Angiotensin II in General Anesthesia

• ClinicalTrials.gov Identifier: NCT03733145
• Recruitment Status: Recruiting
• First Posted: November 7, 2018
• Last Update Posted: August 4, 2020
• Sponsor: Wake Forest University Health Sciences
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief Summary:

Hypotension in adult patients undergoing general anesthesia is common. This can lead to hypoperfusion of vital organs, organ damage, and states of increased metabolic duress. This may be worse in patients with underlying essential hypertension and worse in patients taking Angiotensin Converting Enzyme Inhibitors (ACE) and Angiotensin Receptor Blockers (ARBs). Intravenous (IV) administration of Ang II may be an effective treatment of hypotension in this patient population.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Angiotensin II	Phase 1

Detailed Description:

Hypotension in adult patients undergoing general anesthesia is common. Many of the body's normal mechanisms to maintain adequate blood pressure in the non-anesthetized state are significantly altered by anesthetic agents, which may lead to hypotension. This can lead to hypoperfusion of vital organs, organ damage, and states of increased metabolic duress. In response to this it has become standard of care to attempt to maintain blood pressure levels within 20% of baseline in most patients under anesthesia. Maintaining the baseline blood pressure is important as patients may have pathology such as coronary artery disease, carotid stenosis, and renal artery stenosis, and hypotension may compromise the perfusion of these organs. Vasodilation also plays a key role in hypotension due to general anesthesia. Therefore, the intravenous (IV) administration of Ang II may be an effective treatment of hypotension in this patient population.The objective of this study is to determine the infusion rate of Ang II that is necessary to return systolic blood pressure (SBP) to within 5% of baseline or greater in patients with essential hypertension taking ACE inhibitors, ARBs, or different classes of antihypertensive agents and further to determine the plasma levels of different RAAS components

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Dose Finding Trial for Angiotensin II in Hypertensive Adults on Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers With Anesthesia-Mediated Hypotension
• Actual Study Start Date: October 3, 2019
• Estimated Primary Completion Date: October 2021
• Estimated Study Completion Date: October 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Participants on ACE inhibitors; Participants taking ACE inhibitors (angiotensin-converting enzyme inhibitors)will be placed into this group. Intervention: Drug: Angiotensin II.	Drug: Angiotensin II; Participants in the ACE inhibitors, ARBs, and Other Classes of Antihypertensive Agents who's systolic blood pressure (SBP) is less than 80% of the baseline reading is detected, will have Ang II initiated at 2 ng/kg/min through a peripheral IV. The infusion will be increased at the discretion of the clinical team based on the response of the patient until a SBP within 5% of the baseline SBP.; Other Names: Ang II; Giapreza
Experimental: Participants on ARBs; Participants taking ARBs (angiotensin-receptor blockers) will be placed into this group. Intervention: Drug: Angiotensin II.	Drug: Angiotensin II; Participants in the ACE inhibitors, ARBs, and Other Classes of Antihypertensive Agents who's systolic blood pressure (SBP) is less than 80% of the baseline reading is detected, will have Ang II initiated at 2 ng/kg/min through a peripheral IV. The infusion will be increased at the discretion of the clinical team based on the response of the patient until a SBP within 5% of the baseline SBP.; Other Names: Ang II; Giapreza
Experimental: Other Classes of Antihypertensive Agents; Participants taking any other class of Antihypertensive Agents will be placed into this group. Intervention: Drug: Angiotensin II.	Drug: Angiotensin II; Participants in the ACE inhibitors, ARBs, and Other Classes of Antihypertensive Agents who's systolic blood pressure (SBP) is less than 80% of the baseline reading is detected, will have Ang II initiated at 2 ng/kg/min through a peripheral IV. The infusion will be increased at the discretion of the clinical team based on the response of the patient until a SBP within 5% of the baseline SBP.; Other Names: Ang II; Giapreza

Outcome Measures

Primary Outcome Measures :

1. Mean dose required to increase the SBP [ Time Frame: up to 1 hour ]
   The mean dose required to increase the SBP in these 3 cohorts with essential hypertension (ACE inhibitor, ARB, or those on another class of hypertensive agents) to within 5% of baseline or higher will be calculated.

Secondary Outcome Measures :

1. Mean value of Bradykinin [ Time Frame: up to 1 hour ]
   Mean values of Bradykinin 1-8 and Bradykinin 1-7 will be calculated and reported.
2. Mean value of Angiontensin [ Time Frame: up to 1 hour ]
   Mean values of Angiotensin I, Angiotensin II, Angiotensin IV, Angiotensin 1-7, Angiotensin 1-5, Angiotensin 1-9, Angiotensin 2-10, Angiotensin 2-7, and Angiotensin 3-7 will be calculated and reported.
3. Mean value of Aldosterone [ Time Frame: up to 1 hour ]
   Mean value of Aldosterone will be calculated and reported.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of hypertension and treatment with at least one medication including an ACE inhibitor, ARB, and other agents for greater than 2 months
• Patients undergoing general anesthesia

Exclusion Criteria:

• BMI > 40
• History of deep venous thrombosis / thromboembolic disease
• History of stroke,
• Baseline SBP of ≥ 160 mmHg,
• History of myocardial infarction or cardiac stents
• Difficult airway
• Asthma
• Congestive heart failure
• Chronic obstructive pulmonary disease
• Pregnant patients

Contacts and Locations

Contacts

Contact: Rohesh Fernando, MD; 3367162712; rfernan@wakehealth.edu

Contact: Thomas Templeton, MD; 3367164285; ttemplet@wakehealth.edu

Locations

United States, North Carolina

Wake Forest Baptist Medical Center; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Rohesh Fernando, MD 336-716-2712 rfernan@wakehealth.edu

Sponsors and Collaborators

Wake Forest University Health Sciences

Investigators

• Principal Investigator: Rohesh Fernando, MD; Wake Forest University Health Sciences

More Information

Publications:

Comfere T, Sprung J, Kumar MM, Draper M, Wilson DP, Williams BA, Danielson DR, Liedl L, Warner DO. Angiotensin system inhibitors in a general surgical population. Anesth Analg. 2005 Mar;100(3):636-44, table of contents.

Singh A, Antognini JF. Perioperative hypotension and myocardial ischemia: diagnostic and therapeutic approaches. Ann Card Anaesth. 2011 May-Aug;14(2):127-32. doi: 10.4103/0971-9784.81569. Review.

Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hästbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21.

Ferreira AJ, Murça TM, Fraga-Silva RA, Castro CH, Raizada MK, Santos RA. New cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis. Int J Hypertens. 2012;2012:147825. doi: 10.1155/2012/147825. Epub 2012 Jan 26.

Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z, Seneff MG. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5):534. doi: 10.1186/s13054-014-0534-9.

Tallarida RJ, Stone DJ Jr, Raffa RB. Efficient designs for studying synergistic drug combinations. Life Sci. 1997;61(26):PL 417-25.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT03733145
• Other Study ID Numbers: IRB00054661
• First Posted: November 7, 2018
• Last Update Posted: August 4, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Wake Forest University Health Sciences:

Angiotensin II; Angiotensin Converting Enzyme Inhibitors; Angiotensin Receptor Blockers; Anesthesia-Mediated Hypotension

Additional relevant MeSH terms:

Angiotensin II; Giapreza; Hypertension; Hypotension; Vascular Diseases; Cardiovascular Diseases; Angiotensinogen; Vasoconstrictor Agents; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action