients with shock. Intensive Care Med. 2019 Nov;45(11):1503–17.
