Transient Cross-Resistance to Neuromuscular Blocking Agents in a Patient with Tetanus

A 49-yr-old woman (weight, 55 kg; height, 156 cm) was referred to our medical center in October 2000 because of trismus and nuchal rigidity. Tetanus toxoid had been given to her in a local clinic a week prior to this admission because of general malaise and masseter rigidity. When hospitalized, she presented with tachycardia, hypertension, tachypnea, profuse sweating, copious saliva, trismus, nuchal rigidity, and hyperreactivity to noise. Past history was unremarkable except chronic onychomycosis with paronychia over right thumb. She worked in rice fields and made a recent trip to southeast Asia 40 days prior to this episode. Physical examination revealed no obvious skin wound. Laboratory findings showed only leukocytosis (12,600/mm³). Cerebrospinal fluid examination was unremarkable. Due to intractable trismus, dribbling, and impending respiratory failure, she was scheduled to receive emergent tracheostomy under general anesthesia. Before induction of anesthesia, a train-of-four (TOF) electromyography was installed in order to monitor neuromuscular function during operation. Anesthesia was induced with glycopyrrolate 0.2 mg, propofol 200 mg, and fentanyl 50 μg. Anesthesia was maintained with isoflurane 1.5% and oxygen. Short-acting neuromuscular blocking agent (NMBA), mivacurium (11 mg), was administered to facilitate tracheal intubation. Surprisingly, the full dose of mivacurium did not provide an adequate muscle relaxation measured by TOF and was accompanied by undesirable spontaneous movement (fig. 1, M). Additional doses of 4 mg mivacurium (fig. 1, M), 25 mg atracurium (fig. 1, A), and 5 mg vecuronium (fig. 1, V) still did not suppress the TOF value to zero. The patient was sent to intensive care unit after tracheostomy was completed.

In the quiet, isolated room of the intensive care unit, antibiotics with penicillin (3 million units every 6 h for 5 days) were prescribed and later was replaced by metronidazole (500 mg every 6 h for 13 days). Muscle spasm was controlled with atracurium (0.6–0.8 mg · kg⁻¹· h⁻¹) and propofol (0.02 to 0.03 mg · kg⁻¹· min⁻¹for 7 days). Propofol was later replaced by midazolam (0.3 mg · kg⁻¹· h⁻¹for 7 days). An electromyography and a nerve conduction study were performed 16 h after surgery at bedside. The nerve conduction study (NCS) revealed only mild suppression of amplitude of compound muscle action potentials (CMAP). Nerve conduction velocity and sensory nerve conduction study were within normal range. The needle electromyography studies revealed reflex spasm with persistent electromyographic activity in the masseter muscle. A follow-up of TOF revealed a normal twitch suppression following atracurium 40 h after surgery (fig. 2). The patient was weaned from the ventilator and artificial airway 21 days after initiation of artificial ventilation. No significant sequela was ever noted and the patient was discharged from our hospital uneventfully.

Resistance to nondepolarizing NMBAs has been noted in patients with burns, 1hepatic disease, sepsis, cerebral palsy, 2immobilization, 3and in patients taking anticonvulsants. 4The potential contributing factors to the resistance are altered pharmacokinetics, 5resulting from escape of drug via  wounds, increased protein binding, altered volume of distribution, depressed plasma cholinesterase activity and enhanced hepatic or renal elimination. As a receptor-mediated potential for resistance, the nicotinic receptor (AChRs) characteristics can be altered at the level of number, functions and localization by thermal injury. 6,7However, the cellular mechanism responsible for, e.g. , up-regulation of AChRs, remains unclear.

The diagnosis of tetanus in this patient was favored because of her typical symptoms and signs, and clinical progress under standard treatment against tetanus. 8,9Although no obvious deep penetrating wounds were identified, this occurred in 30% of patients with tetanus. The differential diagnosis of tetanus includes orofacial infection, drug-induced dystonic reactions and other neurologic diseases, which were all excluded in this patient. The characteristic electrophysiological findings of tetanus include a short or absent silent period, an exaggerated F-response, and persisted electromyography activity. 10The mild suppressed CMAP amplitude noted in this patient might be due to tetanus toxin itself or due to effect of atracurium when the patient had recovered from resistance.

Effects of clostridial neurotoxins on synaptic neurotransmission have been well documented. 11–13In contrast to botulism, Clostridium tetani  binds to the presynaptic membrane of the neuromuscular junction (NMJ), is internalized and transported retroaxonally to the spinal cord. The toxin-induced inhibition of neurotransmitter release from spinal inhibitory interneurons results in spastic paralysis. 14In various animal species (including human beings), direct blocking action of C. tetani  at NMJ has been reported. The toxin lowers the presynaptic resting membrane potential, decreases both evoked and spontaneous transmitter release at NMJ. 15Whether the binding efficacy of nondepolarizing NMBAs onto postsynaptic nicotinic receptors is therefore indirectly changed by toxin remains unknown. It is worthy to note that the tolerance in this patient was crossing over 3 different competitive NMBAs, although the conventional doses we used were only approximately 2 to 3 times the ED⁹⁵and so would not block all receptors at the NMJ. Interestingly, similar resistance to NMBAs has also been reported in the early phase of tetanus, 16while NMBAs have been widely used in patients with tetanus. 17Failure to detect any transient loss of response to NMBAs in early phase of tetanus might be caused either by a lack of opportunity of using TOF monitoring or being masked by heavy intravenous sedation without notice. The exact cellular mechanisms for the resistance to NMBAs and its recovery in tetanus still need further exploration.

The authors thank Ya-Chun Chu, M.D., Ph.D., and Mei-Yung Tsou, M.D., Ph.D. (Associate professors, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan) for their technical assistance.