key: cord-0926179-8xrehbd1
authors: Wang, Hanyin; Das, Subhraleena; Wieruszewski, Patrick M.; Taji, Jamil; Bartlett, Brian; Azad, Nabila; Chowdhury, Arnab; Kolar, Gururaj; Jain, Nitesh; Subla, Mir R.; Khan, Syed Anjum
title: Unexpected BP Sensitivity to Angiotensin II in a Patient With Coronavirus Disease 2019, ARDS, and Septic Shock
date: 2020-04-23
journal: Chest
DOI: 10.1016/j.chest.2020.04.015
sha: b223b6c4be8a1740b0c9e80ab8b96e6c66b22690
doc_id: 926179
cord_uid: 8xrehbd1

We report the case of an 88-year-old man with coronavirus disease 2019 (COVID-19) who presented with ARDS and septic shock. The patient had exquisite BP sensitivity to low-dose angiotensin II (Ang-2), allowing for rapid liberation from high-dose vasopressors. We hypothesize that sensitivity to Ang-2 might be related to biological effect of severe acute respiratory syndrome coronavirus 2 infection. The case is suggestive of a potential role for synthetic Ang-2 for patients with COVID-19 and septic shock. Further studies are needed to confirm our observed clinical efficacy.

of March 26, 2020, the outbreak of 2019 novel coronavirus (SARS-CoV-2) had 462,684 confirmed cases and 20,834 deaths globally. 1 An estimated 5.0% of patients with coronavirus disease 2019 (COVID-19) required ICU admission, 2.3% underwent mechanical ventilation, and 1.1% had septic shock. 2 Angiotensin II (Ang-2) is a synthetic vasopressor that received US Food and Drug Administration approval in 2017 for treatment of refractory vasodilatory shock. We report our experience with Ang-2 for septic shock in a critically ill patient with COVID-19.

An 88-year-old man with a history of hypertension, coronary artery disease, and type 2 diabetes mellitus presented to clinic with a 3-day history of cough and shortness of breath. He denied any travel history outside of Minnesota.

The patient was febrile to 38.4 C, tachycardic, and tachypneic with oxygen saturation of 48% on room air. He was transferred to the ED and received intubation. Laboratory tests were notable for lymphopenia, leukocytosis, mildly increased creatinine, and markedly increased C-reactive protein and D-dimer (Table 1) . CT chest angiogram showed diffuse perihilar ground-glass interstitial opacities with consolidation at lung bases. A nasopharyngeal swab was sent for SARS-CoV-2 polymerase chain reaction (Mayo Medical Laboratories, Rochester, MN). The patient promptly received 30 mL/ kg of crystalloid resuscitation and guideline-concordant broad-spectrum antibiotics and was admitted to the ICU. He became hypotensive and required ABBREVIATIONS: ACE = angiotensin-converting enzyme; ACE2 = angiotensin-converting enzyme 2; Ang-2 = angiotensin II; COVID-19 = coronavirus disease 2019; SARS-CoV = severe acute respiratory syndrome-related coronavirus; SARS-CoV-2 = 2019 novel coronavirus On ICU day 2, the SARS-CoV-2 polymerase chain reaction result was positive. The infectious diseases team started hydroxychloroquine and azithromycin. The patient began neuromuscular blocker therapy for ventilator dyssynchrony and was placed in prone position to improve dorsal lung aeration. Throughout the day, his vasopressor requirements worsened severely. Transthoracic echocardiography showed an ejection fraction of 61%, normal right ventricular systolic function, and an estimated right ventricular systolic e2 Novel Report pressure of 57 mm Hg. Noninvasive cardiac output monitor (FloTrac; Edwards Lifesciences Corp) showed severely reduced vascular resistance and high cardiac output. Although corticosteroids are not recommended for COVID-19, stress dose methylprednisolone was added for refractory septic shock. Ang-2 (10 ng/kg/min) was added as the third vasopressor. Soon after initiation of Ang-2 therapy, we observed considerable reduction in norepinephrine and vasopressin requirements (Fig 1) .

On ICU day 3, he was weaned of all vasopressors. The patient's respiratory status improved, with a better PAO 2 to FIO 2 ratio and less PEEP requirement. He had right upper extremity catheter-associated DVT and received therapeutic heparin. On ICU day 4, neuromuscular blocker and methylprednisolone were discontinued. On ICU day 7, the patient developed acute kidney injury with peak creatinine 2.7 mg/dL but did not require dialysis. He remained off vasopressor with stable ventilator requirement. On ICU day 9, family elected to transition to comfort measures and the patient died after compassionate extubation.

Physiologically, angiotensin-converting enzyme (ACE) converts angiotensin I to Ang-2, which stimulates Ang-2 type 1 receptors in the systemic vasculature and causes potent vasoconstriction. 3 In the phase 3 approval study ATHOS-3

, synthetic Ang-2 effectively increased BP for patients with vasodilatory shock unresponsive to highdose vasopressor therapy. 4 The patient with COVID-19 was critically ill with ARDS and septic shock. His acute sensitivity to low-dose Ang-2 treatment allowed for rapid liberation from high-dose vasopressors. Although he received hydroxychloroquine and corticosteroids before Ang-2, we would not expect these medications to have such marked hemodynamic effects.

Heterogeneous BP sensitivity to Ang-2 has been reported. In ATHOS-3, 48.5% of patients (79 of 163) in the treatment group were able to have Ang-2 downtitration to # 5 ng/kg/min at 30 min. 5 This subgroup of patients had significantly lower endogenous serum Ang-2 levels, but unlike the present patient, they had lower baseline norepinephrine-equivalent requirements. The present patient had ARDS and was taking an ACE inhibitor (lisinopril). Severe ARDS has been shown to disrupt ACE function, 6 and an ACE inhibitor directly inhibits ACE activity. 7 These factors lead to endogenous Ang-2 insufficiency and were suspected to be related to Ang-2 sensitivity in prior studies. 8, 9 However, in ATHOS-3, no difference was observed in ARDS or exposure to ACE inhibitor between the different Ang-2 sensitivity subgroups. 5 Treatment with Ang-2 in COVID-19 may have special biological consideration. SARS-CoV-2 recognizes angiotensin-converting enzyme 2 (ACE2) as a receptor for cell entry. 10 ACE2 converts Ang-2 to heptapeptide angiotensin (1-7), counteracting ACE effects. 3 In vitro, Ang-2 has been shown to downregulate ACE2 expression. 11, 12 A recent paper promoted early use of Ang-2 for COVID-19-associated vasodilatory shock. 13 Chow et al 13 asked whether Ang-2 could cause downregulation of ACE2 in vivo and, subsequently, modulate cell entry and viral replication of SARS-CoV-2.

ACE2 is the same receptor used by severe acute respiratory syndrome-related coronavirus (SARS-CoV). 14 In animal models, SARS-CoV infection resulted in considerable reduction of ACE2 expression in the lung, with subsequent increase in Ang-2 level that promoted lung injury. 15 We expect SARS-CoV-2 infection to cause a similar biological process. However, exquisite sensitivity to Ang-2 in the present case raised the question of possible Ang-2 deficiency during SARS-CoV-2 infection. In the patient, we did not observe worsening ARDS with Ang-2 treatment.

Our case report has several limitations. First, Ang-2 hypersensitivity has been observed during septic shock without COVID-19 and is thought to be caused by relative Ang-2 insufficiency. 5 Although it is possible our observation may not have been directly related to SARS-CoV-2 infection, it is suggestive the patient had a dysregulated renin-angiotensin system. Second, although it is unlikely that the reduction in vasopressor requirements was secondary to receipt of corticosteroid, this cannot be entirely ruled out. Third, the biological effects of Ang-2 in patients with COVID-19 remain unknown, and are beyond the scope of our case report.

Our report highlights an interesting observation of Ang-2 treatment of COVID-19-related septic shock. Further studies are needed to confirm our observed clinical efficacy. Measurement of serum Ang-2, lung ACE2 activity, and SARS-CoV-2 viral load in patients with COVID-19 treated with Ang-2 may provide important insight. In Italy, compassionate use of Ang-2 for COVID-19-associated septic shock was approved. 16 We look forward to hearing about their experience.

World Health Organization

Clinical characteristics of coronavirus disease in 2019 in China

An update of the role of renin angiotensin in cardiovascular homeostasis

Angiotensin II for the treatment of vasodilatory shock

Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial

Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury

Endogenous angiotensin II levels and the mechanism of action of angiotensin-converting enzyme inhibitors and angiotensin receptor type 1 antagonists

Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study

The use of angiotensin II in distributive shock

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway

Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism

Angiotensin II for the treatment of COVID-19-related vasodilatory shock

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

La Jolla Pharmaceutical company to provide GIAPREZAÔ (angiotensin II) in Italy for compassionate use in patients with septic shock associated with COVID-19

Financial/nonfinancial disclosures: Q10 None declared.Other contributions: Editing, proofreading, and reference verification were provided by Scientific Publications, Mayo Clinic. CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.