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 |
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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 |
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.
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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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