Sugammadex induced bradycardia and hypotension

Abstract Rationale: There is evidence that sugammadex can facilitate extubation post-surgery and attenuate postoperative pulmonary complications resulting from postoperative residual neuromuscular blockade. However, it may induce adverse effects, including bronchospasm, laryngospasm, bradycardia, hypotension, and cardiac arrest. Here, we present a case of sugammadex-induced bradycardia and hypotension. Patient concerns: An 82-year-old female received video-assisted thoracic surgery decortication and wedge resection of the lung for empyema. Post-surgery, she developed bradycardia, hypotension, hypoxia, and weakness. Diagnoses: The patient was suspected to have sugammadex-induced bradycardia, hypotension, hypoxia and weakness. Interventions: The patient received immediate treatment with atropine (0.5 mg) for bradycardia. Glycopyrrolate (0.1 mg) and neostigmine (1 mg) were administered to improve the train-of-four (TOF) ratio. Outcomes: Following initial management, we observed improvement in the hemodynamics of the patient. She was discharged without any sequelae. Lessons: Sugammadex-induced bradycardia or cardiac arrest are rare; however, anesthesiologists must consider the possibility of the occurrence of such events and initiate appropriate management measures. Immediate treatment with atropine and inotropic or vasopressors is warranted if the patient presents with bradycardia.


Introduction
Neuromuscular blocking agents are often employed to facilitate intubation, mechanical ventilation, and favorable surgical conditions. However, postoperative pulmonary complications, such as pulmonary hemorrhage, difficulty breathing, reintubation, and prolongation of the patient's length of stay could be attributed to postoperative residual neuromuscular blockade. [1,2] Reversal agents are used to speed up recovery time from neuromuscular blockade and prevent postoperative residual neuromuscular blockade. [3] In contrast to acetylcholinesterase inhibitors, sugammadex has been demonstrated to shorten extubation time, resulting in improved operating room turnover in clinical anesthesia settings and attenuation of postoperative pulmonary complications. [4,5] However, sugammadex has been associated with several adverse effects, including bronchospasm, [6] pulmonary edema, [6] desaturation, hypotension, laryngospasm, [7] bradycardia, and cardiac arrest. [8][9][10][11][12][13][14][15][16] Here, we present a case of sugammadex-induced bradycardia, hypotension, and hypoxia in a patient following video-assisted thoracic surgery decortication and wedge resection of the lung. In addition, we analyzed adult cases of bradycardia or hypotension following sugammadex administration between January 2014 and January 2021 with a detailed literature review as well.

Case presentation
The patient was an 82-year-old woman (146 cm, 44 kg) diagnosed with hypertensive heart disease with no known history of allergy. Upon being diagnosed with empyema, she was scheduled for video-assisted thoracic surgery decortication and wedge resection of the lung. Pre-procedural electrocardiography revealed a normal sinus rhythm. Cardiac echocardiography showed a left ventricular ejection fraction of 71% and impaired left ventricular relaxation. Abnormal laboratory data demonstrated a white blood cell count of 15500/uL and C-reactive protein level of 220.7 mg/L. Vital signs were unremarkable except for oxygen saturation being around 90% to 95% on room air.
Routine monitoring included electrocardiography (lead II), noninvasive blood pressure, pulse oximetry, end-tidal carbon dioxide measurement, entropy, and the use of neuromuscular transmission monitors (NMTM). General anesthesia was induced with thiamylal (225 mg), rocuronium (50 mg), lidocaine (40 mg), fentanyl (75 mg), and glycopyrrolate (0.1 mg). The patient was intubated with a 32 Fr left double-lumen tube, and inspected using a fiberoptic bronchoscope. Following tracheal intubation, a right radial arterial line and central venous catheter were inserted. Anesthesia was maintained with sevoflurane (0.5-0.9), minimum alveolar concentration and propofol (20 mL/h) ti4trated to effect under entropy. In addition, the patient received a continuous dose of rocuronium (15-10 mg/h) under NMTM. Ventilation was adjusted to maintain an end-tidal carbon dioxide of 35 to 45 mmHg. The surgery was completed uneventfully in 2 hours and 40 minutes. At the completion of the procedure, arterial blood pressure of the patient was estimated to be 124/85 mmHg; heart rate, 65 beats per minute (bpm); SpO 2, 99%; NMTM count, 4; and train-of-four (TOF) ratio, 64. The patient regained consciousness and spontaneous breathing. A dose of 200 mg sugammadex was next administered. One minute following sugammadex administration, the patient developed sinus bradycardia with 34 bpm without diffuse ST depression, hypotension (67/34 mmHg), hypoxia (SpO 2 : 65%), with an NMTM count of 0, and TOF ratio of 0. The patient was immediately administered atropine (0.5 mg) intravenously, following which her hemodynamics improved, with a corresponding heart rate of 65 bpm, SBP of 89/50 mmHg, and SpO 2 of 93%. Subsequent administration of glycopyrrolate (0.1 mg) and neostigmine (1 mg) improved the TOF ratio to 69. Arterial blood gas values were as follows: pH, 7.291; PaO 2 , 75 mmHg; PaCO 2 , 51.4 mmHg; HCO 3 À , 22.8 mmol/L; lactate, 1.1 mmol/L; hemoglobin, 12.6 g/dL; and hematocrit, 36.7%. The anesthesiologist replaced the double-lumen tube with a single-lumen 4endotracheal tube, following which the patient was transferred to the intensive care unit for further care. The patient was extubated and discharged 4 and 10 days post-surgery, respectively, without any sequelae.

Discussion
PubMed and Cochrane Database were searched for the terms "sugammadex AND (bradycardia operating room cardiac arrest)" in January 2021. Articles between January 2014 and January 2021 were included regardless of the type of publication or journal. The full text of the articles was retrieved. The authors assessed the articles using the following set of criteria: 1. the article is written in English; 2. the study is a case report or case series; 3. the study includes a description of the dose of sugammadex used, its adverse effects, and the treatment strategy; 4. the subjects are adult patients.
Information such as the type of publication (case report), year of publication, description of adverse effects, treatment adminis-tered for the reaction, and patient outcome were extracted from the articles. The results have been summarized in Table 1.
Different management practices were adopted according to clinical symptoms and signs. A total of nine cases were reported to have bradycardia. Therefore, atropine (4 out of 11) [9,10,14,16] or glycopyrrolate (1 out of 11) [11] were administered. Although the mechanism of anticholinergic agents remains unknown, and their effects are limited, the use of anticholinergic agents to treat s44ugammadex-induced bradycardia is still being considered in some case reports. [18] However, some patients did not respond to anticholinergic agents such as atropine. [16] In cases where hypotension was reported, vasopressors with epinephrine, norepinephrine, or ephedrine were administered. [8,[10][11][12][13][14][15][16][17] Additionally, other drugs, including lidocaine, calcium, and nicorandil, were administered to prevent further progression of cardiac ischemia and arrhythmia. Vasopressors have been preferred over anticholinergic agents for the treatment of sugammadex-induced bradycardia owing to the absence of known muscarinic effects of sugammadex [19] and inadequate response to atropine. [16] In our case, hypotension and bradycardia were effectively treated via administration of ephedrine and atropine.
The etiology of cardiac and pulmonary adverse effects in all the other cases is unknown. Two cases were suspected to be associated with hypersensitivity to sugammadex, as indicated by serum tryptase level and/or skin prick test. [12,15] Another case was clinically diagnosed with hypersensitivity to sugammadex with tryptase and IgE levels within the normal range. [17] These patients immediately experienced erythema, hypotension, or desaturation following the administration of sugammadex. Therefore, anaphylactic medications, such as methylprednisolone, and antihistamine drugs with hydroxyzine pamoate were administered. [12,17] Pühringer et al [18] reported that hypotension was observed in a study involving large doses of sugammadex. However, at three different doses of sugammadex (2, 4, and 16 mg/kg) in pooled phase I-III patients, the incidence of marked bradycardia was found to be 1%, 1%, and 5%, respectively. [6] Upon reviewing these 11 cases, we found that the dose of sugammadex ranged from 2.08 to 4.17 mg/kg. [8][9][10][11][12][13][14][15][16][17] In our case, the dosage of sugammadex used was 4.55 mg/kg. Therefore, the correlation between the dose of sugammadex and severity of bradycardia needs to be further investigated. From 2014 to December 31, 2020, a total of 282 cases of major cardiac events were reported following sugammadex/sugammadex sodium/bridion administration as per the Food and Drug Administration Adverse Event Reporting System database. These events include bradycardia (n = 160), cardiac arrest (n = 110), cardiorespiratory arrest (n = 16), hypotension (n = 83), and decreased oxygen saturation (n = 55). [20] However, in this study, we have investigated only 11 case reports from previous literature. [8][9][10][11][12][13][14][15][16][17] Therefore, the incidence of adverse effects associated with sugammadex could have been underestimated.

Conclusions
Although sugammadex-induced bradycardia or cardiac arrest are rare, anesthesiologists should consider the possibility of the occurrence of such events. Immediate treatment with atropine and inotropic or vasopressors is recommended in such cases. Furthermore, advanced cardiac life support is required if initial management fails to manage the adverse effects.