By Samuel Nadler, MD, PhD

Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle; Clinical Instructor, University of Washington, Seattle

Dr. Nadler reports no financial relationships relevant to this field of study.

SYNOPSIS: Infusion of recombinant angiotensin II improved blood pressure control in patients with vasodilatory shock already receiving conventional vasopressors.

SOURCE: Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-430.

Shock is a common and life-threatening condition often seen in the ICU. Sepsis commonly causes vasodilatory shock and continues to produce a significant mortality, despite improvements in care. The treatment of shock includes fluid resuscitation and vasopressor agents such as norepinephrine, epinephrine, or vasopressin. Some patients require multiple vasopressor agents and still are unable to meet resuscitation goals.

The authors of the ATHOS-3 trial examined a new class of vasopressor agent, angiotensin II (ATII), as add-on therapy to conventional vasopressors. This study of 344 patients ≥ 18 years of age randomized patients with confirmed vasodilatory shock despite fluid resuscitation to receive an infusion of ATII or placebo in addition to conventional vasopressor agents. Vasodilatory shock was defined by cardiac index > 2.3 L/min/m2, central venous O2 saturation > 70% with central venous pressure > 8 mmHg with a mean arterial pressure (MAP) 55-70 mmHg despite vasopressor therapy. During the first three hours of the study, the conventional vasopressor agents were held constant while ATII or placebo could be titrated with a goal MAP > 75 mmHg. Between three and 48 hours, all vasopressor infusions could be titrated with goal MAP 65-75 mmHg. The primary endpoint was MAP > 75 mmHg or an increase in MAP of > 10 mmHg without an increase in baseline vasopressors.

During the first three hours of the study, more patients in the ATII arm achieved MAP > 75 mmHg than in the placebo arm (69.9% vs. 23.4%; P < 0.001). During the 48-hour trial period, patients in the ATII group required less conventional vasopressors than placebo and demonstrated greater improvements in cardiovascular SOFA scores (-1.75 vs. -1.28; P = 0.01), although overall SOFA was unchanged at 48 hours. Patients with hypoalbuminemia were more likely not to respond to ATII therapy. Adverse effects leading to discontinuation of study medications occurred in 14.1% of patients receiving ATII and 21.5% of patients on placebo. All-cause mortality at seven and 28 days was not statistically different between the two groups.

COMMENTARY

ATII is a novel vasopressor agent that works via the renin-angiotensin-aldosterone system. It increases blood pressure via vasoconstriction mediation by G-coupled proteins as well as the stimulation of both antidiuretic hormone and aldosterone secretion. As in previous trials, the ATHOS-3 trial demonstrated that infusion of recombinant ATII increases blood pressure compared with placebo. However, several features of this study deserve attention. First, during the first three hours of the study, only ATII could be titrated, and other vasopressors were continued at their pre-study doses. Thus, the conclusion that ATII improved MAP does not imply that these goals could not have been achieved with conventional vasopressors alone. Second, the primary endpoint was MAP > 75 mmHg or an increase in MAP by at least 10 mmHg. Current guidelines recommend goal MAP > 65 mmHg, and it is unclear what benefit, if any, would be achieved by increasing the MAP beyond 65 mmHg.1 In fact, most patients enrolled in the study started with MAP > 65 mmHg (68.1% and 68.4% in the ATII and placebo groups, respectively). Thus, most patients in this trial did not exhibit an indication for additional vasopressors under current guidelines. Ultimately, the goal of shock treatment is to improve organ perfusion and preserve function. MAP is a surrogate but as with phenylephrine, vasopressors may increase MAP yet decrease perfusion. Indeed, there was no change in total SOFA scores between the two groups. Although underpowered to detect a change in mortality, no statistically significant change was observed.

The ATHOS-3 trial represents an important proof of concept trial regarding ATII as a new vasopressor in the armamentarium to treat vasodilatory shock. Clearly, ATII increases blood pressure in patients. The appropriate indications for ATII still must be established. One might consider the synergistic use of ATII to enable reducing dosing of adrenergic agonists and reduce adverse effects. However, while there were fewer episodes of supraventricular tachycardia in the ATII arm, there were more episodes of ventricular tachycardia and tachycardia overall. The notion of synergism of vasopressin with adrenergic agents is increasingly coming under question. Future well-powered and well-designed trials of ATII are required before further adoption of this agent for the treatment of vasodilatory shock.

REFERENCE

  1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45:486-552.