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).