Treatment With Angiotensin II Is Associated With Rapid Blood Pressure Response and Vasopressor Sparing in Patients With Vasoplegia After Cardiac Surgery: A Post-Hoc Analysis of Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Study

Abstract

Objective: The present study investigated outcomes in patients with vasoplegia after cardiac surgery treated with angiotensin II plus standard-of-care vasopressors. Vasoplegia is a common complication in cardiac surgery with cardiopulmonary bypass and is associated with significant morbidity and mortality. Approximately 250,000 cardiac surgeries with cardiopulmonary bypass are performed in the United States annually, with vasoplegia occurring in 20%to-27% of patients.Design: Post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.Setting: Multicenter, multinational study.Participants: Sixteen patients with vasoplegia after cardiac surgery with cardiopulmonary bypass were enrolled.Interventions: Angiotensin II plus standard-of-care vasopressors (n = 9) compared with placebo plus standard-of-care vasopressors (n = 7).Measurements and Main Results: The primary endpoint was mean arterial pressure response (mean arterial pressure ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in the dose of standard-of-care vasopressors). Vasopressor sparing and safety also were assessed. Mean arterial pressure response was achieved in 8 (88.9%) patients in the angiotensin II group compared with 0 (0%) patients in the placebo group (p = 0.0021). At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by 76.5% in the angiotensin II group compared with an increase of 7.8% in the placebo group (p = 0.0013). No venous or arterial thrombotic events were reported.Conclusion: Patients with vasoplegia after cardiac surgery with cardiopulmonary bypass rapidly responded to angiotensin II, permitting significant vasopressor sparing. Objective: The present study investigated outcomes in patients with vasoplegia after cardiac surgery treated with angiotensin II plus standard-of-care vasopressors. Vasoplegia is a common complication in cardiac surgery with cardiopulmonary bypass and is associated with significant morbidity and mortality. Approximately 250,000 cardiac surgeries with cardiopulmonary bypass are performed in the United States annually, with vasoplegia occurring in 20%to-27% of patients. Design: Post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. Setting: Multicenter, multinational study. Participants: Sixteen patients with vasoplegia after cardiac surgery with cardiopulmonary bypass were enrolled. Interventions: Angiotensin II plus standard-of-care vasopressors (n = 9) compared with placebo plus standard-of-care vasopressors (n = 7). Measurements and Main Results: The primary endpoint was mean arterial pressure response (mean arterial pressure ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in the dose of standard-of-care vasopressors). Vasopressor sparing and safety also were assessed. Mean arterial pressure response was achieved in 8 (88.9%) patients in the angiotensin II group compared with 0 (0%) patients in the placebo group (p = 0.0021). At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by 76.5% in the angiotensin II group compared with an increase of 7.8% in the placebo group (p = 0.0013). No venous or arterial thrombotic events were reported. Conclusion: Patients with vasoplegia after cardiac surgery with cardiopulmonary bypass rapidly responded to angiotensin II, permitting significant vasopressor sparing. VASOPLEGIA is a type of distributive shock commonly defined as hypotension or requirement for vasopressors to maintain mean arterial pressure (MAP), with reduced systemic vascular resistance and preserved or increased cardiac output.1Lambden S Creagh-Brown BC Hunt J et al.Definitions and pathophysiology of vasoplegic shock.Crit Care. 2018; 22: 174-181Crossref PubMed Scopus (67) Google Scholar Approximately 250,000 cardiac surgeries with cardiopulmonary bypass (CPB) are performed in the United States annually.2Bowdish ME D'Agostino RS Thourani VH et al.The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2020 update on outcomes and research.Ann Thorac Surg. 2020; 109: 1646-1655Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Vasoplegia is a common complication in cardiac surgery with CPB, occurring in 20%to-27% of patients.3Levin MA Lin HM Castillo JG et al.Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome.Circulation. 2009; 120: 1664-1671Crossref PubMed Scopus (144) Google Scholar,4Weis F Kilger E Beiras-Fernandez A et al.Association between vasopressor dependence and early outcome in patients after cardiac surgery.Anaesthesia. 2006; 61: 938-942Crossref PubMed Scopus (49) Google Scholar Vasoplegia may be associated with significant morbidity and mortality as a result of organ hypoperfusion.4Weis F Kilger E Beiras-Fernandez A et al.Association between vasopressor dependence and early outcome in patients after cardiac surgery.Anaesthesia. 2006; 61: 938-942Crossref PubMed Scopus (49) Google Scholar,5Tecson KM Lima B Lee AY et al.Determinants and outcomes of vasoplegia following left ventricular assist device implantation.J Am Heart Assoc. 2018; 7 (pii:e008377)Crossref PubMed Scopus (16) Google Scholar Patients with vasoplegia after cardiac surgery with CPB demonstrate increases in the following: (1) incidence of postoperative renal failure, (2) duration on ventilation, (3) duration in the intensive care unit (ICU); and (4) mortality.4Weis F Kilger E Beiras-Fernandez A et al.Association between vasopressor dependence and early outcome in patients after cardiac surgery.Anaesthesia. 2006; 61: 938-942Crossref PubMed Scopus (49) Google Scholar Due to similar pathophysiologic mechanisms and limited specific treatment recommendations,6Ortoleva JP Cobey FC. A systematic approach to the treatment of vasoplegia based on recent advances in pharmacotherapy.J Cardiothorac Vasc Anesth. 2019; 33: 1310-1314Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar blood pressure management in vasoplegia tends to be similar to that in septic shock.7Busse LW Barker N Petersen C Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options.Crit Care. 2020; 24: 36-46Crossref PubMed Scopus (27) Google Scholar As in septic shock, norepinephrine is considered the first-line vasopressor therapy for the treatment of vasoplegia. Vasopressin is a second-line treatment option in septic shock and also has been investigated in vasoplegia because endogenous vasopressin levels are depleted during CPB.7Busse LW Barker N Petersen C Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options.Crit Care. 2020; 24: 36-46Crossref PubMed Scopus (27) Google Scholar Additional options for the treatment of vasoplegia include methylene blue, hydroxocobalamin, and high-dose vitamin C, although the data are limited and equivocal.8Armour S Armour TK Joppa WR et al.Use of hydroxocobalamin (vitamin B12a) in patients with vasopressor refractory hypotension after cardiopulmonary bypass: A case series.Anesth Analg. 2019; 129 (e1-4)Crossref PubMed Scopus (12) Google Scholar, 9Pasin L Umbrello M Greco T et al.Methylene blue as a vasopressor: A meta-analysis of randomised trials.Crit Care Resusc. 2013; 15: 42-48PubMed Google Scholar, 10Yanase F Bitker L Hessels L et al.A pilot, double-blind, randomized, controlled trial of high-dose intravenous vitamin C for vasoplegia after cardiac surgery.J Cardiothorac Vasc Anesth. 2020; 34: 409-416Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar An alternative approach to the treatment of vasoplegia after cardiac surgery with CPB is the targeting of the renin-angiotensin-aldosterone system (RAAS) with exogenous angiotensin II. The RAAS is relevant because angiotensin-converting enzyme (ACE) inhibitor use is common in patients undergoing cardiac surgery and ACE activity is disrupted during CPB, each of which can create a relative deficiency of angiotensin II. Initial reports indicated that exogenous angiotensin II is effective in correcting vasoplegia after CPB in patients refractory to multiple vasopressors.11Evans A McCurdy MT Weiner M et al.Use of angiotensin II for post cardiopulmonary bypass vasoplegic syndrome.Ann Thorac Surg. 2019; 108 (e5-7)Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 12Wieruszewski PM Sims CR Daly RC et al.Use of angiotensin II for vasoplegic shock in a combined heart and liver transplant recipient with systolic anterior motion physiology.J Cardiothorac Vasc Anesth. 2019; 33: 2366-2367Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 13Wieruszewski PM Radosevich MA Kashani KB et al.Synthetic human angiotensin II for postcardiopulmonary bypass vasoplegic shock.J Cardiothorac Vasc Anesth. 2019; 33: 3080-3084Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In December 2017, angiotensin II was approved by the US Food and Drug Administration as a vasoconstrictor indicated to increase blood pressure in adults with septic or other distributive shock on the basis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.14Khanna A English SW Wang XS et al.Angiotensin II for the treatment of vasodilatory shock.N Engl J Med. 2017; 377: 419-430Crossref PubMed Scopus (324) Google Scholar To further examine the efficacy of angiotensin II in the treatment of patients with vasoplegia after cardiac surgery with CPB, the authors of the present study conducted a post-hoc analysis of ATHOS-3, hypothesizing that angiotensin II would increase blood pressure and reduce vasopressor requirements in this subset of patients. ATHOS-3 was a multinational, randomized, double-blind study in 321 adults with septic or other distributive shock who remained hypotensive despite adequate volume resuscitation over the previous 24 hours and administration of high-dose vasopressors (>0.2 µg/kg/min of norepinephrine-equivalent dose (NED)) and who had an MAP between 55 and 70 mmHg. The primary endpoint was MAP response, defined as MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3, without an increase in the dose of standard-of-care vasopressors. ATHOS-3 was sponsored by La Jolla Pharmaceutical Company, San Diego, CA, and conducted under a Special Protocol Agreement with the US Food and Drug Administration. ATHOS-3 was conducted in accordance with current Good Clinical Practice guidelines, applicable local regulations, and the ethical principles described in the Declaration of Helsinki. ATHOS-3 enrolled adult patients (ages ≥18 years) with septic and other distributive shock (defined as a cardiac index >2.3 L/min/m2 or central venous oxygen saturation >70% with central venous pressure >8 mmHg), despite adequate volume resuscitation, who displayed refractory hypotension (receipt of >0.2 µg/kg/min of NED, including vasopressin, for at least 6-to-48 hours before enrollment). The present analysis identified patients enrolled in ATHOS-3 who experienced vasoplegia after cardiac surgery with CPB. After informed consent was obtained and study eligibility was established, patients were randomly assigned to treatment groups based on the following 2 stratification criteria: (1) MAP at screening (<65 mmHg or ≥65 mmHg) and (2) baseline Acute Physiology and Chronic Health Evaluation II score (≤30, 31-40, and ≥41). Patients were randomly assigned (1:1) to receive either angiotensin II or placebo, both in addition to standard-of-care vasopressors. The starting dose of angiotensin II was 20 ng/kg/min and could be titrated as frequently as every 5 minutes to a maximum of 200 ng/kg/min to achieve an MAP of ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in the dose of standard-of-care vasopressors. From hours 3-to-48, the dose of angiotensin II could be titrated as low as 1.25 ng/kg/min or as high as 40 ng/kg/min to maintain a MAP of 65-to-70 mmHg. Standard-of-care vasopressors could be down-titrated. Angiotensin II was discontinued at hour 48; however, if the NED requirement remained >0.10 µg/kg/min, the investigator could restart treatment. Standard-of-care vasopressors were titrated according to institutional protocols. The protocol-specified maximum duration of angiotensin II use was 7 days. The primary endpoint was MAP response, defined as MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg at hour 3 without an increase in standard-of-care vasopressors. Secondary endpoints included change in NED, mortality to day 28, and safety endpoints. With a sample of 16 patients, this post-hoc analysis had power of approximately 65% to detect a 50% absolute difference in MAP response across treatment groups. The method for multiple comparisons mirrored ATHOS-3, with a hierarchical testing procedure of MAP response, followed by change in NED and then mortality. MAP response was compared across treatment groups using the Cochran-Mantel-Haenszel test, with strata defined by the randomization strata. Changes in NED were compared using a 2-sample t test. Mortality to day 28 was estimated by Kaplan-Meier methods and compared by log-rank test. All statistical analyses were performed using SAS (SAS, Cary, NC). Of the 321 patients randomized and treated in ATHOS-3, 16 (5.0%) patients with vasoplegia after cardiac surgery with CPB (9 patients in the angiotensin II plus standard-of-care vasopressors group and 7 patients in the placebo plus standard-of-care vasopressors group) were enrolled in the present study. Patient baseline characteristics were well-balanced between treatment groups (Table 1). Individual vasopressor type and dose at baseline for patients in the present cohort are provided in Table S1. Median baseline MAP was 68.3 mmHg in the angiotensin II group and 67.7 mmHg in the placebo group. The median NED at baseline was 0.28 µg/kg/min in the angiotensin II group and 0.29 µg/kg/min in the placebo group. Vasopressin within the 6 hours before randomization was administered to 6 (66.7%) patients in the angiotensin II group and 4 (57.1%) patients in the placebo group. Few patients had prior exposure to ACE inhibitors (3/16 [18.8%]) or angiotensin II receptor blockers (1/16 [6.3%]). Median circulating levels of angiotensin I in the group as a whole were elevated (306 pg/mL) relative to a previously reported group of healthy control volunteers (42 pg/mL), as was the median ratio of angiotensin I:angiotensin II (2.3 v 0.4 in healthy control volunteers).15Bellomo R Wunderink RG Szerlip H et al.Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock.Crit Care. 2020; 24: 43-50Crossref PubMed Scopus (34) Google ScholarTable 1Patient Demographics and Baseline CharacteristicsCharacteristicAng IIPlaceboTotal(n = 9)(n = 7)(n = 16)Age, n (%)°<65 y5 (55.6)2 (28.6)7 (43.8)°≥65 y4 (44.4)5 (71.4)9 (56.3)Sex, n (%)°Female1 (11.1)2 (28.6)3 (18.8)°Male8 (88.9)5 (71.4)13 (81.3)Race, n (%)°White9 (100.0)6 (85.7)15 (93.8)°Native Hawaiian or Pacific Islander0 (0.0)1 (14.3)1 (6.3)Baseline weight (kg)°Median (IQR)87.1 (80.0-93.9)87.0 (70.3-98.5)87.1 (75.2-95.6)Baseline albumin (g/dL)°Median (IQR)3.0 (2.5-3.1)2.8 (2.3-3.3)2.8 (2.3-3.2)Baseline MAP (mmHg)°<65 mmHg2 (22.2)1 (14.3)3 (18.8)°≥65 mmHg7 (100.0)6 (85.7)15 (0.0)1 (14.3)1 NED use during 6 before n angiotensin I angiotensin II angiotensin II, angiotensin Acute Physiology and Chronic Health mean arterial NED, norepinephrine-equivalent in a II, angiotensin Acute Physiology and Chronic Health mean arterial NED, norepinephrine-equivalent MAP response at hour 3 was achieved in 8 (88.9%) patients in the angiotensin II group compared with 0 (0%) patients in the placebo group (p = and Table All in the angiotensin II group achieved MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg) within the hour of treatment with a median MAP of mmHg at hour of by baseline mean arterial pressure and Acute Physiology and Chronic Health Evaluation II = 9)(n = response at at in NED at 3 to change in NED at to at in NED at to to change in NED at to to II, angiotensin Acute Physiology and Chronic Health mean arterial NED, norepinephrine-equivalent by baseline mean arterial pressure and Acute Physiology and Chronic Health Evaluation II in a arterial pressure response over mean arterial II, angiotensin Acute Physiology and Chronic Health mean arterial NED, norepinephrine-equivalent the administration of angiotensin II are in Table The dose of angiotensin II was rapidly from the starting dose of 20 ng/kg/min to a median of 5 ng/kg/min by with 6 (66.7%) patients a dose of The median dose of angiotensin II at hour 3 was 5 of Angiotensin = dose at at 3 at II, angiotensin in a II, angiotensin Treatment with angiotensin II in a significant 3, A and The response to angiotensin II was and in the dose of standard-of-care vasopressors. At hour 3, the median standard-of-care vasopressor dose had decreased from baseline by µg/kg/min change of in the angiotensin II group compared with change in the placebo group = change = At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by µg/kg/min change of in the angiotensin II group compared with an increase of µg/kg/min change of in the placebo group = change = 0.0013). Mortality to day 28 between with in each treatment Median change in norepinephrine-equivalent dose over the hours of treatment. Median change in norepinephrine-equivalent dose over the hours of treatment. NED, norepinephrine-equivalent A of events is in Table both and were reported in 5 patients in the angiotensin II group compared with 7 patients in the placebo group. Of 3 patients experienced that were by the study investigator in the angiotensin II group compared with 5 patients in the placebo group. in (n = in the placebo group. was in each treatment group. on study day 2 because of shock in the angiotensin II group. on study day 3 because of of in the placebo group. were of venous or arterial events reported. patients in the angiotensin II treatment group were on compared with 6 patients in the placebo = 9)(n = in of study outcome II, angiotensin in a II, angiotensin In the present post-hoc analysis of patients with vasoplegia who were enrolled in ATHOS-3, angiotensin II to a of vasoplegia. pressure increased rapidly and was of vasoplegia is because hypotension in the is associated with In a study of patients after cardiac surgery with CPB, patients with vasoplegia compared with without experienced increased (1) incidence of postoperative renal compared with (2) duration on hours compared with 8 (3) duration in the compared with 2 and (4) mortality compared with F Kilger E Beiras-Fernandez A et al.Association between vasopressor dependence and early outcome in patients after cardiac surgery.Anaesthesia. 2006; 61: 938-942Crossref PubMed Scopus (49) Google Scholar The blood pressure response to angiotensin II a significant in the dose of standard-of-care vasopressors. At hour 12, the median standard-of-care vasopressor dose had decreased from baseline by 76.5% in the angiotensin II group compared with an increase of 7.8% in the placebo group (p = 0.0013). patients experienced events in the angiotensin II group compared with patients in the placebo which may be to this data that exogenous angiotensin II is a treatment option for vasoplegia after cardiac surgery with CPB. is because high may be for patients with vasoplegia and are associated with in patients who cardiac surgery with CPB.7Busse LW Barker N Petersen C Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options.Crit Care. 2020; 24: 36-46Crossref PubMed Scopus (27) Google Scholar according to a study in patients, the and duration of therapy were associated with and may to the of cardiac C et cardiac events during vasopressor A Care Med. PubMed Scopus Google Scholar are in the management of patients. Vasopressin was in the Vasopressin in Patients with Vasoplegic Shock After Cardiac Surgery trial to be associated with and renal compared with norepinephrine in patients with postoperative et norepinephrine in patients with vasoplegic shock after cardiac The randomized controlled 2017; PubMed Scopus Google Scholar treatment options for patients refractory to and vasopressin were blue and hydroxocobalamin been investigated for use as alternative to based on their on and in MAP and of vasopressor requirements been reported for both S Armour TK Joppa WR et al.Use of hydroxocobalamin (vitamin B12a) in patients with vasopressor refractory hypotension after cardiopulmonary bypass: A case series.Anesth Analg. 2019; 129 (e1-4)Crossref PubMed Scopus (12) Google L Umbrello M Greco T et al.Methylene blue as a vasopressor: A meta-analysis of randomised trials.Crit Care Resusc. 2013; 15: 42-48PubMed Google Scholar analyses the for of morbidity and mortality for methylene Lin HM et al.Methylene blue is associated with outcomes in vasoplegic shock.J Cardiothorac Vasc Anesth. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar and in response to N et for the treatment of cardiac A case J 2018; PubMed Scopus Google Scholar methylene blue may or syndrome in with also can in patients with for Scholar vitamin C also has been as a treatment option for vasoplegia to and because is a for C was reported to reduce vasopressor requirements in 3 patients with refractory PM S et C for vasoplegia after cardiopulmonary bypass: A case A 2018; PubMed Scopus (15) Google Scholar were significant in mean to of or the median NED in the 2 between vitamin C and placebo in a recent double-blind, randomized study in patients with vasoplegia after cardiac surgery with F Bitker L Hessels L et al.A pilot, double-blind, randomized, controlled trial of high-dose intravenous vitamin C for vasoplegia after cardiac surgery.J Cardiothorac Vasc Anesth. 2020; 34: 409-416Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar The present analysis is in the of angiotensin II as a alternative for patients with vasoplegia. The data are with recent reports that angiotensin II is effective in patients with vasoplegia. MAP and of angiotensin II in a case of vasoplegia after a bypass that was refractory to 5 including methylene blue and hydroxocobalamin, has been A McCurdy MT Weiner M et al.Use of angiotensin II for post cardiopulmonary bypass vasoplegic syndrome.Ann Thorac Surg. 2019; 108 (e5-7)Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar of angiotensin II for vasoplegia in 5 patients refractory to multiple after combined heart and liver heart and and bypass and and of both left and ventricular assist also been PM Sims CR Daly RC et al.Use of angiotensin II for vasoplegic shock in a combined heart and liver transplant recipient with systolic anterior motion physiology.J Cardiothorac Vasc Anesth. 2019; 33: 2366-2367Abstract Full Text Full Text PDF PubMed Scopus (8) Google PM Radosevich MA Kashani KB et al.Synthetic human angiotensin II for postcardiopulmonary bypass vasoplegic shock.J Cardiothorac Vasc Anesth. 2019; 33: 3080-3084Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar in was incidence of The was in the present with events occurring in the angiotensin II group. Angiotensin II may be effective in blood pressure in patients with vasoplegia to a in ACE activity in a reduced of angiotensin I to angiotensin II. ACE is present in the although also is in other as the and J Angiotensin II in septic shock.Crit Care. PubMed Scopus Google Scholar cardiac surgery with CPB, the vascular and the of ACE is in an of angiotensin I and a relative of angiotensin II. angiotensin I is by to the vasodilatory angiotensin levels of circulating angiotensin with which increases vascular are associated with increased McCurdy et Angiotensin II and vasopressin for vasodilatory A of of J Care Med. Scholar with this CPB duration is an for the of R F factors for vasoplegia after cardiac A Thorac Surg. 2019; PubMed Scopus (14) Google Scholar In an response has been reported blood with the CPB with occurring within the of the the is S A J et after and Cardiothorac Vasc Anesth. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar would be to ACE activity and the relative of angiotensin II. events were to be in the present as by an increase in the ratio of angiotensin ACE which a in ACE The present analysis had was a post-hoc analysis and was the In the sample in this group a analysis of the safety of angiotensin II and on data however, with other reports of safety of angiotensin II in patients with vasoplegia. The present post-hoc analysis of patients with vasoplegia enrolled in ATHOS-3 study blood pressure response to treatment with angiotensin II. Angiotensin II a of standard-of-care vasopressors. No of were with recent reports of efficacy and safety of angiotensin II in patients with the data that angiotensin II may be an effective in the management of vasoplegia. Additional the use of angiotensin II may be in a randomized study to and on outcomes in patients with vasoplegia after cardiac surgery with CPB.

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