Skip to content

Advertisement

  • Letter
  • Open Access

Angiotensin in ECMO patients with refractory shock

Critical Care201822:288

https://doi.org/10.1186/s13054-018-2225-4

  • Received: 29 September 2018
  • Accepted: 10 October 2018
  • Published:

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.

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

Declarations

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.

Authors’ contributions

MO wrote the first draft of the paper and DWB, MDH, and KG revised the draft. GWL is a clinical fellow who helped with data collection. All authors reviewed the drafts, provided input, and approved the final version.

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.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Authors’ Affiliations

(1)
Department of Critical Care, King’s College London, Guy’s & St Thomas’ Foundation Hospital, London, SE1 7EH, UK
(2)
Department of Anesthesiology and Critical Care Medicine, UCLA Healthcare System, West Los Angeles, USA
(3)
Integris Baptist Medical Center, Nazih Zuhdi Transplant Institute, Oklahoma City, USA
(4)
Departments of Emergency Medicine, Anesthesiology and Internal Medicine, Michigan Center for Integrative Research in Critical Care, University of Michigan, Ann Arbor, MI, USA

References

  1. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–30.View ArticleGoogle Scholar
  2. Tumlin JA, Murugan R, Deane AM, et al. Outcome in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II. Crit Care Med. 2018;46(6):949–57.View ArticleGoogle Scholar
  3. Busse LW, McCurdy MT, Ali O, Hall A, Chen H, Ostermann M. The effect of angiotensin II on blood pressure in patients with circulatory shock: a structured review of the literature. Crit Care. 2017;21(1):324.View ArticleGoogle Scholar
  4. Orfanos SE, Armaganidis A, Glynos C, et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury. Circulation. 2000;102(16):2011–8.View ArticleGoogle Scholar
  5. Zhang W, Chen X, Huang L, et al. Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med. 2014;7(5):1342–8.View ArticleGoogle Scholar

Copyright

© The Author(s). 2018

Advertisement