This case study was authorized by our institutional review board (IRB no. 2024-03-011). This study was exempted from written informed consent due to retrospective analysis based on medical records by Institutional Review Board. A male emaciated patient (50 years old, height 168 cm, weight 54 kg, body mass index [BMI] 19.13 kg/m²) presented to the hospital with a left wrist fracture and dislocation of the 3rd-5th metacarpal bones and hamate caused by trauma 2 days before admission, with open reduction and internal fixation scheduled. The patient had no unusual medical history, such as up-regulation or down-regulation of nicotinic acetylcholine receptors, diabetes, hypertension, hepatitis, tuberculosis, neuromuscular disorders, or anaphylaxis. He did not smoke and had no history of surgery or medication (including herbal medicine). In addition, preoperative laboratory tests revealed hemoglobin of 13.7 g/dl and hematocrit of 42.7%, liver function (aspartate aminotransferase and alanine aminotransferase, 32/35 IU/L), total bilirubin (0.77 mg/dl), electrolytes (Na/K/Ca, 142/4.2/102 mEq/L), and renal function (blood urea nitrogen/creatinine, 16.2/0.8 mg/dl). There were no unexpected results in tests for protein/albumin (7.1/4.4 g/dl), blood sugar (94 mg/dl), thyroid function (tiriodothyonine [T3]/free thyroxine [FreeT4]/thyroid stimulating hormone, 78.58/0.98 ng/dl/1.341 uIU/ml), and chest X-ray. The electrocardiogram (EKG) showed an incomplete bundle branch block. The upper airway examination revealed Mallampati class II, and the dental status was satisfactory. After arriving in the operation room and receiving patient confirmation, non-invasive blood pressure, EKG, SpO₂, ETCO₂, body temperature, and bispectral index (BIS) monitoring devices were used. These results revealed that there were no abnormalities within the normal range. Then, NFM (Acceleromyography, Getinge Flow-i anesthesia equipment intelligent model, Maquets) was applied to the right hand, with the forearm and fingers Tightly immobilized. The intravenous route was on the same side, but higher than the NFM location. The intravenous method performed well, with no symptoms of leakage or extravasation. Anesthesia was produced using propofol 100 mg (2 mg/kg) and sufentanil 10 μg (0.2 μg/kg), followed by rocuronium 40 mg (0.74 mg/kg, ED95 × 2.67) as an NMBD, along with regulated breathing. The twitch response to train-of-four (TOF) stimulation subsided roughly 90 s after delivery, and endotracheal intubation (I.D. 7.5) was done 3 min after administration of rocuronium. Anesthesia was maintained with an oxygen-air mixture gas (1:1), a fresh gas flow of 2 L/min, desflurane at 6-8%, BIS at 30-40, ETCO₂ 35-40 mmHg, and a body temperature of 36.0-36.6°C.

Approximately 5 min after first rocuronium injection, a T1 response developed in TOF stimulation, followed by T3-4 responses 20 min later. Accordingly, 10 mg of rocuronium was delivered as the initial booster dosage. However, after 10 min, a T4 response occurred, and after 20 min, the TOF ratio had reached 46%. Rocuronium 20 mg was given as a second booster dosage. After less than 5 min, T1 reaction resurfaced, and 20 min later, T4 reaction reappeared. Because of the short duration and rapid recovery, no additional rocuronium was administered during surgery, allowing anesthesia to be maintained while spontaneous assisted breathing (ETCO₂ 35-40 mmHg) was maintained for the patient’s safety (Figs. 1, 2). Forty minutes after T4 emerged, the TOF ratio surpassed 75%. The surgery was completed 15 minutes later, sugammadex 100 mg (1.85 mg/kg, Ilsung sugammadex sodium inj^Ⓡ, prefilled syringe IlsungIS Co.) was delivered to prevent residual neuromuscular blockade. And then 5 min later, extubation was conducted after ensuring that the patient had verbal responses such as raising the head for 5 s, tongue protrusion, and eyelids opening, as well as maintaining a BIS greater than 75 and a tidal volume of 6 ml/kg or above. During the procedure, the patient’s vital signs were stable, and the estimated blood loss was less than 50 ml with a tourniquet (250 mmHg) for 80 min. We investigated the rocuronium’s storage state and expiration date, as well as the administration method, and found no concerns. Following that, the patient passed through the recovery room and was transferred to the ward with no complications. The patient was advised to have additional tests to determine muscle power, such as muscle mass, electromyography, muscle strength tests, and an isolated arm neuromuscular function test, but he was discharged without incident on the 10th day following surgery because he had no difficulty with daily activities.

Resistance is described as a decrease in the effectiveness of a drug to treat a disease or condition. Tolerance is a phenomenon in which the body becomes accustomed to a medicine, necessitating the administration of more or different medications. Tachyphylaxis (Greek: tachys, "rapid" and phylaxis, "protection") is a medical term that refers to an acute, sudden decrease in responsiveness to a drug following its administration, i.e. a rapid and short-term onset of tolerance. It may occur after a single dose or a succession of minor doses [1,2]. Although these three words can have comparable connotations, this study will utilize acute tolerance. In this situation, the onset time of the initial dose of rocuronium 40 mg (0.74 mg/kg, ED95 × 2.67) was 1 min and 30 s, which is considered a normal response [9]. However, because the reaction to two more booster doses of rocuronium was shorter than the expected effect period, acute tolerance or tachyphylaxis, rather than resistance, can be assumed.

Among anesthetics and its adjuvants drugs, acute resistance to cardiovascular and analgesic effects has been documented for penthotal sodium, ephedrine, nitrous oxide, local anesthetics, and opioids [1,10-12]. There have been numerous reports of acute resistance to a depolarizing NMBDs, succinylcholine [13,14]. Though the mechanism of action has not been determined, a self-antagonist of succinylcholine caused by the interaction of non-depolarizing NMBDs, alterations in sensitivity of nicotinic acetylcholine receptors, and acetylcholinesterase are suspected as causes [13,14]. Acute and chronic tolerance of non-depolarizing NMBDs has been found in cases of long-term use in intensive care units [3,4]. Most of the difficulties were caused by pharmacokinetics or pharmacodynamic alterations. The pharmacokinetic changes may include impacts on protein binding, distribution volume, metabolic rate and clearance, etc. depending on the patient’s disease, drugs, and condition [1,4].

In this example, a 50-year-old male patient had a low BMI and no other diseases that were thought to affect NMBDs. There were no contributing factors such as smoking, alcohol consumption, medication, or a previous medical history. Furthermore, this patient didn’t take any other medicines for hormonal agents, anticonvulsants, or acetylcholine esterase inhibitors, which are thought to be resistant to non-depolarizing NMBDs [3-7,14,15]. However, rocuronium’s action time was reduced, and a comparable reaction was found with subsequent booster doses. Another point to consider while using the i.v. route is that the site of medication administration on the right forearm and NFM application were on the same side of the right thumb. It may affect rocuronium’s start time, although the duration of action and recovery will differ.

From the pharmacological qualities of rocuronium, the rate of clearance, mean residence time and volume of distribution at steady state were 3.3 ± 0.77 ml/kg/min, 67.2 ± 18.8 min and 212.5 ± 40.1 ml/kg, respectively. The distribution α and elimination β-half lives were 7.5 ± 3.33 min and 85.6 ± 18.4 min, respectively. Achieving a T1 of 90 % and a TOF ratio of 0.7 required 31±11.7 min and 36 ±7.3 min, respectively [9,15]. Because there were no problems in kidney or liver function in this example, distribution and clarity should be normal. As the drug’s potency declines, the onset time increases, yet rocuronium 2 x ED95 (0.6 mg/kg) in adductor pollicis muscle takes 60-90 s [1,9,15-17]. In this example, the onset time was 90 s, which is within normal range, but the length was shorter than in most situations. Furthermore, the dose was doubled between the first (10 mg) and second booster doses (20 mg), however there appeared to be no difference in the duration of action, raising the possibility of acute tolerance following the initial dose. The diaphragm has stronger resistance than the adductor pollicis because each muscle responds differently. Therefore, in most cases, diaphragm function can be recovered before TOF stimulation in the adductor pollicis is restored. Inhalation anesthetics used simultaneously improve the action of NMBDs, because desflurane has a low blood gas partition coefficient, allowing it to take effect quickly in the body [9,18]. Thus, it may have had an effect on the efficacy of NMBDs for a brief length of time following induction of anesthesia [9,17,18]. In this situation, the administration of desflurane to maintain anesthesia is thought to have influenced the length of the initial dose of rocuronium [9,18]. However, when the booster dose was given, it took less than 20 min from the TOF reaction to the return of T4. It is feasible to forecast that the patient’s qualities were superior, but unfortunately, there is no method to test this.

Other possible causes include the following. The first patient was malnourished, yet he lived a normal social before the tragedy. The second is insufficient dose or a technical problem. The initial dose was rocuronium 40 mg (0.74 mg/kg, ED95 × 2.67) with two booster doses (10 and 20 mg). However, it was not deemed an insufficient dose (70 mg/54 kg/h) for this patient. The pharmacologic impact of rocuronium may be influenced by the mix of bodily components. Rocuronium dose based on total body weight may extend neuromuscular blockade in patients with a minimal amount of skeletal muscle [19]. However, the activity time of rocuronium was reduced in this situation. The third, a technical error, is implausible because the patient’s breathing efforts were highly energetic, resulting in relatively strong NFM via acceleromyography and good immobilization of the arm and fingers. Fourth, we examined the intravenous route and injection site but found no signs of leakage or extravasation.

In conclusion, non-depolarizing NMBDs are widely employed in general anesthesia and intensive care. While the elements that contribute to acute tolerance are known as pharmacodynamic and pharmacokinetic alterations, such as metabolic rates, clearance, medication interactions, hereditary factors, and neuromuscular diseases or injuries, there will be many other aspects that are unknown at this time. If acute tolerance to NMBDs develops during surgery with long operating times, specific continuous infusion or intermittent bolus injection techniques may be used to increase the dose with NFM. Then, anesthesiologists must always be consulted to avoid overdose of NMBDs and prevent postoperative residual neuromuscular blockade with antagonists such as anticholinesterase or sugammadex.

We believe that additional research is required to understand the underlying mechanisms of acute resistance to NMBDs and to establish effective management options.