Ashish Khanna, MD: Checking In On Angiotensin 2

Ashish Khanna, MD

Last December, the US Food and Drug Administration (FDA) approved angiotensin 2 injection (Giapreza) for the treatment of adults with septic or other distributive shock. The intravenous infusion therapy was designed to increase blood pressure in adult patients with hypotension, a condition in which a patient has significantly low blood pressure. The condition can cause shock — in which the brain, kidneys, and other vital organs are no longer receiving the appropriate amount of blood flow to function correctly.

In its first year of real-world clinical use, nothing new has emerged to lead Ashish Khanna, MD, to believe the therapy isn't a critical addition to the care of patients with hypotension. In an interview with MD Magazine®, the Cleveland Clinic anesthesiology and critical care provider discussed how angiotensin 2's fast-acting capabilities, endogenous background—and potential benefits for particular patient populations—highlight what's already considered a popular life-saving therapy.

MD Mag: What made the FDA approval of angiotensin 2 so exciting in your field?

Khanna: The approval and availability of angiotensin 2 is exciting because right now most physicians, surgeons, principal care physicians, and hospitalists have been limited to 2 kinds of drugs when it comes to the management of hypotension in a patient with vasodilatory shock, or septic shock. So right now, we only have 2 classes of drugs designated for treatment.

The current problem is the 2 drugs are not enough, either by themselves or in combination, to hemodynamically stabilize the patient and get their blood pressure when suffering hypotension secondary to vasodilatory shock. And that’s why angiotensin 2 is exciting and groundbreaking: because it is an endogenously found hormone in the human system, and we have been able to show that exogenous angiotensin 2—synthetic, stable, and exactly the same compound—can replace the deficiency or the dysfunction of endogenous angiotensin 2, and can quickly stabilize and bring up blood pressure in patients with high-output vasodilatory shock.

So, we have provided a third alternative mechanism or pharmacological pathway for the entire community to utilize, when it comes to blood pressure stabilization in these patients with vasodilatory shock. This is what we believe is the missing piece in the management of hypotension in these patients, and may be the third leg on the three-legged stool of managing hypotension in patients with vasodilatory shock. We were missing this piece before, and now we have it available.

We’re nearly at the one-year anniversary of the drug’s approval. What are we seeing in real-world patient response to this drug?

The early real-world results are encouraging. The number of institutions and patients across the country to have utilized this drug have been a part of institution protocol or as protocol for rescue therapy. There are at least a couple of case reports now about angiotensin 2 being the rescue drug in patients who would otherwise too unstable and would likely have had high risk of mortality in the ICU. And then there’s a number of institutions where it’s part of standard-of-care now, and part of the hypotension treatment plan in the ICU.

Most of the feedback I’ve received has been positive. Most declare it takes action pretty quickly. In trials we estimated a median response time of 5 minutes, which is pretty dramatic in comparison to everything else we have available. Most of the feedback has been it works pretty quickly, it brings the blood pressure up quickly, it allows for hemodynamic stability, it preserves all system functions, and it allows the primary source of the problem to be treated so patients can have outcomes.

I have not received, to date, any issues with adverse events, potential patient safety issues, and such.

Regarding the rapid response—how critical is that facet in the ICU setting?

A lot of people don’t realize how damaging exposure to hypotension is. I have done work in this area where I have shown that any exposure to mean arterial pressure (MAP) less than 70 mL in the ICU is significantly deleterious in term of causing other system injuries (acute kidney disease, myocardial conditions, mortality), and an exposure up to an hour to a MAP less than 60 mL is similarly deleterious to auto system injuries. Exposure to hypotension is bad in you and me. Exposure to hypotension in a patient who is getting operation under anesthesia.

Exposure to hypotension is worse in a patient critically ill in the ICU with significant comorbidity, possibly 2 or 3 other systems already compromised. We need higher blood pressure in the ICU to preserve system function, and that’s why a drug like angiotensin 2 is crucial because there’s a lot of patients who come into the ICU, who as an intensive care provider, you’re really struggling to keep up with blood pressure.

That’s why a drug like angiotensin 2 is truly life-saving, because it’ll allow you a period of stability of hemodynamics while you intervene otherwise, and you can keep your patients stable.

To your knowledge, is MAP something that’s being checked for enough in the ICU setting?

Any patient who’s on blood pressure-stabilizing medication generally has an arterial line with continuous beat-to-beat pressure monitoring, and we’re keeping a very close eye on the MAP. That doesn’t necessarily mean we’re keeping a close eye to make sure we are doing enough to keep the blood pressure above a certain threshold.

We are guilty, as a community, of not responding enough to a blood pressure drop. That’s where we need to bring in that culture change, that we realize we need to be religiously defending the MAP. That’s going to be critical when we bring about a culture change in our patient management.

Let’s say you give your patient a MAP target of 70 mL. You do everything you can to keep the MAP above 70, you do it religiously, and you don’t allow the blood pressure to drip down all the time. That’s what we’re particularly guilty of right now: allowing the blood pressure to continually drip down to dangerous levels before we intervene. That’s where we need more tools, and that’s what angiotensin 2 provides us.

Thinking forward, could you speak to ongoing clinical research you’re involved with or interested in focused on angiotensin 2?

I think the biggest thing we’re trying to establish is seeing if a certain patient population could exquisitely benefit from the drug and therapy.

We do believe patients with chronic ACE (angiotensin converting enzyme) inhibitor use—almost two-thirds of our population above the age of 60 are on an inhibitor to treat hypertension, heart failure, or as a secondary therapy for the management of myocardial infarction—present to the emergency room with a bad case of sepsis, septic shock or surgical abdomen that’s infected. And these patients do not have the same endogenous angiotensin 2 response that a 30-year old would have. And it’s probably these patients who would end up being significant responders to exogenous angiotensin 2. And it’s in these patients who we’re struggling with current therapies to get their blood pressure stabilized.

We’re trying to work further on this hypothesis, but also look back at the data we have, to see if there’s a signal of benefit for care in these patients.