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When All Else Fails: Novel Use of Angiotensin II for Vasodilatory Shock: A Case Report

Chow, Jonathan H. MD*; Galvagno, Samuel M. Jr DO, PhD*; Tanaka, Kenichi A. MD, MSc; Mazzeffi, Michael A. MD, MPH; Chancer, Zackary MD*; Henderson, Reney MD; McCurdy, Michael T. MD

doi: 10.1213/XAA.0000000000000775
Case Reports
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Angiotensin (AT) II is an endogenous hormone that acts on venous and arterial smooth muscle to cause vasoconstriction. Recent trials have sparked great interest in its ability to be used as a vasopressor for catecholamine-refractory hypotension. Herein, we describe the successful use of AT II in a patient with a colonic perforation with septic shock refractory to conventional treatment. After AT II initiation, there was an immediate reduction in catecholamine requirement, and the patient survived.

From the Department of Anesthesiology, *Division of Critical Care Medicine

Division of Cardiovascular Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland.

Accepted for publication March 6, 2018.

Funding: None.

Conflicts of Interest: See Disclosures at the end of the article.

Address correspondence to Jonathan H. Chow, MD, Department of Anesthesiology, University of Maryland School of Medicine, 22 S Greene St, Suite S11D20, Baltimore, MD 21201. Address e-mail to JChow@som.umaryland.edu.

Angiotensin (AT) II is a naturally occurring hormone in the renin–AT–aldosterone system with a short half-life of 30 seconds. AT II modulates blood pressure through direct arterial and venous vasoconstriction, as well as through direct interaction with other catecholamines and vasopressin.1–4 It also increases secretion of aldosterone and antidiuretic hormone, which potentiates water reabsorption.5 AT II is derived from the hydrolysis of AT I via AT-converting enzyme (ACE) in the lung and renal endothelium (Figure 1). AT II has been used for vasodilatory shock since the 1930s, and its use has been reported in patients with circulatory shock, distributive shock, and ACE-inhibitor overdose.5 Most recently, it has been studied for its catecholamine-sparing effects in vasodilatory shock.1,2 Herein, we describe the successful use of AT II in a patient with a colonic perforation with septic shock refractory to conventional treatment.

Figure 1.

Figure 1.

Written Health Insurance Portability and Accountability Act authorization to use/disclose existing protected health information was obtained.

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CASE DESCRIPTION

A 70-year-old man with a history of stage 4 colon cancer on neoadjuvant chemotherapy, pulmonary embolism, and 3-vessel coronary artery bypass grafting was admitted to the intensive care unit (ICU) in septic shock. He originally underwent a laparoscopic diverting loop ileostomy for a large-bowel obstruction secondary to a colonic mass. Although there was diffuse carcinomatosis, the primary mass was completely resected during the index surgery. Three days postoperatively, he developed leukocytosis to 13,900 cells/μL, abdominal distension, and peritonitis. Because of tachycardia and hypotension, he was emergently taken to the operating room for an acute abdomen. During the exploratory laparotomy, a 5-mm perforation was discovered in his proximal ascending colon that prompted a right hemicolectomy because of the close proximity of the perforation to site of the obstructing tumor. Intraoperative abdominal fluid cultures were positive for Escherichiacoli and Streptococcusanginosus.

Despite 6.1 L of crystalloid resuscitation and transfusion of 3 units of packed red blood cells, his heart rate (HR) exceeded 130 beats per minute (bpm) and his mean arterial pressure (MAP) was <55 mm Hg. Central venous pressure was 19 mm Hg. An infusion of norepinephrine 0.05 μg/kg/min intravenously (IV) was initiated through a central venous catheter. Despite the addition of vasopressin 0.04 units/min IV, the dose of norepinephrine was rapidly escalated to 0.4 μg/kg/min to reach a MAP target of 65 mm Hg (Figure 2).

Figure 2.

Figure 2.

Postoperatively, he was transferred to the ICU with a sequential Sepsis-related Organ Failure Assessment score of 10, indicating a predicted mortality of 40%–50%.6 Myocardial infarction, abdominal compartment syndrome, and severe hemorrhage were excluded as the causes of shock based on an unremarkable troponin, benign postoperative abdominal examination, and hemoglobin of 11.0 g/dL. A noninvasive hemodynamic monitor (FloTrac; Edwards Lifesciences, Irvine, CA) indicated a cardiac index of 5.1 L/min/m2, a stroke volume variation (SVV) of 11%, and a systemic vascular resistance (SVR) of 439 dynes/s/cm5, confirming the presence of vasodilatory shock. Gram-negative and anaerobic coverage with piperacillin/tazobactam and metronidazole initiated in the operating room was broadened to include Gram-positive and fungal coverage with vancomycin and micafungin within 1 hour of arrival to the ICU. Hydrocortisone 50 mg every 6 hours was also administered, and despite an additional 5 L of crystalloids and norepinephrine requirement of 0.48 μg/kg/min, he remained in vasodilatory shock with a HR of 131 bpm, SVR of 550 dynes/s/cm5, SVV of 11%, and a MAP less than the target of 65 mm Hg.

With rapidly increasing lactate to 5.4 mmol/L and white blood cell count to 28,800 cells/μL, the patient received methylene blue 2 mg/kg IV bolus followed by a 0.5 mg/kg infusion over 6 hours. The response was suboptimal, with a decrease in norepinephrine dose by only 0.1 μg/kg/min. Based on sporadic case reports of hydroxocobalamin for rescue treatment of vasoplegia, 5 g was IV administered to the patient.7,8 Although the hemodynamic response to the hydroxocobalamin was brisk, it was only transient. The patient continued to have a rising lactate and a norepinephrine requirement of 0.28 μg/kg/min to maintain the target MAP despite resuscitation now with 13.4 L of crystalloids, vasopressin, hydrocortisone, methylene blue, and hydroxocobalamin.

The decision was made to obtain AT II (Giapreza; La Jolla Pharmaceutical Company, San Diego, CA) through the Food and Drug Administration’s (FDA) Expanded Access Program (EAP). With a norepinephrine-equivalent dose ≥0.2 μg/kg/min, the patient satisfied the FDA’s criteria for inclusion in the compassionate use program, and we were given preliminary access to AT II while it was undergoing FDA review. After permission was obtained from La Jolla Pharmaceutical Company, our institutional review board, and the patient’s family, the drug was flown on a commercial flight from Chicago and arrived at our pharmacy within 15 hours of our initial request. Because the drug was requested on a major holiday, the scarcity of commercial flights is the reason why so much time elapsed between initiation of the FDA-EAP and the acquisition of the drug.

Once the AT II arrived, we started at a dose of 20 ng/kg/min, and rapidly titrated up to 40 ng/kg/min based on the dosing reported in ATHOS-3 (Angiotensin II for High Output Shock).2 There was an immediate and dramatic hemodynamic response to the AT II. Within minutes, the dose of norepinephrine dropped 58% from 0.24 to 0.1 μg/kg/min, and by hour 2 of the infusion, the dose requirement of norepinephrine fell 79% to 0.05 μg/kg/min, while the MAP increased from 66 to 72 mm Hg and the HR remained unchanged (Figure 2). Noninvasive measurements of SVR increased 11.3% from 427 to 489 dynes/s/cm5, and SVV decreased from 17% to 12%, despite no additional fluid bolus during this timeframe (Figure 3).

Figure 3

Figure 3

By hour 12 postinfusion of AT II, the norepinephrine dose was stable at 0.05 μg/kg/min, and the lactate had decreased from 7.2 to 4.3 mmol/L. Because the AT II administration occurred in the 6-hour interval between lactate measurements, it is difficult to interpret whether the lactate started to decrease before or after the AT II administration. Also by hour 12, the HR decreased 15.4% from 136 to 115 bpm and the SVV decreased from 17% to 10%. The MAP rose from 66 to 81 mm Hg, and the SVR increased 28.4% from 427 to 548 dynes/s/cm5. By hour 24, the vasopressin dose was decreased to 0.02 units/min, and the trend of decreased norepinephrine, lactate, SVV, and HR continued, while SVR, MAP, and stroke volume continued to increase (Figure 3). The AT II infusion rate was then titrated down over the next 5 hours until a rate of 5 ng/kg/min was reached. The goal was to reach a low dose of all 3 vasopressors before the discontinuation of any 1 agent. The vasopressin was discontinued 8 hours later, followed by a down-titration of norepinephrine from 0.05 to 0 μg/kg/min 9 hours thereafter. Once the norepinephrine was discontinued, the AT II was weaned from 5 to 2.5 to 0 ng/kg/min, and it remained off for the duration of the admission.

The patient remained in the ICU for 28 days for continued respiratory failure, eventually requiring a tracheostomy. He did not require any further abdominal surgeries. He was discharged to a rehabilitation facility on hospital day 41 on a tracheostomy collar with a speaking valve.

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DISCUSSION

Although norepinephrine is endogenously synthesized and not inherently detrimental to the cardiovascular system, administration of high-dose catecholamines can cause tachydysrhythmias, organ dysfunction, and ischemia of the trunk, mesentery, and distal limbs during catecholamine-resistant vasodilatory shock.9,10 Of the standard-of-care vasopressors, none have demonstrated a mortality benefit over any other in distributive shock.11,12

Most recently, AT II has been studied for its catecholamine-sparing effects in vasodilatory shock.1,2 The ATHOS trial was a small pilot study of 20 patients in vasodilatory shock that demonstrated AT II’s utility as a rescue vasopressor agent and its norepinephrine-sparing effects (mean norepinephrine dose in AT II group 7.4 vs 27.6 μg/min in the placebo group; P = .06).1 The phase 3 follow-up to this study, ATHOS-3, was a double-blinded, randomized controlled trial of 344 patients in vasodilatory shock. Patients randomized to the AT II group had a greater change in norepinephrine-equivalent dose (−0.03 AT II versus 0.03 placebo; P < .001) and achieved the 3-hour MAP target more often than those receiving placebo (69.9% AT II versus 23.4% placebo; odds ratio, 7.95; 95% confidence interval [CI], 4.76–13.3; P < .001).2 The study was not powered to detect a mortality benefit, but it did show a trend toward decreased all-cause mortality at 28 days (46% vs 54%; hazard ratio, 0.78; 95% CI, 0.57–1.07; P = .12). In ATHOS-3, the 3-hour MAP target >75 mm Hg was set artificially higher than consensus guidelines. Because this was a phase 3 trial, Khanna et al13 acknowledge that this was done intentionally to isolate the effect of AT II’s efficacy and safety without having a competing effect from other vasopressor dose changes. It has received criticism for the low norepinephrine-equivalent requirement of 0.2 μg/kg/min for entry into the study, which many do not consider to be “high dose.” No consensus guidelines exist on what constitutes “high dose,” and Khanna et al13 derived their threshold by doubling the highest dose of norepinephrine found in the Sepsis-related Organ Failure Assessment score. This threshold is associated with a 30-day all-cause mortality of 50%.

There are no absolute contraindications to AT II administration, but ATHOS-3 did find an increased incidence of venous and arterial thromboembolic events in patients who received AT II (13% AT II versus 5% placebo). Therefore, patients should receive concurrent venous thromboembolism prophylaxis if it is medically indicated. A subsequent systematic review of AT II in 31,281 patients in 1124 studies did not report this increased risk and found that the AT II was safe to administer in humans.14

Post hoc analysis of the data in ATHOS-3 found that patients receiving placebo who were AT II deplete, as measured by higher AT I:AT II ratios, had increased mortality (hazard ratio, 1.78; 95% CI, 1.25–2.53; P = .002).15 In the placebo arm, the risk of death was associated with depleted AT II levels (hazard ratio, 1.77; 95% CI, 1.10–2.85; P = .019). However, in the AT II-treated arm, the effect of this depletion on mortality was diminished after AT II administration (hazard ratio, 0.64; 95% CI, 0.41–1.00; P = .047), indicating not only that AT II levels are predictive of mortality but also that AT II supplementation can decrease mortality in that population. Because ACE, the enzyme that hydrolyzes AT I to AT II, is predominantly found in the vascular endothelial cells of the lung and kidney, use of AT II in influenza, extracorporeal membrane oxygenation, acute respiratory distress syndrome, and renal failure populations is of particular interest.

In our patient, we saw similar results to those described in the ATHOS and ATHOS-3 trials. Administration of the drug resulted in an improvement of the patient’s MAP within minutes, followed by an immediate reduction in SVV and norepinephrine required to reach the target MAP. Over the next several hours, we observed a concomitant improvement in serum lactate, indicating improved perfusion, in addition to improved SVR, stroke volume, and HR. Because SVV and SVR are surrogates of preload and afterload, respectively, the improvement in these parameters is not surprising because AT II has been described to modulate receptors in both the arterial and venous circulation.3,4 It is possible that venous blood is being mobilized from the mesenteric vasculature to increase preload.

Our patient was on maximal hemodynamic support in the ICU before initiation of AT II. Despite conventional methods to treat septic shock with source control, antibiotics, crystalloids, steroids, and standard-of-care vasopressors, he remained refractory to all of those interventions. Rescue therapy with other adjuncts such as methylene blue and hydroxocobalamin was also unsuccessful. Only after initiating AT II did the patient’s hemodynamics start to improve, as demonstrated by improvement of multiple hemodynamic parameters, including HR, MAP, SVR, and SVV.

As with any new drug, all due pessimism should be used in interpreting the outcomes. We acknowledge that the use of a noninvasive hemodynamic monitor has known limitations in septic shock. Low tidal volumes and low lung compliance can lead to false-negative SVV values, while arrhythmias and spontaneous breathing can lead to false-positive results. Mechanical ventilation does not guarantee the lack of spontaneous breathing unless paralytics are used, and this was not done in our patient. However, our patient did not have any arrhythmias or changes in positive end expiratory pressure, and we felt that it was appropriate to use this device in a population that has not yet been validated. We did utilize a lung-protective strategy, which could also falsely decrease the SVV. However, the decreased SVV that we reported after AT II administration should not have been influenced by ventilation strategy, as this was held constant throughout the ICU course. Perhaps a better surrogate for preload would be echocardiographic measurement of the variation in the velocity time integral, but this was not performed in our patient. In addition, another confounder could have been the natural course of antibiotics. Despite rapid administration early in the resuscitation, our reported findings could have simply been the patient’s natural course after antibiotic administration and surgical source control. Finally, our case involved only a single patient, and as such, the results may not be generalizable to a broader population.

Distributive shock is the most common form of hypotension,2 and with the increasing frequency of medication shortages, it is relieving to have another drug in the armamentarium for our fight against vasodilatory shock. Although the FDA’s criteria for compassionate use required patients to meet a strict norepinephrine-equivalent threshold ≥0.2 μg/kg/min, this threshold has now been removed, as the FDA has approved AT II as a first-line vasopressor for the treatment of distributive shock.16 Perhaps AT II can now be used earlier in the algorithm for resuscitation instead of as a last-line rescue therapy as it has been used during ATHOS-3 and the EAP. Additional studies on its use during resuscitation must take place to elucidate the populations who may benefit the most from early use.

Although AT II was not yet approved by the FDA when the patient was treated, its recent approval represents an important step forward for critical care medicine. Novel treatments for vasoplegia are much needed, and the development of this new class of vasopressor provides promise for those patients who are refractory to conventional methods of treatment. Its catecholamine-sparing effects have been clearly shown in ATHOS-3, and further studies are necessary to define those populations who may gain additional benefits from its use.

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DISCLOSURES

Name: Jonathan H. Chow, MD.

Contribution: This author helped conceive the report.

Conflicts of Interest: Jonathan H. Chow declares that he serves on the speaker’s bureau for La Jolla Pharmaceutical Company.

Name: Samuel M. Galvagno Jr, DO, PhD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Kenichi A. Tanaka, MD, MSc.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Michael A. Mazzeffi, MD, MPH.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Zackary Chancer, MD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Reney Henderson, MD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: None.

Name: Michael T. McCurdy, MD.

Contribution: This author helped write the manuscript.

Conflicts of Interest: Michael T. McCurdy declares that he was the principal investigator in the ATHOS-3 trial.

This manuscript was handled by: Raymond C. Roy, MD.

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REFERENCES

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12. Russell JA, Walley KR, Singer J, et al.; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877887.
13. Khanna A, Ostermann M, Bellomo R. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377:2604.
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