Angiotensin II for Refractory Vasodilatory Shock

Kenneth L. Smith, Mercer University College of Pharmacy

Vasodilatory shock is a medical emergency where the organs and tissues undergo a decrease in perfusion which can lead to organ failure and death if not treated immediately.  In this syndrome, a drop in blood pressure can occur despite preserved cardiac output. [1]  When intravenous fluid resuscitation fails to restore blood pressure, few choices are available other than vasopressors such as catecholamines (or other sympathomimetics) in addition to vasopressin.[2] However, these can be toxic at highdoses, and when these options fail, prognosis is considered poor.[3] Angiotensin II is a component of the renin-angiotensin –aldosterone-system (RAAS) which causes the release of anti-diuretic hormone (ADH), also known as vasopressin, from the posterior pituitary.[4] This leads to vaso-constrictive effects that can increase blood pressure. Consequently, use of angiotensin II for vasodilatory shock has been considered to provide a more natural physiological response to treat this serious condition.[5]

 

Angiotensin II for the Treatment of Vasodilatory Shock [5 ]
Design International, randomized, double-blind, placebo-controlled trial
Objective To measure the effectiveness of angiotensin II for the treatment

of patients with vasodilatory shock

Study Groups Angiotensin II (N = 163) and Placebo (n = 158)
Methods A response as, included in the primary endpoint, was defined as a mean arterial pressure of 75 mm Hg or higher or an increase in mean arterial pressure from baseline of at least 10 mm Hg, without an increase in the dose of background vasopressors. Patients had to have vasodilatory shock despite intravenous volume resuscitation. Vasodilatory shock was defined as a cardiac index > 2.3 liters/min●m2 or central venous oxygen saturation of >70% coupled with a central venous pressure of more than eight mmHg with a mean arterial pressure between 55-70 mmHg. Eligible patients in the study had an indwelling bladder catheter and an arterial catheter.
Duration May 2015 through January 2017
Primary Outcome Measure the response with respect to mean arterial pressure at hour three
Baseline Characteristics
Characteristic All Angiotensin II (N = 163) Placebo(N = 158) Patients(N = 321)
Age
Median (IQR) — yr 63 (52–75) 65 (53–75) 64 (52–75)
≥65 yr — no. (%) 73 (44.8) 81 (51.3) 154 (48.0)
≥75 yr — no. (%) 41 (25.2) 42 (26.6) 83 (25.9)
Male sex — no. (%) 92 (56.4) 103 (65.2) 195 (60.7)
Geographic region — no. (%)
United States or Canada 116 (71.2) 120 (75.9) 236 (73.5)
Europe 19 (11.7) 14 (8.9) 33 (10.3)
Australia or New Zealand 28 (17.2) 24 (15.2) 52 (16.2)
BMI ≥30 — no./total no. (%)† 69/161(42.9) 71/155 (45.8) 140/316 (44.3)
Mean arterial pressure
Median (IQR) — mm Hg 66.3 (63.7–69.0) 66.3 (63.0–68.3) 66.3 (63.7–68.7)
<65 mm Hg — no. (%) 52 (31.9) 50 (31.6) 102 (31.8)
APACHE II score‡
Median (IQR) 27 (22–33) 29 (22–34) 28 (22–33)
Distribution — no. (%)
≤30 105 (64.4) 93 (58.9) 198 (61.7)
31–40 (30.7) 54 50 (34.2) 104 (32.4)
≥41 8 (4.9) 11 (7.0) 19 (5.9)
Albumin
Median (IQR) — g/dl 2.2 (1.8–2.7) 2.4 (1.9–2.8) 2.3 (1.8–2.7)
<2.5 g/dl — no./total no. (%) 103/154 (66.9) 89/156 (57.1) 192/310 (61.9)
Scvo2
Median (IQR) — % 76.9 (73.0–82.8) 77.0 (72.5–82.0) 77.0 (72.9–82.2)
Data missing — no. 43 41 84
Central venous pressure
Median (IQR) — mm Hg 13 (10–15) 12 (10–16) 12 (10–15)
Data missing — no. 37 35 72
Cardiac index
Median (IQR) — liters/min/m2 3.0 (2.6–3.8) 3.2 (2.7–3.9) 3.1 (2.6–3.8)
Data missing — no. 94 85 179
Median MELD score (IQR)§ 21 (15–25) 23 (17–26) 22 (16–26)
Cause of shock — no. (%)
Sepsis 127 (77.9) 132 (83.5) 259 (80.7)
Other, potentially sepsis 20 (12.3) 11 (7.0) 31 (9.7)
Pancreatitis 0 2 (1.3) 2 (0.6)
Postoperative vasoplegia 10 (6.1) 9 (5.7) 19 (5.9)
Multifactorial 6 (3.7) 4 (2.5) 10 (3.1)
Exposure to ACE inhibitors — no. (%) 15 (9.2) 15 (9.5) 30 (9.3)
Exposure to ARBs — no. (%) 11 (6.7) 11 (7.0) 22 (6.9)
Results
Endpoint Angiotensin II

(N =163)

Placebo

(N = 158)

Odds or Hazard ratio (95% CI) p Value
Primary efficacy end point: MAP response at

3 h  no (%)

114(69.9) 37(23.4) Odds ratio, 7.95

(4.76-13.3)

<0.001
Secondary efficacy end points
Mean change in cardiovascular  SOFA score at 48h -1.75 +/-1.77 -1.28+/-1.65 0.01
Man change in total SOFA score at 48h 1.05 +/-5.50 1.04+/-5.34 0.49
Additional end points
Mean change in norepinephrine equivalent dose -0.03+/-0.10 0.03+/-0.23 <0.001
All-cause mortality at

day 7

47(29) 55(35) Hazard ratio, 0.78

(0.53-1.16)

0.22
All-cause mortality at

day 28

75(46) 85(54) Hazard ratio, 0.78 (0.57-1.07) 0.12
Adverse Events Common Adverse Events: N/A
Serious Adverse Events (defined as frequency ≥1%):

cardiovascular events (38.3%), metabolism and nutrition disorders (29.9%), infections and infestations (24.6%), vascular disorders (23.1%), Respiratory, thoracic and mediastinal disorders (24.9%), gastrointestinal disorders (21.8%), blood and lymphatic disorders (16.5%), psychiatric disorders (10%)

Percentage that discontinued due to adverse events:
Study Author Conclusions Angiotensin II was demonstrated to effectively increase blood pressure in patients with vasodilatory shock that failed to respond to high doses of conventional vasopressors.

The study was only carried out for 28 days, which may risk the possibility of not addressing long term effects that may be associated with angiotensin II treatment. Another limitation of the study was the small sample size which may have excluded the possibility of other clinical side effects attributable to angiotensin II treatment. A larger study that includes more patients for a longer duration would provide more meaningful information about adverse effects and potential long term side effects due to treatment with this drug.  Due to the positive results in this study, angiotensin II does appear to be a valuable treatment option for vasodilatory shock in patients that are resistant to other vasopressors.

References

[1] Gamper G, Havel C, Arrich J, et al. Vasopressors for hypotensive shock. Cochrane Database Syst Rev.  2016;2:CD003709.

[2] Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228.

[3] Brown SM, Lanspa MJ, Jones JP, et al. Survival after shock requiring high-dose vasopressor therapy. Chest 2013;143:664-71.

[4] Paul M, Poyan mehr A, Kreutz R. Physiology of local renin-angiotensin systems. Physiol Rev. 2006;86(3):747-803.

[5] Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377(5):419-430.

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