Background: As I walk to the bedside to re-examine my patient with refractory hypotension, I start thinking what else can I do? My patient came into the hospital with septic shock secondary community acquired pneumonia requiring me to intubate her due to impending respiratory failure. I subsequently placed a central venous catheter and an arterial line as I carefully volume resuscitated her.  I turned up her tidal volume momentarily on the ventilator to assess for pulse pressure and stroke volume variation, did a bedside echo, and attempted a passive leg raise, but it appears that she is volume replete. I started a norepinephrine infusion, and as the dose escalated, I added a vasopressin infusion, but she still remains hypotensive even after giving her stress dose steroids. As I contemplate my next move I am haunted by her bedside monitor alarming; MAP 50 mm Hg. What’s my next move?

Managing a patient with refractory vasodilatory shock already on high dose vasopressors can be extremely frustrating, but more importantly, it carries a high mortality for our patients.  Vasodilatory shock results from systemic vasodilation despite adequate cardiac output seen most commonly as a result of septic shock.  Our current medications to treat this form of shock are limited to catecholamine infusions, vasopressin and perhaps steroids. The first line agents after fluids resuscitation remain catecholamine vasopressor therapies targeting alpha-1 adrenergic receptors, Beta-1 adrenergic receptors and Beta-2 adrenergic receptors.

The problem with adding a second or even third catecholamine agent is that their effects are limited, and tend to put patient’s at increased risk of potentially life threatening side effects such as dysrhythmia’s, myocardial ischemia, and splanchnic vasoconstriction leading to mesenteric ischemia.

Arginine Vasopressin (Antidiuretic Hormone), a peptide hormone, has also been used to increase blood pressure through V1 receptor mediated peripheral vasoconstriction. Besides having a different site of action, vasopressin levels have been demonstrated to be low in patients with septic shock (1-2), so adding vasopressin may benefit these patients with significant deficiencies.  The 2016 Surviving Sepsis Guidelines suggest adding vasopressin or epinephrine as second line agents to norepinephrine for refractory hypotension. The VAST trial showed the addition of vasopressin to norepinephrine compared to norepinephrine alone had catecholamine-sparing effects, but did not demonstrate a mortality benefit between the two groups at 28 or 90 days (2).

Many clinicians may attempt to add stress dose steroids in attempts to treat undiagnosed adrenal failure or relative adrenal insufficiency, but after this, our options are limited. A consideration of occult causes of non-response to vasopressors should be considered (See Swami’s July 13,2017 post Occult Causes of Non-Response to Vasopressors), but if persistent vasodilatory shock continues to be refractory there are only a few less favorable options such as Methylene Blue, high-volume hemofiltration, or VA ECMO.

Another endogenous vasopressor that is produced by the body in response to shock is angiotensin II produced through the renin angiotensin aldosterone system (RAAS). Angiotensin I is converted to angiotensin II by angiotensin converting enzyme (ACE) located on the endothelium of the pulmonary vasculature. Angiotensin II has various effects from potentiating sympathetic activity, direct vasoconstriction, and fluid retention directly and indirectly (via release of aldosterone and vasopressin/antidiuretic hormone). It’s use as a vasopressor has been demonstrated to raise blood pressure, spare catecholamine use, without increasing adverse effects (4). This drug class offers a new and exciting possibility in the treatment of vasodilatory shock.

Clinical Question:

Is the addition of angiotensin II effective at raising the mean arterial blood pressure in patients with refractory vasodilatory shock already requiring high dose norepinephrine infusion (>0.2 mcg/kg/min or equivalent dosing of vasopressor)?

What They Did:

• They added angiotensin II infusion versus placebo to patients who remained hypotensive with vasodilatory shock, requiring high dose norepinephrine (>0.2mcg/kg/min or equivalent vasopressor dose).
• Patients had to be requiring this dose of vasopressor for at least 6 hours, but no more than 48 hours.
• Patients were started on angiotensin II at starting dose of 20 ng/kg/min and adjusted accordingly for MAP goals (Max dose 200 ng/kg/min)
• Between hour 3 (after trial ended) to 48 hours angiotensin II was attempted to be weaned off, but could be continued if baseline norepinephrine or equivalent dose increased >0.1mcg/kg/min once drug discontinued, however could not be continued for more than 7 days.
• The majority of the patients with refractory vasodilatory shock were secondary to septic shock (80.7%) or potential sepsis (9.7%).

Outcomes:

Primary Outcome:

• A response in mean arterial blood pressure (MAP), 3 hours after the start of angiotensin II infusion.
• A response was defined as an increase in MAP of at least 10 mm Hg from baseline or a MAP of at least 75 mm Hg without an increase in baseline vasopressor infusions.

Secondary Outcomes:

• Mean change in cardiovascular SOFA score at 48 hours
• Mean change in total SOFA score at 48 hours
• Mean change in norepinephrine equivalent dose from baseline (0 to 3 hours)
• All-cause 7-day mortality
• All-cause 28-day mortality

Results:

• At hour 3, the MAP increased to 75 mm Hg or increased by 10 mm Hg from baseline in nearly 70% of patient compared to placebo, only 23.4% (p <0.001).
• The mean change in norepinephrine equivalent dose decreased over 3 hours in the angiotensin II group compared to placebo (p=0.054).
• The cardiovascular component of SOFA score was improved at 48 hours in the angiotensin II group (p=0.01), but overall SOFA score was no different between the two groups (p=0.49).
• There were less adverse effects in the angiotensin II group (87.1%) vs. placebo (91.8%), less serious adverse effects (60.7% vs. 77.1%), and less adverse event-related drug discontinuation (14.1% vs. 21.5%).

Strengths:

• Randomized, double-blind, control trial
• Multinational/Multi-centered
• Studied therapy for refractory vasodilatory shock, a common condition associated with high mortality
• Examines a potentially new class of vasopressor in which our therapies are limited to only a couple of drug classes

Limitations:

• Study powered to show improvement in blood pressure, a clinically important parameter, but underpowered to demonstrate a mortality difference, a patient oriented outcome
• Study blinded, but difficult for examiners to be truly blinded as 70% of the treatment group had a significant response in blood pressure
• Lakhmir Chawla, one of the investigators of the trial, is also the CMO of La Jolla Pharmaceuticals which is the company that manufactures angiotensin II and funded the trial

Discussion:

• It appears that the addition of angiotensin II to patients requiring high dose norepinephrine infusion or equivalent vasopressor dose is associated with an improvement in blood pressure.
• The addition of angiotensin II appears to improve blood pressure and leads to decreased catecholamine infusion without causing an increase in adverse effects.
• Keep in mind that vasopressin added to norepinephrine infusion vs. norepinephrine alone also decreased norepinephrine dosing, but did not show a difference in mortality (2).
• Angiotensin II is associated with improved blood pressure, however this study was underpowered to show if there is a mortality difference and additional studies are needed.
• This potentially gives us an exciting new class of vasopressor, however it remains to be seen how it can be best used.
• Perhaps angiotensin II will be used in combination with other vasopressors, as monotherapy, or in a specific subset of patients with vasodilatory shock or other forms of shock?
• Angiotensin II is an exciting new class of vasopressor that is associated with improved blood pressure in refractory vasodilatory shock.  It remains to be seen how it should be best used; monotherapy, in combination with other vasopressors, or in specific types of shock states? It also remains to be seen if its use will show a more clinically significant effect such as a reduction in mortality?

Author’s Conclusion:

“Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors.” 

Clinical Bottom Line:

Angiotensin II added to high dose norepinephrine infusion (>0.2mcg/kg/min) is associated with an improvement in blood pressure at hour 3 of therapy vs. placebo without an increase in adverse effects, however more studies are still required to determine patient oriented outcomes.

Guest Contributor

Frank J. Lodeserto MD
Adult & Pediatric Critical Care
Geisinger Medical Center
Janet Weis Children’s Hospital
Danville, PA

References:

1. Sharshar T et al. Circulating Vasopressin Levels in Septic Shock. Cris Care Med 2003; 31(6): 1752 – 8. PMID: 12794416
2. Russell JA et al. Vasopressin Versus Norepinephrine Infusion in Patients with Septic Shock. NEJM 2008; 358(9): 877 – 87. PMID: 18305265
3. Chawla LS et al. Intravenous Angiotensin II for the Treatment of High-Output Shock (ATHOS Trial): A Pilot Study. Crit Care 2014; 18(5): 534. PMID: 25286986

For More on This Topic Checkout:

• Scott Weingart at EMCrit: EMCrit 201 – Deeper on Vasopressors and Athos 3 with Mink Chawla
• Celia Bradford at The Bottom Line: ATHOS-3

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami) and Salim Rezaie (Twitter: @srrezaie)