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

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

Disclosures

Crit Care. 2018;22(52) 

In This Article

The Future

Selepressin, an Improved Vasopressin Receptor Agonist?

Since vasopressin comparably stimulates all vasopressin receptor subtypes (i.e., V1a, V1b, and V2 receptors), it may also have serious undesirable side effects through V2 stimulation (fluid accumulation, microvascular thrombosis, vasodilation).[44] Selepressin, a short-acting selective V1a receptor agonist, may overcome these disadvantages.[45] Furthermore, selepressin does not induce release of the procoagulant Willebrand factor.[46] In a study by Maybauer et al.[47] describing the effects of selepressin in an ovine model of severe sepsis, the effects of V1a and V2 receptor activation were compared using selective V1a (selepressin) and V2 (desmopressin) receptor agonists. Accumulation of fluid was blunted by arginine vasopressin while reversed by selepressin. When selepressin was combined with desmopressin, fluid accumulation was restored to levels similar to the sepsis + vasopressin group. These findings were also confirmed by He et al.,[48] who found that early administration of selepressin as first line vasopressor treatment improved MAP, cardiac index, blood lactate levels, lung edema, and fluid balance and was associated with higher survival rates compared to vasopressin and norepinephrine. In light of the above, several completed or currently ongoing clinical trials are investigating the clinical implications of selepressin. The preliminary results of two phase II trials (NCT01612676 and NCT01000649) showed that selepressin enabled the dose requirements of norepinephrine to be reduced. In addition, incremental doses of selepressin were found to reduce overall excessive fluid balance and were associated with higher rates of ventilator-free days, shock resolution, and patient survival within the first 7 days.[49] Accordingly, an ongoing double-blinded phase IIB/III, randomized clinical trial (NCT02508649) is studying the effects of selepressin compared to placebo on ventilator and vasopressor-free days.

Angiotensin II

Activation of the renin–angiotensin–aldosterone system leads to angiotensin II production.[50] Angiotensin II acts by binding to specific GPCRs, namely AT1 and AT2.[51] The main hemodynamic effects mediated by AT1 receptor activation include vasoconstriction, aldosterone secretion, vasopressin release, and cardiac remodeling.[52] In the ATHOS-3 study, patients with vasodilatory shock who were receiving more than 0.2 μg.kg−1.min−1 of norepinephrine or the equivalent dose of another vasopressor were assigned to receive infusions of either angiotensin II or placebo.[53] The primary end point was MAP response at 3 h after initiation of infusion, with response defined as an increase from baseline of at least 10 mmHg or an increase to at least 75 mmHg, without an increase in dose of background vasopressors. The primary endpoint was reached by more patients in the angiotensin II group than in the placebo group (p < 0.001). At 48 h, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score was greater in the angiotensin II group than in the placebo group (p = 0.01). Serious adverse events were reported in 60.7 % of the patients in the angiotensin II group and in 67.1 % in the placebo group. Death by day 28 occurred in 75/163 patients (46 %) in the angiotensin II group and in 85/158 patients (54 %) in the placebo group (p = 0.12).

Methylene Blue

Inhibition of excessive production and activity of both NO and cGMP may be critical in the treatment of refractory vasodilatory shock occurring in cardiac bypass, septic shock, poisoning, and anaphylaxis patients. Methylene blue (MB) has several actions that may counteract the effect of increased NOS stimulation. First, it may antagonize endothelial NOS activity. Furthermore, it may scavenge NO directly and inhibit guanylate cyclase activity.[54] Experimental animal studies report that, in addition to a reduction in vasopressor requirements, inotropic support is reduced after the administration of MB, likely due to attenuation of ischemia/reperfusion injury.[55] In a human septic shock study, MAP and cardiac index were both found to be increased.[56] A systematic review of the literature regarding the use of MB in sepsis by Kwok and Howes[57] concluded that, while the studies were mostly observational, MB increased systemic vascular resistances and MAP; however, its effects on oxygen delivery and mortality are unknown. Moreover, all of the aforementioned studies are relatively old and likely do not take into account current recommendations.

The use of MB has been proposed not only for septic shock but also for treating vasoplegia after cardiac surgery, drug poisoning, anaphylactic shock, and post-reperfusion syndrome after liver transplantation.[54] Similar to septic shock, however, data are currently insufficient to propose MB as a first line agent.[58]

The potential dangers of treatments targeting iNOS overexpression in septic shock should nonetheless be kept in mind. For example, non-selective iNOS blockers, while improving systemic vascular resistance and MAP, also reduce cardiac output and increase mortality in patients with septic shock.[59] Similarly, non-selective iNOS inhibition with tilarginine versus placebo in cardiogenic shock patients failed to reduce the mortality rate at 30 days.[60] Interestingly, there was also no difference in hemodynamic outcomes such as duration of shock. This negative result may be the consequence of the inhibition of other beneficial NO isoforms.[61]

Despite these limitations, the place of MB in vasoplegia treatment is currently being evaluated in a number of ongoing studies (NCT03038503, NCT01797978, NCT03120637).

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