The use of angiotensin II in distributive shock

The interest in the use of non-catecholamine vasopressors for the treatment of hypotension
and shock has increased in recent years. The use of vasopressin as an adjunctive vasopressor
in shock was reinvigorated by Landry and colleagues 1] and then carefully assessed in the Vasopressin versus Norepinephrine Infusion in
Patients with Septic Shock (VASST) trial 2]. In a large, international, multi-center trial, vasopressin demonstrated a satisfactory
safety profile, but did not show an improvement in survival compared to norepinephrine
2]. In addition to vasopressin, angiotensin II (ATII) has been proposed as a useful
vasopressor for the management of shock 3], 4]. The original studies that assessed ATII for the management of shock were conducted
decades ago 3], 5]. In those trials, ATII was assessed primarily in head-to-head studies compared to
catecholamine vasopressors, and was shown to have comparable vasopressor effect to
norepinephrine 5]. Multiple case reports demonstrated the ability of ATII to work effectively as a
vasopressor and also showed that ATII could be used in combination with catecholamines.
However, ATII has not been subjected to a randomized controlled trial (RCT) and ATII
has not been available at the bedside for at least 15 years. ATII has been used extensively
in physiology, hypertension, cancer, and pregnancy studies in humans and has a good
safety profile.

Recently, we published in Critical Care the first RCT of ATII in patients with distributive shock, and showed that a dose
of ATII of 5–40 ng/kg/min was associated with improved blood pressure that resulted
in significant catecholamine sparing 6]. In that modest-sized study, we noted that 2 of the 10 patients treated with ATII
were exquisitely sensitive to ATII. In these two cases, the subjects receiving physiologic
doses of ATII were hypertensive despite the discontinuation of their norepinephrine.
When ATII was stopped in these two patients, re-initiation of a high dose of norepinephrine
(i.e., 0.3 ?g/kg/min) was immediately required in order to maintain mean arterial
pressure goals. We speculated that the reason for this sensitivity was likely due
to premorbid exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the
development of shock. Our theory was that if the subjects were previously treated
with ACE inhibitors, their ATII Type I receptors would be upregulated, thus making
the patient more sensitive to exogenous ATII infusion. However, after a thorough chart
review and re-review, we could not document an ACE inhibitor exposure. While it is
possible that the ACE inhibitor exposure was present and not documented, there is
an alternative explanation which is related to the nature and distribution of ACE.
Angiotensin I (ATI) is converted efficiently to ATII almost exclusively in the lung
7]. ACE is an ectoenzyme which is distributed primarily on the pulmonary capillary endothelium
8], 9]. As a consequence, diseases that affect the pulmonary capillary endothelium can disrupt
ACE functionality. Acute respiratory distress syndrome (ARDS) is often associated
with significant pulmonary endothelial injury 10]. Patients with more severe ARDS have less capacity to convert angiotensin ATI to
ATII, and this disturbance is inversely correlated to the severity of ARDS 11]. Upon re-review, we found that the two patients in our study who were exquisitely
ATII sensitive had severe ARDS.

Our revised hypothesis is that patients with severe ARDS may have significant pulmonary
endothelial injury, which results in either an absolute or relative insufficiency
of ATII due to loss of pulmonary ACE. Pre-clinical and human case reports demonstrate
that when ATII production is inhibited by ACE inhibition, patients become catecholamine
resistant 12]. Thus, patients with ARDS may be at particular risk for ATII insufficiency, which
would likely exacerbate existing hypotension. In addition, ATII insufficiency can
lead to acute kidney injury due to decreased intra-glomerular pressure. We hypothesize
that some patients with shock and ARDS may be at particular risk for a deleterious
cascade of events related to ATII insufficiency (Fig. 1).

Fig. 1. Proposed cascade of events leading to angiotensin II insufficiency. The figure outlines
a cascade of events that could occur amongst patients with inflammation and/or lung
injury. When acute lung injury is significantly complicated by pulmonary endothelial
injury, ACE activity is diminished 11]. Thus, patients who lose ACE activity may be a risk for angiotensin II insufficiency
and catecholamine resistance 12]. ACE angiotensin-converting enzyme, ARDS acute respiratory distress syndrome, PCE pulmonary capillary endothelium

We would anticipate that, for those patients with ATII insufficiency, increased levels
of ATI and reduced ATII may be indicative of this pathophysiology, and that ATI and
ATII levels, as well as the ratio of ATI/ATII, may be useful as biomarkers of early
ARDS or ARDS severity prior to the development of severe hypoxemia. Moreover, we would
anticipate these patients to be ATII-sensitive. We believe that further research to
test this hypothesis is warranted. Currently, ATII is being studied in a multi-center
international RCT (NCT02338843) wherein some of these parameters will be assessed
and may shed further light on this proposed hypothesis.