Two thirds of ventilated COVID-19 patients require vasopressor support [1]. Recommended
vasopressors include norepinephrine and vasopressin. Recently, based on a randomized
trial [2], angiotensin II (ANGII) was FDA- and EMA-approved for catecholamine-resistant
vasodilatory shock. ANGII use as primary vasopressor for vasodilatory shock has never
been reported, let alone for COVID-19-associated vasodilatory shock. ANGII may be
logical in this setting. It specifically assists patients recently exposed to angiotensin-converting
enzyme inhibitors [2, 3] and increases the internalization and downregulation of angiotensin-converting
enzyme 2 [4], the receptor for COVID-19. Its use may also inform the debate about
the risks and benefits of angiotensin receptor blockers in COVID-19-infected patients
[5]. In this pilot compassionate-use case series, we used ANGII either as primary
or rescue vasopressor in ventilated patients with COVID-19-associated vasodilatory
shock and assessed the course of key physiological variables during the first 48 h
of treatment.
We studied a cohort of consecutive ventilated patients in COVID-19-dedicated ICUs
at San Raffaele Scientific Institute, Milan, Italy. Patients had vasodilatory shock
and COVID-19-related infection (positive viral RNA biospecimen and typical clinical
and radiological features). The Ethics Committee approved compassionate use of the
drug.
All cases received commercial ANGII (Giapreza®, La Jolla San Diego, CA) as continuous
infusion started at 20 ng/kg/min and titrated to a MAP target > 65 mmHg. We collected
key data before and during 48 h of angiotensin II infusion.
Over 6 days (March 12 to March 18, 2020) we treated 16 patients, 10 with ANGII as
first-line agent, five as second-line agent (Table 1), and one patient with unobtainable
data. ANGII dose was relatively constant. MAP and urine output remained stable; lactate
and creatinine increased and C-reactive protein decreased (Table 1). However, the
SpO2/FiO2 ratio increased significantly with a decrease in FiO2 and PEEP (Fig. 1).
At latest follow-up (1 week), 14 patients were alive.
Table 1
Baseline characteristics and physiological changes in treated patients
Baseline(
n
= 15)
After 24 h(
n
= 15)
After 48 h(
n
= 15)
Age, years
64 (54–69)
–
–
Male gender
11 (73.3)
–
–
Angiotensin II as first-line agent
10 (66.7)
–
–
Angiotensin II dose, ng/kg/min
20.0 (5.0–20.0)
20.0 (8.4–20.8)
20.0 (8.1–20.8)
Support and drugs
High dose catecholamine (> 0.25 μg/kg/min)
1 (6.7)
–
–
Receiving catecholamine > 12 h
2 (13.3)
–
–
Prone positioning
5 (41.7)
11 (78.6)
11 (78.6)
Use of tocilizumab
5 (35.7)
–
–
Norepinephrine dose, μg/kg/min
0.10 (0.10–0.20)
0.02 (0.00–0.09)
0.01 (0.00–0.14)
Hours using before
8.5 (1.8–15.8)
–
–
Vital signs at start
Systolic arterial pressure, mmHg
110 (95–115)
110 (105–129)
120 (115–120)
Diastolic arterial pressure, mmHg
60 (52–64)
60 (56–64)
70 (59–70)
Mean arterial pressure, mmHg
71 (65–79)
77 (76–80)
85 (80–87)
Heart rate, bpm
82 (70–92)
72 (68–83)
71 (66–76)
Atrial fibrillation
1 (7.1)
–
–
Cumulative urine output, mL
237.5 (71.2–365.0)
620.0 (385.0–750.0)
727.0 (470.0–1050.0)
Oliguria
3 (30.0)
–
–
Ventilatory support
FiO2
0.70 (0.61–0.70)
0.50 (0.40–0.60)
0.40 (0.36–0.54)
PEEP, cmH2O
14 (12–15)
12 (10–12)
11 (10–14)
SpO2, %
97 (94–99)
98 (96–98)
97 (91–98)
PaO2/FiO2
121.4 (98.1–218.1)
195.2 (148.3–245.0)
200.0 (168.0–248.5)
SpO2/FiO2
140.7 (132.5–150.6)
191.5 (118.4–258.0)
193.8 (142.2–235.9)
Laboratory tests at start
Lactate, mmol/L
1.49 (1.36–1.56)
1.72 (1.58–2.00)
1.83 (1.53–2.15)
Creatinine, mg/dL
1.00 (0.85–1.68)
1.69 (1.16–2.38)
1.69 (1.06–2.43)
C-reactive protein, mg/dL
232.3 (165.4–269.2)
202.0 (148.4–231.1)
115.0 (95.0–190.4)
White blood cell count, × 1000 cells/mm3
11.9 (7.7–13.2)
10.1 (6.2–12.4)
9.2 (7.2–14.2)
Lymphocyte count, × 1000 cells/mm3
5.30 (3.05–16.222)
7.90 (3.70–12.85)
8.30 (5.20–13.50)
Data are median (quartile 25% to quartile 75%) or N (%)
PEEP positive end-expiratory pressure
Fig. 1
Changes in oxygenation parameters in the first 48 h of angiotensin II infusion. Data
are median and quartile 25% to quartile 75%. The changes in the parameters over time
were assessed with a mixed–effect quantile model based on the asymmetric Laplace distribution
(τ = 0.50, a median regression), taking into account repeated measurements and considering
the time of measurements (as a continuous variable) as fixed effect. The p value in
the graphs represents the changes over this time. In all models, only values at and
after the start of the infusion drug were taken into account, and the values before
the start were used only for graphic purpose. All results were confirmed after bootstrapping
with 10,000 replications. All analyses were conducted in R (R Foundation), version
3.6.3
In ventilated patients with COVID-19-associated vasodilatory shock, we assessed the
initial physiological changes associated with ANGII infusion as primary or rescue
vasopressor. Overall, the administration of ANGII was associated with achievement
and maintenance of target MAP, an increase on SpO2/FiO2 ratio, and a decrease in FiO2.
These oxygenation improvements were significant.
This represents the first experience with ANGII in COVID-19-associated vasodilatory
shock and with ANGII as primary vasopressor in humans. The findings are consistent
with those of a previous trial and subsequent subgroup [2] and ANG I/II ratio-related
analyses [3]. They suggest the absence of early physiologically harm and improved
oxygenation with ANG II.
The key limitations of this study are obvious. It is single-center, small, observational
in nature; lacks a control population; and is open-label. However, in this pandemic
setting, the ethics of ensuring compassionate drug use to all patients were considered
a priority. Moreover, before considering controlled trials, evidence of some physiological
safety was considered important. Finally, under the extraordinary pressures of the
most dramatic health disaster in Italy’s history in a century, this study was the
best possible under the circumstances.
In conclusion, we provide the first observational cohort study of ANGII infusion in
ventilated patients with COVID-19-associated vasodilatory shock. Our findings provide
preliminary evidence to assist clinicians in their choice of vasopressors and justify
and help design future controlled studies.