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Clinical Experience With IV Angiotensin II Administration: A Systematic Review of Safety

Busse, Laurence W. MD1; Wang, Xueyuan Shelly MD2; Chalikonda, Divya M. MD3; Finkel, Kevin W. MD4; Khanna, Ashish K. MD5; Szerlip, Harold M. MD6; Yoo, David MD7; Dana, Sharon L. PhD8; Chawla, Lakhmir S. MD8,9

doi: 10.1097/CCM.0000000000002441
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Objective: Angiotensin II is an endogenous hormone with vasopressor and endocrine activities. This is a systematic review of the safety of IV angiotensin II.

Data Sources: PubMed, Medline, Scopus, and Cochrane.

Study Selection: Studies in which human subjects received IV angiotensin II were selected whether or not safety was discussed.

Data Extraction: In total, 18,468 studies were screened by two reviewers and one arbiter. One thousand one hundred twenty-four studies, in which 31,281 participants received angiotensin II (0.5–3,780 ng/kg/min), were selected. Data recorded included number of subjects, comorbidities, angiotensin II dose and duration, pressor effects, other physiologic and side effects, and adverse events.

Data Synthesis: The most common nonpressor effects included changes in plasma aldosterone, renal function, cardiac variables, and electrolytes. Adverse events were infrequent and included headache, chest pressure, and orthostatic symptoms. The most serious side effects were exacerbation of left ventricular failure in patients with congestive heart failure and bronchoconstriction. One patient with congestive heart failure died from refractory left ventricular failure. Refractory hypotensive shock was fatal in 55 of 115 patients treated with angiotensin II in case studies, cohort studies, and one placebo-controlled study. One healthy subject died after a pressor dose of angiotensin II was infused continuously for 6 days. No other serious adverse events attributable to angiotensin II were reported. Heterogeneity in study design prevented meta-analysis.

Conclusion: Adverse events associated with angiotensin II were infrequent; however, exacerbation of asthma and congestive heart failure and one fatal cerebral hemorrhage were reported. This systematic review supports the notion that angiotensin II has an acceptable safety profile for use in humans.

Supplemental Digital Content is available in the text.

1Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, Emory St. Joseph’s Hospital, Atlanta, GA.

2Division of Critical Care, Department of Anesthesia, Duke University Medical Center, Durham, NC.

3Department of Medicine, Thomas Jefferson University, Philadelphia, PA.

4Division of Renal Diseases and Hypertension, Department of Medicine, University of Texas Health Science Center, Houston, TX.

5Anesthesiology Institute, Center for Critical Care and Department of Outcomes Research, Cleveland Clinic Foundation, Cleveland, OH.

6Division of Nephrology, Department of Medicine, Baylor University Medical Center, Dallas, TX.

7Department of Medicine, University of Maryland Medical Center, Baltimore, MD.

8La Jolla Pharmaceutical Company, San Diego, CA.

9Division of Intensive Care Medicine and Division of Nephrology, Department of Medicine, Veterans Affairs Medical Center, Washington, DC.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by La Jolla Pharmaceutical Co.

Drs. Busse and Wang served as the principal investigators (PIs) for their institutions in a global multi-institution phase 3 trial evaluating angiotensin II as a pressor drug in catecholamine resistant shock. This phase 3 trial was sponsored by La Jolla Pharmaceuticals, which manufactures the drug and supported this manuscript. However, neither physician nor their institutions received any compensation for time and contributions to the manuscript. Dr. Busse reports having received consulting fees from La Jolla. Dr. Khanna was the site PI for the Angiotensin II in High Output Shock trial (ATHOS3). Drs. Dana and Chawla are employed by La Jolla Pharmaceuticals. Dr. Dana was a former employee of Merck & Co and Cubist Pharmaceuticals, as well as a current shareholder in Ligand Pharmaceuticals and La Jolla Pharmaceutical Company. Dr. Chawla is a current shareholder of La Jolla Pharmaceutical Company. The authors discuss angiotensin II in this article, an investigational drug. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: Laurence.w.busse@emory.edu

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