Vasoplegia Treatments: The Past, the Present, and the Future

Bruno Levy; Caroline Fritz; Elsa Tahon; Audrey Jacquot; Thomas Auchet; Antoine Kimmoun


Crit Care. 2018;22(52) 

In This Article

Vasoplegia Treatment

The Use of Adrenergic Vasopressors

Vascular hyporeactivity-associated hypotension is clearly associated, both significantly and independently, with mortality.[19] After volume resuscitation, the use of catecholamines is considered to be the cornerstone of septic shock hemodynamic treatment.[20] This therapeutic class includes dopamine, epinephrine, norepinephrine, and phenylephrine. All of these molecules increase MAP by stimulating the α1 adrenergic receptor. Nevertheless, aside from phenylephrine, all of the above catecholamines stimulate other adrenergic receptors, leading to various hemodynamic, metabolic, and inflammatory effects.[21,22] Comparison of the affinity of these different drugs for receptor subtypes as well as the effects associated with receptor stimulation is depicted in Table 1. Hence, the choice of best adrenergic vasopressor should take into account not only its vasopressor effect but also its cardiac, metabolic, microcirculatory, and immune effects.

The Current Recommendations

A recent Cochrane analysis concluded that there was not sufficient evidence to prove that any one vasopressor was superior to others in terms of mortality and that the choice of a specific vasopressor may, therefore, be individualized and left to the discretion of treating physicians.[23] Despite low levels of evidence, the Surviving Sepsis Campaign (SSC) published several recommendations based on the physiological effects of vasopressors and selection of inotrope/vasopressor combinations in septic shock outlined in an extensive number of literature reviews.[20]

Norepinephrine as a First Line-agent

Norepinephrine is a very potent and reliable vasopressor. It increases MAP without any concomitant increase in heart rate. Generally, cardiac index is increased due to both a rise in end-diastolic stroke volume through a mobilization of splanchnic unstressed volume and to a direct effect on cardiac myocytes due to β1 adrenergic receptor stimulation.[24] Norepinephrine has numerous advantages when compared to other vasopressors, including: a) a very potent vasopressor effect equivalent to epinephrine and phenylephrine and higher than dopamine;[25] b) contrary to epinephrine, norepinephrine does not act on β2 adrenergic receptors—hence, lactate levels do not increase and may be used to guide resuscitation;[26] c) contrary to dopamine and epinephrine, norepinephrine increases cardiac index without increasing heart rate and thus without excessively increasing myocardial oxygen consumption;[27] d) contrary to phenylephrine, which acts only on α1 adrenergic receptors, norepinephrine also acts on cardiac β1 adrenergic receptors and may therefore preserve ventricular–arterial coupling.[28]

Finally, adrenergic vasopressors have potential side effects such as increased oxidative stress, interaction with cellular energy metabolism, and/or modulation of the inflammatory response.[22] As a result, a new concept has emerged called "decatecholaminization", which consists in using non-catecholamine vasopressors in order to decrease catecholamine exposure.[29]

Vasopressin as a Second Line Agent or a Catecholamine-sparing Agent

Patients with severe septic shock often require very high doses of norepinephrine in order to achieve the target MAP, thereby potentially leading to adverse side effects.[30] The SSC suggests adding either vasopressin (up to 0.03 U/min; weak recommendation, moderate 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. The rationale for vasopressin use is that there is a relative vasopressin deficiency in septic shock such that addition of exogenous vasopressin restores vascular tone by acting on non-adrenergic receptors, increases blood pressure, thereby reducing norepinephrine requirements, and possibly has favorable effects on cytokine production.[31–33] Globally, vasopressin is as effective as norepinephrine in increasing MAP and, when used in combination with norepinephrine, low vasopressin doses have a norepinephrine-sparing effect. The VASST study, in which vasopressin was used in substitutive doses (< 0.04 U/min), showed no overall improvement in mortality.[34] In a post-hoc analysis, however, patients with less severe septic shock (i.e., < 15 μg.min−1 of norepinephrine) at vasopressin initiation had a lower 28-day mortality rate compared with norepinephrine-only infusion (26.5 vs 35.7 %; p = 0.05). Higher doses of vasopressin have been associated with cardiac, digital, and splanchnic ischemia and should be reserved for situations in which alternative vasopressors have failed.[35] The VANCS trial compared norepinephrine to vasopressin in treating vasoplegia syndrome after cardiac surgery.[36] The primary endpoint was a composite of mortality or severe complications (stroke, requirement for mechanical ventilation for longer than 48 h, deep sternal wound infection, reoperation, or acute renal failure) within 30 days. The primary outcome occurred in 32 % of vasopressin patients compared to 49 % of norepinephrine patients (unadjusted hazard ratio 0.55; 95 % CI 0.38 to 0.80; p = 0.0014). With regard to adverse events, the authors found a lower occurrence of atrial fibrillation in the vasopressin group (63.8 vs 82.1 %; p = 0.0004) and no difference between groups with regard to rates of digital ischemia, mesenteric ischemia, hyponatremia, or myocardial infarction. These results thus suggest that vasopressin can be used as a first-line vasopressor agent in postcardiac surgery vasoplegic shock and improves clinical outcomes. Lastly, the VANISH study, assessing vasopressin versus norepinephrine with or without adding hydrocortisone (factorial 2X2 study) as initial therapy in septic shock, demonstrated no improvement in the number of kidney failure-free days.[37] Addition of hydrocortisone as an adjunct in the two vasopressor groups was used to upregulate receptor expression on VSMCs and to enhance anti-inflammatory effects.

Terlipressin, a long acting vasopressin analog with predominant V1 receptor activity, has also been proposed. When compared to norepinephrine, terlipressin significantly reduced catecholamine requirements, and led to fewer rebound hypotension events, without increasing bilirubin levels.[38] There is still ongoing debate regarding its ideal dose and mode of administration (continuous infusion despite long half-life or intermittent administration). Notwithstanding, terlipressin may result in pulmonary vasoconstriction and affect coagulation systems whereas vasopressin does not.[38] Hence, terlipressin is not considered to offer a greater advantage compared to vasopressin due to its longer half-life and clinical evidence that supports its use in circulatory shock remains scarce.[20] In spite of these caveats, the place of terlipressin is currently being evaluated in two ongoing studies (NCT03038503 and NCT02468063).

Phenylephrine Use Should be Limited

Phenylephrine is a pure α1 adrenergic agonist for which clinical trial data are limited. It has the potential to produce splanchnic vasoconstriction. Moreover, in a model of rat septic shock, phenylephrine use has been associated with a detrimental effect on intrinsic cardiac function.[39] Lastly, among patients with septic shock in US hospitals affected by the 2011 norepinephrine shortage, Vail et al.[40] found that the most commonly administered alternative vasopressor was phenylephrine. Patients admitted to these hospitals during times of shortage had higher in-hospital mortality.

A Critical View of the Recommendations

Two recommendations should be addressed. The first recommendation concerns the use of epinephrine as a second-line agent and the second regards the use of dopamine in highly selected patients. The relevance of using epinephrine in association with norepinephrine should be discussed since a) epinephrine markedly increases lactate levels and may therefore preclude the use of lactate clearance to guide resuscitation,[25] b) norepinephrine and epinephrine both act on α1 adrenergic receptors so there is no therapeutic value in adding the same molecule type when norepinephrine has failed to increase MAP, and c) the combination of norepinephrine and dobutamine, allowing the separate titration of vasopressor and inotropic effects, is more logical than using epinephrine alone. Therefore, we firmly believe that epinephrine has no place in septic shock treatment with the exception of countries with limited resources (it is cheaper than norepinephrine). In these countries, it is acceptable to use epinephrine since no data support a difference in efficacy, mortality, or morbidity.[29,41] With regard to dopamine, there is currently ample evidence that norepinephrine or epinephrine is more efficient in restoring MAP and that both drugs could be used through a peripheral venous access.[42,43] Thus, dopamine should no longer be used in septic shock. Moreover, in a randomized study comparing dopamine and epinephrine in the treatment of shock, a subgroup analysis of 280 patients with cardiogenic shock showed dopamine to be associated with an increase in 28-day mortality compared to norepinephrine.[27]