Critical Care Alert: Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-III)

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A 68-year-old female with recurrent UTIs presents to the ED with 3 days of fever, back pain, and dysuria. She is diagnosed with septic shock because of an ESBL E.Coli and is unresponsive to an appropriate fluid challenge. Her hypotension does not improve despite antibiotics and high doses of norepinephrine and vasopressin. What other vasopressors could be used in the management of this patient’s septic shock?

 

Article
Khanna A, English SW, Wang XS et. al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017; 377(5):419-430.1

Objective
Does Angiotensin II improve hypotension in patients with vasopressor resistant vasodilatory shock?

Background
Vasodilatory shock causes end organ-ischemia through a variety of mechanisms (e.g. sepsis, neurogenic shock, anaphylaxis).  Definitive management of vasodilatory shock is identification and treatment of the underlying pathology. Operating in parallel are treatments aimed at restoring end-organ perfusion, accomplished through intravenous crystalloids and/or vasopressor administration.

Vasodilatory shock requiring high doses of vasopressors has a 30-day mortality exceeding 50%.1 [Physiologically the human body uses 3 systems to maintain blood pressure: 1) Catecholamines, 2) Arginine-Vasopressin, and the 3) Renin-Angiotensin System.2 Synthetic vasopressors are only available from the first two groups and have significant toxicity when used at high doses. This study examines the effect of Angiotensin II as a vasopressor.

Design

  1. Study Design – randomized, double-blind, placebo-controlled trial (FDA Phase 3 Trial)
    • Sites – 75 Intensive Care Units (ICUs) across North America, Europe, Australia
    • Time – May 2015-Jan 2017
  2. Sponsor – La Jolla Pharmaceutical Company (Note – Several authors of this article have professional ties to the sponsoring company)
  3. Intervention – Synthetic Human Angiotensin II (LJPC-501) vs Saline Placebo. Each infusion was prepared in identical saline bags with unblinded personnel. No other personnel were aware of treatment assignment.1
  4. Randomization – performed in blocks via a web-based system and stratified according to:
    • MAP < 65 mm Hg or > 65 mm Hg
    • Acute Physiology and Chronic Health Evaluation II (APACHE II) scores

 

  1. Inclusion Criteria:
    • Adults > 18 years with hypotension unresponsive to a 25 cc/kg intravenous fluid challenge*, and requiring the administration of high-dose vasopressors to maintain a MAP between 55-70 mmHg.
      1. * these patients were determined to be appropriately volume resuscitated by the treating clinician.2
    • Patients must have physiologic parameters of high-output shock, defined as:
      1. Central Venous O2 Sat > 70% and Central Venous Pressure > 8 mmHg, OR:
      2. Cardiac Index > 2.3 L/min/m2
    • All subjects were required to have an indwelling bladder catheter, central venous catheter, and arterial catheter for the initial 48 hours of the study.

 

  1. Exclusion Criteria:2
    • Patients < 18 years old
    • Pregnancy
    • Patients participating in another interventional trial
    • Cardiovascular Sequential Organ Failure Assessment (SOFA) Score < 3
    • Expected lifespan < 12 hours
    • Mannitol allergy
    • Specific Pathologies:
      1. Burn patients with > 20% body surface area
      2. Acute Coronary Syndrome requiring intervention
      3. Use of VA ECMO or patients on ECMO for < 12 hrs
      4. Liver failure with MELD Score > 30
      5. Asthma or bronchospasm necessitating the use of bronchoconstrictors
      6. Mesenteric ischemia (acute or a history of)
      7. Abdominal aortic aneurysm (acute or a history of)
      8. Receiving > 500 mg hydrocortisone or equivalent glucocorticoid/day
      9. History of Raynaud’s phenomenon, systemic sclerosis, or vasospastic disease
      10. Patients with active bleeding and anticipated need for > 4 units of packed red blood cell transfusion within 48 hrs
      11. Patients with active bleeding and hemoglobin < 7 g/dL
      12. Absolute Neutrophil Count < 1000/mm3

 

  1. Primary Outcome:
    • Changes in MAP 3 hours after treatment initiation. A response was defined as a MAP > 75 mm Hg + OR increase in MAP > 10 mm hg from baseline (with no increase in dose of background vasopressors).
  2. Secondary Outcome:
    • Changes in SOFA score between baseline and hour 48
    • Total SOFA score
    • All adverse events, event-related drug discontinuations
    • All-cause mortality at 7 and 28 days

 

Key Results

  1. Patient Screening – 404 subjects screened, 344 enrolled and randomly assigned. 23 patients were further removed from the protocol, leading to 163 patients (Angiotensin II Arm) v 158 patients (Placebo Arm). No significant differences in baseline characteristics, APACHE II Scores, or baseline vasopressor doses.
    • Angiotensin II Group – 119 patients completed the end of study; 88 survived to 28-day follow-up
    • Placebo Group – 102 patients completed the study; 72 patients survived to 28-day follow-up
  2. Most significant cause of shock = Sepsis (80.7%)
  3. Primary Outcome – Significantly more patients in the angiotensin II group met the MAP goal at hour 3 (69.9% vs. 23.4%, P<0.001; OR 7.95; 95% Confidence Interval: 4.76-13.3) [1]. Angiotensin II was noted to promote a rapid increase in MAP, and was decreased from the original dose in 67% of patients.
  4. Secondary Outcomes: cardiovascular SOFA scores were significantly improved in the Angiotensin II group v placebo group (-1.75 vs. -1.28, P=0.01) but there were no significant differences in other components. Additionally, background vasopressor doses were lower in the Angiotensin II group.
  5. Mortality Data – No significant change in all-cause mortality at day 7 or at day 28
  6. Multivariate Analysis – After adjusting for age, sex, and various stratification variables, the use of angiotensin II was noted to have the most significant effect on the MAP.
  7. Safety – There were similar rates of significant adverse events (eg, cardiac arrest, dysrhythmia, cardiogenic shock, myocardial infarction, respiratory and gastrointestinal complications) between both groups. 14.1% of patients that received Angiotensin II and 21.5% of patients that received placebo had their respective infusions discontinued for safety reasons. The most common reasons for discontinuation included multiorgan failure, cardiac arrest, septic shock, and cardiogenic shock.

Strengths

  1. Well-defined population of patients with vasodilatory shock, with appropriate monitoring equipment to guide resuscitation (arterial catheter, indwelling bladder catheter)
  2. Randomized placebo controlled trial with appropriate blinding
  3. Multicenter trial – recruited patients from 75 ICUs across several continents
  4. Study included follow-up for up to 28 days.

Limitations

  1. Clinician blinding may have been confounded due to Angiotensin II’s rapid effect on MAP.
  2. The study’s primary outcome is not directly a patient centered outcome. More interesting would have been data on changes in mortality, but the study was underpowered to detect this effect.
  3. Angiotensin II was compared only to placebo; we are unable to determine its efficacy compared to usual vasopressors. This will undoubtedly be an area for future study.

Conclusions

Angiotensin II improved hypotension among patients in vasodilatory shock, and its use was associated with decreased doses of concurrent vasopressors. There were similar rates of significant adverse events compared to placebo.

ED Take-Away

The use of Angiotensin II as a vasopressor is supported by robust data, and may be an agent available in the ED and ICU armamentarium in the near future. More head-to-head data is needed on the efficacy of Angiotensin II against cheaper, more readily available vasopressors.

References

  1. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377:419-30.
  2. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the Treatment of Vasodilatory Shock (Supplementary Appendix). N Engl J Med. 2017;377:419-30.
Sam Khan, MD

Sam Khan, MD

Department of Emergency Medicine | Icahn School of Medicine at Mount Sinai | Social Media Liaison | EMRA Critical Care Division
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