Failure of neuromuscular blockade despite high doses of rocuronium and atracurium in a patient with colorectal carcinoma

Abstract

Resistance to the effects of rocuronium and other neuromuscular blocking agents (NMBA) has been previously reported, including delayed onset of relaxation, rapid recovery and incomplete paralysis under recommended doses. These conditions have been associated with denervation injury, burns, immobilisation, infections, metabolic disorders, and drug interactions.

In this report, we describe the case of a young male without any known pre-disposing factor for NMBA resistance, who failed to attain muscle relaxation with non-depolarising NMBA despite high doses of rocuronium and atracurium during two surgeries for colorectal cancer, several months apart. Investigations for drug failure and genetic testing did not indicate a plausible cause. After chemotherapy and tumour resection, the patient underwent a third surgical procedure under general anaesthesia with normalised NMBA response.

Patient's written consent was obtained for publication.

Introduction

Neuromuscular blocking agents (NMBA) are drugs administered during general anaesthesia to provide muscle relaxation required for tracheal intubation and surgical procedures. Non-depolarising NMBA act as competitive antagonists of acetylcholine at the nicotinic cholinergic receptors (nAChR) located at the motor endplate. Resistance or attenuation of the effects of rocuronium and other NMBA have been previously reported and include delayed onset of relaxation, incomplete paralysis under recommended doses, or unusually rapid recovery from neuromuscular block. These conditions have been reported^1–5 in association with denervation injury, burns, lengthy immobilisation, congenital heart defects, infections, continued use of NMBA, chronic use of anticonvulsants and steroids.

In this report, we describe the case of a healthy young male without any known pre-disposing factor for NMBA resistance, who failed to attain muscle relaxation during abdominal surgery despite very high doses of rocuronium and atracurium.

The patient provided written consent for the publication of this case report. This work follows the CARE guidelines from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network.

Case description

A 31-year-old male was admitted in May 2023, requiring emergency laparotomy due to bowel obstruction caused by a rectal carcinoma. Except for rectal bleeding during defaecation (haematochezia) and abdominal pain for the preceding week, his past medical history was uneventful. He had never had surgery or general anaesthesia. He reported regular physical activity, a body mass index of 21.2 kg m⁻² and no chronic illnesses, medications or drug consumption of any kind.

A rapid sequence induction of anaesthesia with propofol, sufentanil and suxamethonium was followed by tracheal intubation without complications. Anaesthesia was maintained using inhaled sevoflurane. Additionally, the patient received sufentanil, rocuronium, dexamethasone and magnesium sulphate. The patient received rocuronium 20 mg upon incision, and further 20 mg after 10 min, but muscle relaxation was ineffective with persisting four twitches at the train-of-four (TOF) monitoring without fading (ratio ∼1 between the fourth and the first twitch of the TOF sequence). The surgeon reported excessive abdominal wall tension (poor relaxation, grade 4, in a four-point scale).⁶ To exclude potential causes of rocuronium effect failure, rocuronium from a different batch stored at 4°C was administered through another intravenous catheter. Over 20 min, the patient received three doses of 30 mg rocuronium without any effect on relaxation. To rule out technical issues, we placed a second TOF monitor over the contralateral ulnar nerve (adductor pollicis) and at the facial nerve (orbicularis oculi muscle) and we verified adequacy of the setup parameters (four pulses, amplitude 60 mA, 2 Hz rate, 0.2 ms duration, 200 μs sensitivity). Following these interventions, after a total of 130 mg of rocuronium during the first hour of surgery, we administered atracurium 30 mg; however, muscle paralysis remained unsuccessful with persisting four twitches without fading. The abdominal wall remained tense throughout the whole surgery and the ileostomy was performed under suboptimal conditions.

NMBA reversal was performed with sugammadex 600 mg, neostigmine 2.5 mg and glycopyrronium 0.5 mg before extubation. After the reversal agents, the TOF count demonstrated four twitches without fading. Post-surgical surveillance was uneventful, and the patient was discharged without complications.

Seven months later, the patient was re-admitted for laparoscopy-assisted resection of colorectal cancer after neo-adjuvant chemotherapy. After induction, rocuronium 100 mg was administered for intubation. Upon surgical incision, over 30 min, the patient received further rocuronium 200 mg and atracurium 100 mg; however, muscle relaxation was never attained. The TOF monitoring has revealed 4 twitches without fading during the whole procedure and the surgeon reported inadequate relaxation, grade 4.⁶ The total NMBA administered dose was 440 mg rocuronium and 100 mg atracurium over 4 h.

The patient was referred to a clinical pharmacology evaluation. Blood tests including protein electrophoresis and pharmacogenetic tests did not identify any plausible cause.

Three months later, a third surgery was planned for colon anastomosis. During the procedure, the patient received suxamethonium, rocuronium and atracurium, separately. All three drugs led to complete muscle relaxation (TOF zero) with the customary, progressive fading pattern for the non-depolarising NMBA. The patient paralysis was further confirmed by optimal surgical conditions (grade 1).

Discussion

This report presents a case of complete resistance to rocuronium and atracurium in a patient operated for colorectal cancer, without any known pre-disposing factors. The anaesthesiologists were able to rule out problems with pharmaceutical aspects, monitoring and route of administration. During two surgeries performed several months apart, the administration of high doses of rocuronium and atracurium did not result in muscle relaxation. After complete resection of the colorectal carcinoma, a third procedure was performed, with rocuronium and atracurium leading to adequate muscle relaxation.

Careful neuromuscular monitoring and surgical evaluation of muscle paralysis were carried out during the three separate surgeries.

Rocuronium is an aminosteroid, whereas atracurium is a benzylisoquinoline. These NMBA have different duration of action, distribution, metabolism and excretion; however, paralysis was unsuccessful with both drugs. Pharmacokinetic modifications of volume of distribution, clearance, and protein binding could contribute to NMBA resistance. Kidney function and volaemic status were normal; elevation of α1-acid glycoprotein was ruled out.

Drug interactions are often responsible for attenuation or potentiation of drug effects. We identified three potential drugs interacting with NMBA: dexamethasone, sevoflurane and magnesium. While chronic corticosteroid treatment has been reported to attenuate NMBA effects, a randomised controlled trial demonstrated that dexamethasone during induction of anaesthesia does not modify NMBA response.⁷ Sevoflurane and magnesium sulphate are known to potentiate NMBA effects rather than attenuate them.

Upregulation, availability and modification of nAChR structure at the neuromuscular junction are mechanisms of NMBA resistance.⁸ Upper motor neuron lesions, burns, liver disease, renal failure, disuse atrophy are conditions known to negatively influence rocuronium action.⁸ Such conditions were absent in this patient. Moreover, he did not take any drugs prior to the first surgery; specifically no anticonvulsants, steroids or chemotherapy agents, whose negative influences on NMBA have been previously described.⁹

Polymorphisms of drug transporters could explain drug inefficacy. Because rocuronium is a substrate for the efflux transporter P-glycoprotein (P-gp) and the organic anion transporters (OATPs), altered expression of the P-gp (encoded by the ABCB1), OATP1A2 (SLCO1A2 gene) and OATP1B1 (SLCO1B1 gene) are associated with rocuronium effect duration.¹⁰ Variants of these two hepatocyte transporters, responsible for rocuronium elimination, are associated with prolonged clinical duration and recovery time of rocuronium, without affecting the onset time. However, mutations in the ABCB1 and SLCO1B1 genes have been ruled out in this patient.

Drug storage, temperature and degradation also deserve consideration.¹¹ The hypothesis of an altered medicinal batch (breakage of the thermal preservation chain, unsuitability of the galenic preparation, labelling error) seems unlikely, since the first two procedures objectifying NMBA resistance were 7 months apart.

Finally, we may hypothesise that this patient had a paraneoplastic syndrome causing the drug failure. Since all identifiable causes were reasonably ruled out (drug preparation or administration, drug interactions, excessive protein binding, genetic polymorphisms for elimination and patient comorbidities), the only identifiable factor changing between the first two procedures and the third was curative tumour resection.

Considering that NMBA resistance is most often a response attenuation to NMBA, the anaesthetist may change drug class or increase the dose, while ensuring adequate monitoring and communication with the surgical team. In this case, these interventions were not able to overcome NMBA effect failure.