Cardiology

Efficacy and safety of angiotensin II in cardiogenic shock: A systematic review

a b s t r a c t

Background: Cardiogenic shock (CS) is associated with high morbidity and mortality. In recent times, there is in- creasing interest in the role of angiotensin II in CS. We sought to systematically review the current literature on the use of angiotensin II in CS.

Methods: PubMed, EMBASE, Medline, Web of Science, PubMed Central, and CINAHL databases were systemati- cally searched for studies that evaluated the efficacy of angiotensin II in patients with CS during 01/01/ 2010-07/07/2022. Outcomes of interest included change in mean arterial pressure (MAP), vasoactive medication requirements (percent change in norepinephrine equivalent [NEE] dose), all-cause mortality, and adverse events.

Results: Of the total 2,402 search results, 15 studies comprising 195 patients were included of which 156 (80%) received angiotensin II. Eleven patients (84.6%) in case reports and case series with reported MAP data at hour 12 noted an increase in MAP. Two studies noted a positive hemodynamic response (defined a priori) in eight (88.9%) and five (35.7%) patients. Eight studies reported a reduction in NEE dose at hour 12 after angiotensin II administration and one study noted a 100% reduction in NEE dose. Out of 47 patients with documented informa- tion, 13 patients had adverse outcomes which included Hepatic injury (2), digital ischemia (1), ischemic optic neuropathy (1), ischemic colitis (2), agitated delirium (1), and thrombotic events (2).

Conclusions: In this first systematic review of angiotensin II in CS, we note the early clinical experience. Angioten- sin II was associated with improvements in MAP, decrease in Vasopressor requirements, and minimal reported adverse events.

(C) 2023

  1. Introduction

Cardiogenic shock (CS) is characterized by a state of end-organ hy- poperfusion and dysfunction due to a primary cardiac etiology [1,2]. Ini- tial management typically involves a combination of pharmacological

Abbreviations: CS, Cardiogenic shock; MAP, Mean arterial pressure; MCS, Mechanical circulatory support; NEE, Norepinephrine equivalents.

* Corresponding author at: Section of cardiovascular medicine, Department of Medicine, Wake Forest University School of Medicine, 306 Westwood Avenue, Suite 401, High Point, NC 27262, United States of America.

E-mail address: [email protected] (S. Vallabhajosyula).

1 Drs. Bansal and Mehta contributed equally to this submission as co-first authors.

and Mechanical circulatory support (MCS) with rapid attempts to re- verse the inciting etiology [3,4].

Angiotensin II is an endogenous peptide hormone that causes vaso- constriction and increases blood pressure [3]. Some animal studies have also reported potential inotropic effect of angiotensin II [5]. The use of human-derived synthetic angiotensin II was approved after the ATHOS-3 (Angiotensin II for the Treatment of High Output Shock) trial. This trial excluded CS and demonstrated that the use of angioten- sin II in refractory Vasodilatory shock resulted in significant improve- ments in mean arterial pressure (MAP) with decreased use of other vasopressors [5]. CS, especially secondary to post-cardiac surgery, con- stitutes a unique challenge as it often coexists with vasodilatory shock with limited role for fluid resuscitation [1]. As such, there is an impor- tant need to identify novel therapeutic targets in CS. Given the potential

https://doi.org/10.1016/j.ajem.2023.01.050

0735-6757/(C) 2023

inotropic effect of angiotensin II and the stated benefits in vasodilatory shock, this study sought to summate the existing literature in a system- atic review. The review encompassed all studies in whom patients with cardiogenic shock irrespective of etiology received angiotensin II ther- apy. Our objective was to note if there was a change in norepinephrine equivalents [NEE] and incidence of treatment adverse events after an- giotensin II administration.

  1. Material and methods
    1. Search strategy

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. PubMed, EMBASE, Medline, Web of Science, PubMed Central, and CINAHL databases were systematically searched from January 1st, 2010, to July 7, 2022. Two investigators (MB, AM) performed an inde- pendent literature search using the search terms ‘angiotensin II’, ‘cardio- genic shock’, ‘extracorporeal membrane oxygenation’, ‘all-cause mortality’, ‘efficacy’, ‘safety’, and ‘hemodynamic parameters’ (Appendix 1). Institutional review board approval was not sought because of the use of publicly available data.

    1. Study selection

All English language, observational studies, case reports, case series, and randomized controlled trials that provided data on efficacy of an- giotensin II in CS (irrespective of etiology) were included in this system- atic review. Studies with a primary CS state with superimposed distributive shock (sepsis/vasoplegia) were also included since they constitute a growing population of CS in the cardiac intensive care unit. Studies with animal and Pediatric populations, and abstracts pre- sented at professional societal meetings were excluded. All results were exported to EndNote (Clarivate Analytics), where duplicates were eliminated. Two investigators (MB, AM) independently reviewed and included articles by mutual consensus, and all discrepancies were arbitrated by a third (PMW) and senior (SV) authors.

    1. Data collection

A structured data collection form was used to derive information from each study including author names, Publication year, country, CS etiology, baseline characteristics, hemodynamic parameters, and dose and duration of angiotensin II therapy. The clinical outcome of interest included improvement of MAP, improvement in vasopressor/inotrope requirements (percent change in NEE or other similar scores), all- cause mortality, and adverse events related to the treatment. Each case report in an article was treated as a separate entity. Given the sig- nificant methodological differences and heterogeneity between pub- lished studies, a meta-analysis methodology was not utilized.

  1. Results

A total 2402 studies were identified, of which 15 studies, with a total of 195 patients were included (Supplementary Fig. 1). Angiotensin II was administered to 156 patients. Ten studies were case reports and case series, four retrospective analyses, and one was a post-hoc analysis. All studies were published in the last five years. The primary etiology of CS was post-cardiac surgery vasoplegia (90.3%) (Table 1).

Eleven patients (84.6%) with reported MAP data at hour 12 noted an increase in MAP. The analyses done by Klijian et al. and Mohamed et al. noted a positive hemodynamic response (defined a priori by Klijian et al. as MAP >=75 mmHg or a 10 mmHg increase in MAP at hour three without increase in dose of standard of care vasopressors and by Mohamed et al. as MAP >=65 mmHg or a 10 mmHg increase in MAP with a decrease or no change in total vasopressor dose) in eight (88.9%) and five (35.7%)

patients after angiotensin II administration respectively [1,5]. (Fig. 1A). Eight studies reported a reduction in NEE dose at hour 12 after angio- tensin II administration and one review by Meersch et al. noted 100% re- duction in NEE dose (Fig. 1B) [6]. Other commonly used vasoactive medications included norepinephrine, epinephrine, vasopressin. Milrinone, dobutamine, and dopamine. Six studies reported the use of MCS devices such as the intra-aortic balloon pump, extracorporeal membrane oxygenation, percutaneous and durable ventricular assist devices. Timing of angiotensin-II initiation after weaning from cardio- pulmonary bypass varied between 1 and 13 h. The starting dose of an- giotensin II ranged from 2.5 to 40 ng/kg/min. The minimum duration of angiotensin II administration was five hours and maximum duration was 192 h (Table 2).

Out of 47 patients with documented data, 13 (27.7%) patients devel- oped adverse outcomes such as hepatic injury (2), digital ischemia (1), ischemic optic neuropathy (1), ischemic colitis (2), agitated delirium (1), and thrombotic events (2). Sixty-one (39.1%) patients died during hospitalization.

  1. Discussion

In this systematic review, we summarize the initial experience with the efficacy and safety of angiotensin II in 156 patients with CS, with over 90% secondary to post-cardiac surgery vasoplegia and mixed shock. Angiotensin II therapy allowed for an increase in MAP (~85%) and a decrease in the dosage of other vasoactive drugs. There were lim-

ited side effects in the studies that reported this information.

Over the past decade, there has been increasing recognition of coexisting vasodilatory shock (septic or otherwise) in patients with CS [1]. Different studies noted that mixed vasodilatory-cardiogenic shock was associated with higher illness severity and worse in-hospital out- comes [3,7,8]. The presence of mixed shock is associated with higher va- soactive medication requirements and development of refractory shock [1]. In such circumstances, the increased use of conventional catechol- amine vasopressors like norepinephrine and epinephrine are associated with worse adverse outcomes. In such patients, the use of angiotensin II as an adjunct catecholamine sparing vasopressors reduces the dose of other catecholamine vasopressors [2]. Some animal studies have also demonstrated the inotropic effect of angiotensin II that can further aug- ment its role in patients with mixed shock [5].

In this current review, we report the use, safety, and efficacy of an- giotensin II in CS. The literature thus far, largely focuses on cardiac sur- gery with concomitant vasoplegia [1,3-15]. Though the role of angiotensin II in ‘pure’ CS may be limited, further assessment of its role in mixed shock, either post-cardiotomy vasoplegia or concomitant sepsis in CS, needs careful further evaluation. Standardizing the use of Society of Cardiovascular Angiography and Intervention classification, use of risk prediction models specific to CS and quantification of phar- macological support in CS are the logical next steps prior to evaluating angiotensin II in this population. There is lack of substantial data on use of angiotensin II in patients on MCS. The case series by Mohamed et al. reported an increase in MAP and reduced vasopressor dosage after angiotensin II administration [1]. These findings were corrobo- rated by Ostermann et al. [2] However, only 35.7% patients in the study by Mohamed et al. were able to achieve the hemodynamic re- sponse criteria at hour three as defined in the study. Given the increased incidence of Vasoplegic shock secondary to left ventricular assist device insertion in patients with CS, further studies are needed to explore the use of angiotensin II in this patient subgroup [1].

Our study has certain important limitations. This study is limited by the small sample size of the existing literature. Due to the absence of granular data in the studies we are unable to develop hemodynamic as- sessments at standardized time points. Since most studies included are case series/reports, our review also contains the inherent selection, pub- lication, reporting, and other biases associated with these study designs in a relatively novel field.

Table 1

Study characteristics.

Author

Year

Country

Type of study

Sex (n)

Age in years

Etiology of shock (n)

Mechanical support (n)

Vasoactive medications

Outcome (n)

Bird [6]

Lohius [7]

2022

2022

USA

USA

Retrospective

Retrospective

Males (7)

Males (61)

65.9

(mean) 59.6

PCSV (7)

PCSV (78)

49

Epi

Epi

7-day mortality (1),

30-day mortality (2) In hospital mortality

Mohamed [1]

2022

USA

Retrospective

Females (17)

Total (78)

Males (11)

(mean)

54

PCSV (7), Refractory

VA-ECMO (6),VV- ECMO (4), IABP

(44)

In hospital mortality

Klijian [5]

2021

M

Post hoc

Females (3)

Total (14)

Males (8)

(median)

distributive shock (7)

PCSV (9)

(4), Impella (4), LVAD (3), RVAD (2)

Mil, Dob

(11)

In hospital mortality

analysis

Female (1)

(1)

Konkol [8]

2021

USA

Case report

Total (9)

Male (1)

86

PCSV (1)

Epi

Discharged (1)

Konkol [8]

2021

USA

Case report

Male (1)

75

PCSV (1)

Epi

Died (1)

Konkol [8]

2021

USA

Case report

Male (1)

71

PCSV (1)

Epi

Died (1)

Konkol [8]

2021

USA

Case report

Male (1)

67

PCSV (1)

Epi

Discharged (1)

Konkol [8]

2021

USA

Case report

Male (1)

61

PCSV (1)

Epi

Died (1)

Konkol [8]

2021

USA

Case report

Male (1)

58

PCSV (1)

Epi

Discharged (1)

Meersch [9]

Sovic [10]

2021

2021

Germany

USA

Retrospective

Case report

Males (15)

Females (5)

Total (20)

Male (1)

71.5

(mean)

59

PCSV (1)

PCSV (1)

VA-ECMO

Epi

Discharged (1)

Sovic [10]

2021

USA

Case report

Male (1)

45

PCSV (1)

LVAD

Discharged (1)

Chatterjee [11]

Cutler [3]

2020

2020

USA

USA

Case report

Case report

Male (1)

Male (1)

61

70

PCSV (1)

PCSV (1)

Epi, Dop

Epi

Discharged on POD 18 (1)

Discharged on POD

Cutler [4]

2020

USA

Case report

Male (1)

62

PCSV (1)

IABP

18 (1)

Discharged on POD

Cutler [4]

2020

USA

Case report

Male (1)

61

PCSV (1)

IABP

Mil

28 (1)

Discharged on POD

Cutler [4]

2020

USA

Case report

Male (1)

69

PCSV (1)

IABP

Mil

49 (1)

Discharged on POD

Cutler [4]

2020

USA

Case report

Male (1)

60

PCSV (1)

Mil

15 (1)

Discharged on POD

Evans [12]

2019

USA

Case report

Male (1)

57

PCSV (1)

Epi, Mil

22 (1)

Discharged on POD

Trethowan

2020

USA

Case report

Male (1)

81

PCSV (1)

Epi, Mil

12 (1)

Discharged on POD

[13]

Wieruszewsk

2019

USA

Case report

Male (1)

47

PCSV (1)

Mil

11 (1)

Discharged on POD

[14]

Wieruszewsk

2019

USA

Case report

Male (1)

57

PCSV (1)

IABP

15 (1)

Discharged on POD

[14]

Wieruszewsk

2019

USA

Case report

Male (1)

37

PCSV (1)

Epi

21 (1)

Discharged on POD

[14]

Wieruszewsk

2019

USA

Case report

Male (1)

64

PCSV (1)

LVAD, RVAD

Epi

68 (1)

Died (1)

[14]

Wieruszewski

2019

USA

Case report

Female (1)

34

PCSV (1)

Discharged (1)

[15]

Ostermann [2]

2018

M

Case report

Male (1)

23

Cardiac arrest (1)

VA-ECMO

Epi

Discharged (1)

Ostermann [2]

2018

M

Case report

Male (1)

26

Sepsis (1)

VA-ECMO

Epi

Discharged (1)

Ostermann [2]

Ostermann [2]

2018

2018

M

M

Case report

Case report

Female (1)

Female (1)

41

48

Inf-B and MRSA pneumonia Secondary: Sepsis (1)

Sepsis post-acute MI

VA-ECMO

VV- ECMO

Epi

Discharged (1)

Discharged (1)

Ostermann [2]

2018

M

Case report

Male (1)

38

(1)

Drug overdose,

VV- ECMO

Discharged (1)

Ostermann [2]

2018

M

Case report

Female (1)

50

aspiration (1)

Pulmonary embolus

VA-ECMO

Epi, Mil

Discharged (1)

Ostermann [2]

2018

M

Case report

Male (1)

37

(1)

Aortic dissection and

VA-ECMO

Mil

Died (1)

sepsis (1)

Abbreviations: Dob: dobutamine, Dop: dopamine, Epi: epinephrine, IABP: intra-aortic balloon pump, ICU: intensive care unit, LVAD: left ventricular assist device, Mil: milrinone, MI: myo- cardial infarction, MRSA: methicillin-resistant staphylococcal aureus, M: multi-national, PCSV: post-cardiac surgery vasoplegia, POD: post-operative day, RVAD: right ventricular assist de- vice, USA: United States of America, VA-ECMO: veno-arterial extracorporeal membrane oxygenation, VV-ECMO: veno-venous extracorporeal membrane oxygenation.

Image of Fig. 1

Fig. 1. hemodynamic changes with initiation of angiotensin II in cardiogenic shock.

Legend: 1A: Change in mean arterial pressure after angiotensin II initiation; 1B: Percent change in norepinephrine equivalent doses after initiating angiotensin.

Table 2

Dose and duration of angiotensin II therapy.

Author

Starting dose of angiotensin II (ng/kg/min)

Dose at 3 h (ng/kg/min)

Dose at 12 h (ng/kg/min)

Duration of angiotensin II (hours)

Bird [11]

58.5 (mean)

Lohius [10]

17.1 (mean)

Mohamed [1]

13 (median)

Klijian [5]

20 (median)

5 (median)

5 (median)

Konkol [12]

25

Konkol [12]

26

Konkol [12]

5

Konkol [12]

13

Konkol [12]

23

Konkol [12]

8

Meersch [6]

8 (median)

Sovic [7]

24

Sovic [7]

60

Chatterjee [13]

60

60

40

Cutler [3]

15

15

2.5

24

Cutler [4]

10

50

40

12

Cutler [4]

2.5

30

40

34

Cutler [4]

5

20

25

20

Cutler [4]

5

20

80

29

Evans [9]

25

40

40

17

Trethowan [14]

20

40

10

12

Wieruszewsk [8]

20

16

Wieruszewsk [8]

20

Wieruszewsk [8]

10

24

Wieruszewsk [8]

20

Wieruszewski [15]

20

Ostermann [2]

Ostermann [2]

48

Ostermann [2]

20

Ostermann [2]

20

16

Ostermann [2]

40

144

Ostermann [2]

20

192

Ostermann [2]

20

  1. Conclusions

In this systematic review evaluating the early experience of angio- tensin II in CS, we noted an increase in MAP with reduced requirements of other vasoactive medications. Further data on the safety and efficacy of angiotensin II in CS are needed for understanding and defining the role of this medication in mixed shock.

Author contributions

Study design, literature review, statistical analysis: MB, AM, SV. Data management, data analysis, drafting manuscript: MB, AM,

PMW, SV.

Access to data: MB, AM, PMW, PMB, DXZ, AKK, SV.

Manuscript revision, intellectual revisions, mentorship: PMW, PMB, DXZ, AKK, SV.

Final approval: MB, AM, PMW, PMB, DXZ, AKK, SV.

Funding

None.

CRediT authorship contribution statement

Mridul Bansal: Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Aryan Mehta: Writing – original draft, Project administration, Methodology, Formal analysis, Data curation. Patrick M. Wieruszewski: Writing – review & editing, Supervision, Re- sources, Project administration, Methodology, Data curation, Conceptu- alization. P. Matthew Belford: Writing – review & editing, Visualization, Software, Resources, Data curation, Conceptualization. David X. Zhao: Writing – review & editing, Visualization, Validation, Supervision, For- mal analysis, Data curation, Conceptualization. Ashish K. Khanna: Writ- ing – review & editing, Visualization, Validation, Resources, Project administration, Data curation, Conceptualization. Saraschandra Vallabhajosyula: Writing – review & editing, Visualization, Validation, Supervision, Methodology, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

PMW previously served as a consultant for La Jolla Pharmaceutical Company.

Acknowledgements

None.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2023.01.050.

References

  1. Mohamed A, Berry TP, Welge JA, Thomas EL, Zhurav L, Kozinn J, et al. Angiotensin II in patients with shock on mechanical circulatory support: a single-center retrospec- tive case series. J Cardiothorac Vasc Anesth. 2022;36(8 Pt A):2439-45.
  2. Ostermann M, Boldt DW, Harper MD, Lim GW, Gunnerson K. Angiotensin in ECMO patients with refractory shock. Crit Care. 2018;22(1):288.
  3. Cutler NS, Khanna AK. Catecholamine-sparing effect of angiotensin II in an Anephric patient with mixed shock after cardiac revascularization surgery: a case report. A A Pract. 2020;14(9):e01266.
  4. Cutler NS, Rasmussen BM, Bredeck JF, Lata AL, Khanna AK. Angiotensin II for critically ill patients with shock after heart transplant. J Cardiothorac Vasc Anesth. 2021;35 (9):2756-62.
  5. Klijian A, Khanna AK, Reddy VS, Friedman B, Ortoleva J, Evans AS, et al. Treatment with angiotensin II is associated with rapid blood pressure response and vasopressor sparing in patients with Vasoplegia after cardiac surgery: a post-hoc analysis of an- giotensin II for the treatment of high-output shock (ATHOS-3) study. J Cardiothorac Vasc Anesth. 2021;35(1):51-8.
  6. Meersch M, Weiss R, Massoth C, Kullmar M, Saadat-Gilani K, Busen M, et al. The as- sociation between angiotensin II and renin kinetics in patients after cardiac surgery. Anesth Analg. 2022;134(5):1002-9.
  7. Bird S, Chand M, Tran TL, Ali S, Awad SS, Cornwell LD, et al. Evaluation of the ad- dition of angiotensin II in patients with shock after cardiac surgery at a veterans affairs medical center. Ann Pharmacother. 2023 Feb;57(2):141-7. 10600280 221099928.
  8. Sovic W, Mathew C, Blough B, Monday KA, Sam T, Zafar H, et al. Angiotensin II: a multimodal approach to Vasoplegia in a cardiac setting. Methodist Debakey Cardiovasc J. 2021;17(4):98-101.
  9. Wieruszewski PM, Radosevich MA, Kashani KB, Daly RC, Wittwer ED. Synthetic human angiotensin II for Postcardiopulmonary bypass Vasoplegic shock. J Cardiothorac Vasc Anesth. 2019;33(11):3080-4.
  10. Evans A, McCurdy MT, Weiner M, Zaku B, Chow JH. Use of angiotensin II for post cardiopulmonary bypass vasoplegic syndrome. Ann Thorac Surg. 2019;108(1): e5-7.
  11. Ten Lohuis CC, Burke SC, Jannuzzo CJ, Barker NA, Chen EP, Busse LW. Protocol com- pliance guiding angiotensin II use in post cardiovascular surgery Vasoplegia. Crit Care Explor. 2022;4(5):e0687.
  12. Konkol SB, Morrisette MJ, Hulse MC, Enfield KB, Mihalek AD. Outcomes following the use of angiotensin II in patients with postoperative vasoplegic syndrome: a case series. Ann Card Anaesth. 2022;25(3):359-61.
  13. Chatterjee S, Preventza O, Mousavi MC, Orozco-Sevilla V, LeMaire SA, Coselli JS. Suc- cessful use of angiotensin II for vasoplegia after thoracoabdominal aortic aneurysm repair. JTCVS Tech. 2020;4:72-5.
  14. Trethowan B, Michaud CJ, Fifer S. Use of angiotensin II in severe Vasoplegia after left pneumonectomy requiring cardiopulmonary bypass: a renin response analysis. Crit Care Med. 2020;48(10):e912-5.
  15. Wieruszewski PM, Sims CR, Daly RC, Taner T, Wittwer ED. Use of angiotensin II for Vasoplegic shock in a combined heart and liver transplant recipient with sys- tolic anterior motion physiology. J Cardiothorac Vasc Anesth. 2019;33(8): 2366-7.

Leave a Reply

Your email address will not be published. Required fields are marked *