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01.12.2018 | Letter | Ausgabe 1/2018 Open Access

Critical Care 1/2018

Angiotensin in ECMO patients with refractory shock

Zeitschrift:
Critical Care > Ausgabe 1/2018
Autoren:
Marlies Ostermann, David W. Boldt, Michael D. Harper, George W. Lim, Kyle Gunnerson
Wichtige Hinweise
A comment to this article is available online at https://​doi.​org/​10.​1186/​s13054-019-2337-5.
Abbreviations
ACE
Angiotensin converting enzyme
Ang I
Angiotensin I
Ang II
Angiotensin II
ATHOS
Angiotensin II for the Treatment of Vasodilatory Shock
ECMO
Extracorporeal membrane oxygenation
Refractory vasodilation and catecholamine resistance are common in septic shock. Changes in receptor signaling, excessive production of nitric oxide, and absolute or relative deficiencies of vasoactive hormones, including cortisol, vasopressin, and angiotensin II, play a role. Angiotensin II (Ang II) was previously available as a vasopressor but removed from the market in the 1990s. Interest was re-ignited following the Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) study, a randomized controlled trial in patients with refractory shock which confirmed that Ang II was effective at maintaining mean arterial pressure and reducing norepinephrine requirements without an increase in side effects [ 1]. Patients receiving renal replacement therapy also had improved survival and faster recovery of renal function [ 2]. Recent literature noted the potential role of Ang II in other types of shock [ 3].
The major physiological effects of Ang II relate to maintenance of hemodynamic stability and fluid and electrolyte regulation (Table  1). Angiotensinogen, the precursor of angiotensin, is produced primarily by the liver and released into the systemic circulation where it is converted to angiotensin I (Ang I). Ang I is cleaved into Ang II, predominantly by angiotensin converting enzyme (ACE), an endothelium bound protein that is primarily expressed in the pulmonary and renal capillary beds. In patients with acute respiratory distress syndrome, ACE insufficiency has been reported [ 4]. In veno-arterial ECMO, a proportion of blood bypasses the lungs, which further limits the conversion of Ang I to Ang II. Other conditions associated with reduced Ang II levels include Gram-negative sepsis where endotoxinemia can deactivate ACE. Importantly, low levels of Ang II and ACE are associated with increased mortality [ 5].
Table 1
Main physiological effects of angiotensin II
Organ system
Physiological effects
Vascular
● Vasoconstriction of venous and arterial vessels
● Increased vascular permeability
Renal
● Stimulation of Na reabsorption and H + excretion in the proximal tubule via Na +/H + exchanger
● Stimulation of the release of aldosterone
● Variable effects on glomerular filtration and renal blood flow depending on the physiological and pharmacological setting:
➢ constriction of the afferent and efferent glomerular arterioles with greater effect on the efferent vessel
➢ constriction of the glomerular mesangium
➢ enhanced sensitivity to tubulo-glomerular feedback
➢ increased local release of prostaglandins which antagonize renal vasoconstriction
Endocrine
● Stimulation of the secretion of vasopressin from the posterior pituitary gland
● Secretion of ACTH
● Enhanced release of noradrenaline from postganglionic sympathetic fibers
Nervous
● Enhancement of noradrenaline secretion
Cardiac
● Mediation of cardiac remodeling through activated tissue RAS in cardiac myocytes
Coagulation
● Prothrombotic potential
Immune
● Promotion of cell growth and inflammation
● Increased expression of endothelium-derived adhesion molecules
● Synthesis of pro-inflammatory cytokines and chemokines
● Generation of reactive oxygen species
Abbreviations: ACTH adrenocorticotropin hormone, Ang II angiotensin II, GFR glomerular filtration rate, RAS renin-angiotensin system
We report the successful management of seven patients (four male; mean age 36 years) with severe cardiorespiratory failure and refractory shock treated with extracorporeal membrane oxygenation (ECMO) who received Ang II in the context of the ATHOS-3 trial [ 1] or a compassionate use program (Table  2). Following initiation of Ang II, a profound effect on blood pressure was seen and the doses of vasopressors were reduced quickly. Time to cessation of vasopressors and catecholamines ranged from 16 h to 8 days. Six patients were discharged home alive.
Table 2
Patient characteristics
 
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Age (years)
23
26
41
48
38
50
37
Gender
M
M
F
F
M
F
M
Primary acute illness
Influenza A infection
Sepsis
Influenza B and MRSA pneumonia
Sepsis post acute MI
Aspiration pneumonia
Pulmonary embolism
Type A aortic dissection
Secondary acute illness
Cardiac arrest due to pericardial effusion
Cardiac arrest
Sepsis and cardiogenic shock
 
Drug overdose (calcium channel blocker and beta blocker)
Multi-organ failure
Poly-microbial sepsis
Confounding factors
None
Idiopathic dysautonomy and mast cell activation syndrome
Obesity
HIV positive
Obesity
Recent craniotomy for meningioma
Large RV and LV infarct
Type of ECMO
VA ECMO
VA ECMO
VA ECMO
VV ECMO
VV ECMO
VA ECMO
VA ECMO
Vasopressor support *pre-Ang II administration
Norepinephrine 0.4
Vasopressin 4
Epinephrine 0.07
Norepinephrine 1
Vasopressin 6
Epinephrine 0.3
Epinephrine 0.18
Vasopressin 2
Norepinephrine 0.59
Norepinephrine 1.36
Vasopressin 2.4
Norepinephrine 0.2
Vasopressin 5
Milrinone 0.25
Epinephrine 0.05
Norepinephrine 0.1
Vasopressin 4
Epinephrine 0.02
MAP at initiation of Ang II [mmHg]
Missing
57
76
70
63
59
59
Dose of Ang II [ng/kg/min]
Missing
Missing
20
20
40
20
20
Duration of Ang II
   
7 days
46 h
50 h
27.5 h
80 h
Time to cessation of all vasopressors after initiation of Ang II
Missing
48 h
Missing
16 h
6 days
8 days
NA
Adverse events during Ang II infusion
None
None
Reversible digital ischemia
None
None
None
Bowel ischemia
Patient outcome
Survival
Survival
Survival
Survival
Survival
Survival
Deceased
Duration on ECMO [days]
17
5
119
4
9
9
14
Length of stay in ICU [days]
176
30
128
21
22
13
14
Abbreviations: Ang II angiotensin II, ECMO extracorporeal membrane oxygenation, ICU intensive care unit, LV left ventricle, MAP mean arterial pressure, MRSA methicillin-resistant staphylococcus aureus, RV right ventricle, VA veno-arterial, VV veno-venous
*Units of drugs: norepinephrine in μg/kg/min; epinephrine in μg/kg/min; vasopressin in units/h; milrinone in μg/kg/min
In conclusion, in patients with severe cardio-respiratory failure requiring ECMO, treatment with Ang II in addition to standard supportive care enabled rapid decatecholaminization. Underlying ACE deficiency may be a contributing factor. Further studies are necessary to confirm the findings.

Acknowledgements

The authors would like to thank the patients for allowing the publication of their anonymized data and contributing to the dissemination of information. We are also grateful to the research nurses and coordinators who helped with the successful conduct of the ATHOS -3 study.

Funding

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The case series includes patients who participated in the ATHOS-3 study or received angiotensin II in the context of a compassionate treatment program. The ATHOS-3 study was fully approved by an independent research ethics committee.

Consent for publication

As part of the ATHOS-3 study, patients gave consent for their data and results to be published in an anonymized format.

Competing interests

The authors declare that they have no competing interests.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
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