Author: Anila B. Elliott, MD, University of Michigan - C.S. Mott Children’s Hospital
A 16-year-old boy with hypoplastic left heart syndrome is undergoing a heart transplant for failing Fontan. He is currently on citalopram for a history of depression. After separating from cardiopulmonary bypass, he remains severely hypotensive despite fluid administration, high dose epinephrine, norepinephrine, vasopressin, milrinone and inhaled nitric oxide. Transthoracic echocardiogram shows hyperdynamic function. Which of the following is the MOST appropriate next step for treatment of his vasoplegia?
EXPLANATION
Despite excellent outcomes for Fontan patients in the current era, with 20-year survival of over 85%, many of these patients will require a cardiac transplant.1 These patients are considered high-risk for vasoplegia following cardiopulmonary bypass (CPB).2 Vasoplegic shock is characterized by severe and persistent hypotension (mean arterial pressure < 50mmHg in adolescent and adult patients) with normal or slightly increased cardiac output, low systemic vascular resistance (SVR), lack of fluid responsiveness, and high-dose vasopressor requirement. This can occur in over 30% of patients who undergo heart transplantation.2 Patients with Fontan physiology undergoing heart transplantation face additional risks, including long-standing vascular changes that can result in decreased SVR, complex pulmonary artery reconstruction, and prolonged surgical dissection times leading to extended CPB duration. Extensive surgical dissection, chronic liver congestion with decreased production of clotting factors, and aspirin use increase the risk of hemorrhage and need for blood products which can also increase the systemic inflammatory response in a patient population already at risk for vasoplegia due to long-standing vascular changes. Other factors that may contribute include aortopulmonary collaterals (APCs) that can account for 10-50% of total systemic cardiac output, leading to recirculation and increased volume load on the systemic ventricle pre-operatively. Although these are often intervened-upon prior to transplantation, smaller APCs can potentially contribute to volume load on the new graft as well as a high-output state, contributing to vasoplegia.
Angiotensin II (Giapreza) was approved by the FDA in 2017 to treat hypotension in adults with distributive shock based on data from the ATHOS-3 trial.3 The ATHOS-3 trial (Angiotensin II for the Treatment of High-Output Shock) was a pivotal clinical study to evaluate the efficacy and safety of angiotensin II in patients that remained hypotensive despite high-dose vasoactive medications. This was a double-blinded, randomized, placebo-controlled study, which showed that a significant number of patients had improvement in mean arterial pressure compared to those who received placebo. Angiotensin II acts on angiotensin type I receptors leading to vasoconstriction and activation of the sympathetic nervous system. The recommended starting dose is 20 nanograms/kg/min (0.02mcg/kg/min). The dose can be titrated every 5 minutes by 15ng/kg/min. Recommended maximum dose is not to exceed 80ng/kg/minute within the first 3 hours of treatment according to the manufacturer’s guidelines (https://www.giapreza.com/using-giapreza). Maintenance doses typically should not exceed 40ng/kg/min. Although the data is limited, there are small single-center trials and case reports of use in pediatric patients. In these publications, Angiotensin II infusion has shown improvement in mean arterial pressure in children with catecholamine-resistant vasodilatory shock.4
The correct answer is B. The patient is hypotensive despite multiple vasopressor infusions.
Although milrinone discontinuation may result in some increase of mean arterial blood pressure, its long half-life of 2-2.5 hours may limit the effectiveness of this change. A more specific targeted therapy with another potent vasopressor such as angiotensin II is more likely to be effective in severe catecholamine-resistant vasoplegia, as seen in this patient.
While methylene blue can decrease vasopressor requirements, it may also increase pulmonary vascular resistance. 2 In addition, its monoamine oxidase inhibitor effects are contraindicated in patients with a risk of
serotonin syndrome.5 Given this patient’s history of depression and selective serotonin reuptake inhibitor use, it is best to avoid methylene blue in this patient.
REFERENCES
1. McCormick, AD., Schumacher, KR. Transplantation of the failing Fontan. Translational Pediatrics 2019; 8(4)
2. Chan, JL., Kobashigawa, JA., Aintablian, TL., et al. Characterizing predictors and severity of vasoplegia syndrome after heart transplantation. Ann Thorac Surg. 2018; 105: 770-777
3. Khanna, A., English, SW., Wang, XS., et al for the ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017; 377:419-430
4. Tezel, O., Hutson, TK., Gist, KM., et al. Utilization of synthetic human angiotensin II for catecholamine-resistant vasodilatory shock in critically ill children: a single-center retrospective case series. Crit Care Explor. 2023; 5(9):e0978
5. Otero Luna, AV., Johnson, R., Funaro, M., et al. Methylene blue for refractory shock in children: a systematic review and survey practice analysis. Pediatr Crit Care Med. 2020; 21(6):e378-e386
