Unexpected delayed reversal of rocuronium-induced neuromuscular blockade by sugammadex: A case report and review of literature

Abstract

BACKGROUND

Rocuronium, a nondepolarizing muscle relaxant, is usually administered during general anesthesia to facilitate endotracheal intubation and keep patients immobile during the surgery. Sugammadex, the selective reversal agent of rocuronium, fully reverses the neuromuscular blockade (NMB) at the end of surgery. Most reports show that sugammadex rapidly achieves a ratio of train-of-four (TOF), a quantitative method of neuromuscular monitoring, of 0.9 which ensures adequate recovery for safe extubation. However, very rare patients with neuromuscular diseases may respond poorly to sugammadex.

CASE SUMMARY

A 69-year-old female presented with abdominal fullness and nausea, and was diagnosed with gastroparesis. She underwent gastric peroral endoscopic myotomy under general anesthesia with rocuronium (0.7 mg/kg). At the end of surgery, sugammadex 3.6 mg/kg was administered when TOF showed 2 counts. Afterward, the TOF ratio recovered to 0.65 in 30 min. She was awake but could not fully open her eyelids. The tidal volume during spontaneous breathing was low. After additional doses of sugammadex (up to 7.3 mg/kg) in the following 3 h, the TOF ratio was 0.9, and the endotracheal tube was smoothly removed. After excluding possible mechanisms underlying the prolonged recovery course, we speculated our patient may have had an undiagnosed neuromuscular disease, hinted by her involuntary movement of the tongue and mouth. Furthermore, her poor renal function and history of delayed recovery from general anesthesia may be related to the long duration of rocuronium.

CONCLUSION

In our case, both prolonged rocuronium-induced NMB and poor response to sugammadex were noted. To optimize the dose of rocuronium, perioperative TOF combined with other neuromuscular monitoring is suggested.

Key Words: Sugammadex, Train-of-four, Rocuronium, Neuromuscular blockade, General anesthesia, Case report

Core Tip: Sugammadex reverses rocuronium-induced neuromuscular blocking effect, providing full and rapid recovery from general anesthesia. However, in rare cases, patients with neuromuscular diseases may response poorly to sugammadex. In our patient, suspected neuromuscular disease, renal insufficiency, and a history of delayed recovery from general anesthesia may indicate a delayed recovery course. An optimal dose of rocuronium adjusted by train-of-four neuromuscular monitoring throughout the surgery helps reduce the risk of prolonged recovery from general anesthesia.

INTRODUCTION

General anesthesia consisting of unconsciousness, immobility, analgesia and amnesia facilitates surgical treatment[1]. Steroidal neuromuscular blocking agents, such as rocuronium, are usually administered during general anesthesia to facilitate endotracheal intubation and to keep the patients immobile during the surgery[2,3]. Previous clinical study showed the duration of neuromuscular blocking effect induced by rocuronium 0.6 mg/kg (2 × effective dose 95) is around 23-75 min in adult patients, but varies individually[4]. At the end of surgery, a reversal agent is usually employed to reverse the neuromuscular-blocking effect and helps patients regain their muscle strength. Acceleromyography train-of-four (TOF), a peripheral nerve stimulator placed over the adductor pollicis, is widely used to evaluate the level of perioperative neuromuscular blockade (NMB)[5]. This neuromuscular monitoring facilitates the quantitative measurement of muscle strength by showing the count or ratio of TOF. The TOF count ≥ 2 is considered suitable for the administration of reversal agents[6]. In addition, a TOF ratio ≥ 0.9 recommended by clinical guidelines is safe for endotracheal extubation[7], indicating a minimal risk of residual neuromuscular blocking effect. In clinical, safe extubation is critical for avoiding perioperative respiratory complications[8-12].

The first selective binding reversal agent for steroidal neuromuscular blocking agents, sugammadex (Bridon^®), encapsules rocuronium and reverses the neuromuscular blocking effect[13-15]. Many clinical studies have shown full and rapid recovery of muscle strength by sugammadex, even in circumstances of moderate to profound muscular blockade[12,14-20]. A dose of 2 mg/kg sugammadex is recommended when TOF count > 2[21]. Restoration of neuromuscular function using the recommended dose of sugammadex is demonstrated in 95% of patients within 5 min[21]. Here we report a case of prolonged rocuronium-induced neuromuscular blocking effect and delayed reversal by sugammadex. The underlying mechanism and the role of TOF are discussed.

CASE PRESENTATION

Chief complaints

A 69-year-old female (140 cm/55 kg) complained of poor appetite, nausea and vomiting.

History of present illness

The patient had persistent abdominal fullness with intermittent nausea for several years. She visited our hospital for further evaluation because of a recent exacerbation of gastrointestinal symptoms. The gastric emptying scan showed a significantly prolonged oatmeal-based gastric emptying time, particularly in the first hour. The percentage of gastric retention after one hour (93%), two hours (50.25%), three hours (25.10%) or four hours (14.40%) was higher than the normal limit. Due to gastroparesis, the patient was admitted in our hospital for gastric peroral endoscopic myotomy.

History of past illness

The patient had history of hypertension, type 2 diabetes mellitus (DM) and α-thalassemia. She regularly took antihypertensive drugs and oral hypoglycemic agents.

Personal and family history

The patient was neither a drinker nor a smoker. No family history of myasthenia gravis, neuromuscular disease or autoimmune diseases was recorded. Her surgical history included laparoscopic cholecystectomy, lumbar spinal surgery and functional endoscopy sinus surgery.

Physical examination

Physical examination revealed dry eye and dry mouth, which may be DM-related, and pale conjunctiva that may be a sign of anemia. Hypoactive bowel sound and mild epigastric tenderness were also noted. Raynaud's phenomena or arthritis-related symptoms were not observed. Notably, non-specific involuntary movement of mouth and twitching of the tongue for years were reported by the patient herself. Since these hyperkinetic movements did not cause any daily functional impairment, she did not seek any medical consultation. Slow movement while changing position and poor hand grip muscle strength were found at the bedside.

Laboratory examinations

Before the surgery, routine examinations including levels of electrolytes (potassium 4.1 mmol/L and sodium 140 mmol/L), coagulation function and liver function (alanine transaminase 9 U/L) were all unremarkable. The complete blood count test showed anemia (Hgb 7.8 g/dL). Furthermore, preoperative laboratory findings displayed an increased level of creatinine (1.52 mg/dL) and blood urea nitrogen (26 mg/dL). A low estimated glomerular filtration rate, 34 mL/min/1.73 m², was noted during this admission.

Imaging examinations

Preoperative chest X-ray revealed normal heart size with no significant lung lesion. Electrocardiography revealed a normal sinus rhythm. Abdominal sonography showed bilateral renal cysts and parenchymal renal diseases. Panendoscopy revealed a gastric ulcer scar in the deformed antrum. No obvious obstruction or gastroesophageal reflux was observed in the subsequent barium study.

FINAL DIAGNOSIS

DM-related refractory gastroparesis.

TREATMENT

Surgical procedure

As the endoscope traveled down the esophagus, increased resistance was noted at the pyloric ring. A mucosal incision was made at 5 cm proximal to the pyloric ring, followed by a submucosal tunneling. One 1.5 cm long myotomy was performed at the pylorus. Finally, the mucosal entry point was closed by endoclips.

Induction and maintenance of general anesthesia

On arrival at the operating room, hypertension (190/97 mmHg) with oxygen saturation of 96% on room air was noted. After preoxygenation, rapid sequence induction of general anesthesia was conducted with propofol (100 mg), fentanyl (75 μg) and rocuronium (40 mg). Anesthesia was maintained using sevoflurane (1-1.3 minimum alveolar concentration) through a 7.0^# endotracheal tube. During the entire surgery, the Bispectral Index value was kept between 40-60. No supplemental rocuronium was administered intraoperatively.

Recovery from general anesthesia

Surgery was completed smoothly within 1.5 h. Before administration of the reversal agent, we turned off sevofluorane and applied TOF to this patient. Her body temperature was 36.5 ^oC. The TOF count was 2, therefore, the first dose of sugammadex 200 mg (3.6 mg/kg) was administered. After 30 min, the TOF count increased to 4 with a TOF ratio of 0.65. Though the patient was fully awake and able to follow our instructions by slight nodding, spontaneous breathing with a low tidal volume (30-50 mL) was noted. She tried to lift her eyelids but failed. During the following 2 h, her TOF ratio slowly increased to 0.8 after the second and third doses of sugammadex 200 mg. The patient was able to open her eyes and grip her hands. About 3.5 h after the end of surgery, the TOF ratio was 0.9, and her tidal volume during spontaneous breathing increased to 200 mL. The arterial blood gas analysis data were within normal ranges. About 4.5 h after the end of the surgery, her tidal volume reached 350 mL (TOF ratio = 0.95), followed by smooth removal of the endotracheal tube. The course of recovery from general anesthesia in this patient is shown in Figure 1. The patient was then sent to the post-anesthetic care unit for further care. She was transferred to the ward in 1 h without any discomfort.

Figure 1 Timeline for the trend of train-of-four count or train-of-four ratio at the end of surgery. TOFc: Train-of-four count; TOFr: Train-of-four ratio; TV: Tidal volume.

OUTCOME AND FOLLOW-UP

The patient was discharged uneventfully on postoperative day three. She was followed for 3 mo after the surgery, without recurrent symptoms.

DISCUSSION

According to previous clinical studies, a variety of predisposing factors prolong the neuromuscular blocking effect of rocuronium, including drug interaction or pathological states. First, rocuronium may have an enhanced effect when interacting with anti-arrhythmic agents, aminoglycosides or local anesthetic agents[22]. During the perioperative period, we did not use these drugs in our patient. Second, low calcium or high magnesium levels lead to delay recovery from NMB[23]. In our case, a normal calcium level (1.25 mmol/L) and mildly low magnesium level (0.43 mmol/L) were found at the end of surgery. Third, some autoimmune diseases such as myasthenia gravis may be linked to prolonged postoperative recovery. In our case, undiagnosed myasthenia gravis was ruled out based on the normal level of acetylcholine receptor antibody (< 0.2 nmol/L). In addition, the levels of Anti-Ro antibody (7 U/mL) or Anti-La antibody (9 U/mL) were within the normal ranges, which excluded Sjogren's syndrome. We also excluded other possible mechanism underlying the observed prolonged effect of rocuronium, including hypothermia, human errors, intravenous infusion problems and inaccurate TOF placement.

In addition to the aforementioned factors, the duration of rocuronium-induced neuromuscular blocking effect varies individually. After reviewing our patient’s medical record, delayed extubation was also found after functional endoscopy sinus surgery in 2010, when cisatracurium (10 mg) and neostigmine (3.5 mg) were used. This document led us to speculate that our case was an outlier who was extremely sensitive to nondepolarizing neuromuscular blocking agents. Furthermore, in our case, renal insufficiency may lead to the long duration of rocuronium. Although a previous study has proven the safe and effective use of rocuronium in patients of renal insufficiency[24], poor clearance leads to a longer duration of rocuronium in patients with renal insufficiency than in patients with normal renal function[25]. Moreover, females are more sensitive to rocuronium than males[26,27]. Taken together, in our case, there were multiple predisposing factors for the long duration of rocuronium-induced neuromuscular blocking effect.

Sugammadex reverses the neuromuscular blocking effect by directly binding to rocuronium[13]. This novel agent encapsulates rocuronium and promotes its dissociation from the acetylcholine receptor[13]. One molecule of sugammadex binds to one molecule of rocuronium, and antagonizes its effect[28]. Therefore, in our case, 600 mg sugammadex (2.75 × 10^-4 moles) was sufficient to antagonize the effect of 40 mg rocuronium (6.55 × 10^-5 moles). Theoretically, the effect of sugammadex is poor if the binding affinity between sugammadex and rocuronium is low. To date, very few published reports have discussed about the mechanism underlying the possible poor effect of sugammadex. Only one in vitro study revealed that dexamethasone may mitigate the reversal of rocuronium-induced NMB by sugammadex in a dose-dependent manner[29]. In our case, only 0.09 mg/kg dexamethasone was used, which should not significantly impede the action of sugammadex. Furthermore, sugammadex can be used safely and effectively in patients with renal insufficiency[30,31], although the recovery of TOF ratio to 0.9 may be prolonged in patients with end-stage renal disease[32].

Based on our literature review, there are sporadic previously published case reports about delayed reversal of neuromuscular blocking effect by sugammadex, as summarized in Table 1. Notably, except for patients with high magnesium levels, nearly all cases refractory to the rapid effect of sugammadex are patients with neuromuscular or movement disorders, including myasthenia gravis[33], Charcot-Marie-Tooth disease[34] or Parkinson’s disease[35]. A previous study showed that although most researchers have reported the successful use of sugammadex in patients with neuromuscular diseases, unpredictability in response or individual differences still remains an issue[36]. The possible mechanism was reported to be the redistribution of unbound neuromuscular blocking agent molecules from the peripheral compartments to the central compartments[37]. Interestingly, our patient reported tremor of her tongue with involuntary movement of her mouth for years. The associated signs included poor hand grip strength. Since tongue tremor is a rare initial presentation of essential tremor[38], our patient may be a case of undiagnosed essential tremor or other movement disorders. The correlation between muscle weakness and essential tremor had also been demonstrated[39]. In addition, essential tremor or other movement disorders are known to involve gastrointestinal symptoms such as gastroparesis[40] that was our patient’s diagnosis during this admission. Taken together, we speculated that our case may have undiagnosed neuromuscular diseases, which may partially explain her poor response to sugammadex. Further research and evaluation are required to confirm our hypotheses.

Table 1 Summary of previously reported cases about delayed recovery after sugammadex.

Ref.	Patient data	Past history	Surgery (duration)	Total dose of muscle relaxants; total dose of sugammadex	Time to extubation from first dose of sugammadex	Possible causes of delayed recovery after sugammadex
Ortiz-Gómez et al[28], 2014	60 yr/Male (115 kg/175 cm)	HTN	Sigmoid colon resection (360 min)	SCC 100 mg + rocuronium 83 mg; 1120 mg	208 min	An extreme outlier with resistance to sugammadex
Altıparmak et al[35], 2019	58 yr/Female (75 kg)	HTN, CVD, PD	Hysterectomy (90 min)	Rocuronium 45 mg; 800 mg	30 min	PD
Brown et al[44], 2019	58 yr/Male (69 kg/170 cm)	Glaucoma	Robot-assisted laparoscopic prostatectomy (not mentioned)	Vecuronium 9 mg; 400 mg	27 min	High magnesium
Fernandes et al[33], 2019	27 yr/Female (110 kg/172 cm)	Myasthenia gravis	Laparoscopic cholecystectomy (not mentioned)	Rocuronium 20 mg; 800 mg	45 min	Myasthenia gravis
Moriwaki and Kayashima[23], 2019	37 yr/Female (42 kg/144 cm)	HTN, GDM; preeclampsia	C/S (95 min)	Rocuronium 40 mg; 200 mg	> 15 min	High magnesium, pregnancy
Hiramatsu et al[34], 2022	63 yr/Male (68 kg/164 cm)	RA, DM, Af, restrictive lung disease	Hip arthroplasty (273 min)	Rocuronium 50 mg; 1200 mg	18 h	CMTD type 1A
Kiss et al[37], 2013	25 yr/Male (BMI: 32)	Myasthenia gravis	Thymectomy (120 min)	Rocuronium 50 mg; 12 mg/kg	Not mentioned	Myasthenia gravis

HTN: Hypertension; DM: Diabetes mellitus; CVD: Cerebrovascular disease; PD: Parkinson’s disease; TV: Tidal volume; IBW: Ideal body weight; GDM: Gestational diabetes; RA: Rheumatoid arthritis; BMI: Body mass index; CMTD: Charcot-Marie-Tooth disease.

To date, there have been few studies on the use of TOF in patients of neuromuscular diseases. Some researchers argued about the accuracy of TOF ratio in cases of myasthenia gravis, and recommended the concomitant use of other neuromuscular monitoring techniques such as tetanic stimulation[41]. Others emphasized the placement of neuromuscular monitoring at multiple sites in patients of neuromuscular disorders[42]. We suggest the employment of TOF throughout the surgery to avoid consumption of rocuronium more than the patient’s requirement, since preanesthetic TOF helps predict the requirement of muscle relaxants in patients of myasthenia gravis[43].

CONCLUSION

Our patient’s subclinical symptoms may have been related to an undiagnosed neuromuscular disease. Poor renal function and a history of delayed recovery from general anesthesia also hint at the possible prolonged effect of rocuronium. Our case may be an outlier who was extremely sensitive to nondepolarizing neuromuscular blocking agents or has poor response to sugammadex. The role of perioperative TOF in optimizing the dose of neuromuscular blocking agents cannot be overemphasized.