Two Cases of Rocuronium-Induced Anaphylaxis/Anaphylactic Shock Successfully Treated With Sugammadex

Anaphylactic shock, a severe complication during general anesthesia, is a rapidly occurring severe allergic reaction that may be fatal. Causative agents include drugs, foods, insects, latex, and even exercise. The incidence of allergic reactions due to drugs is 1% to 3% of exposures, but the frequency of anaphylaxis is much lower.¹ The frequency of anaphylaxis during general anesthesia has been reported to be between 1:5,000 and 20,000 cases. Muscle relaxants are the most common causative drugs during general anesthesia, and it is estimated that there is 1 case for every 6,500 administrations.² Rocuronium is thought to have the highest frequency of allergic reactions.³

We report 2 cases of anaphylaxis/anaphylactic shock believed to be induced by rocuronium, in which anaphylactic symptoms disappeared following administration of sugammadex and for which remission was achieved without further complications.

In preparing this report, written consent for this publication was obtained from the patient herself (case 1) and from the patient and her parents (case 2).

CASE PRESENTATION

Case 1

The patient was a 38-year-old woman (height: 156 cm, weight: 48 kg) with a diagnosis of synovial osteochondromatosis of the left temporomandibular joint. She was scheduled for left temporomandibular joint contrast radiography and tumorectomy.

Her medical history was unremarkable. Preoperative evaluation was normal except for decreased mouth opening, with the remainder of the airway examination otherwise unremarkable. No difficulty was expected with mask ventilation.

Prior to anesthesia, Urografin Inj 60% (a hyperosmolar ionic contrast agent, amidotrizoic acid) was injected into the temporomandibular joint to perform contrast radiography. Anesthesia was then rapidly induced with 100% oxygen, 100 μg of fentanyl, and propofol at a target blood concentration 6 μg/mL followed by 30 mg (0.625 mg/kg) of rocuronium. Propofol target concentration was decreased to 4 μg/mL (∼140 μg/kg/min) and maintained after the induction of general anesthesia. Since trismus was observed preoperatively, nasal intubation with a fiberscope was performed. However, the endotracheal tube was removed because of esophageal intubation, and manual mask ventilation was performed. At that time, redness appeared on the anterior thorax, spreading from the abdomen to the thighs and the face. A bulging rash also appeared on the thighs. Although blood pressure had not decreased (95/65 mm Hg), the patient's heart rate was elevated at 150 beats/min. Therefore, according to the clinical diagnostic criteria of anaphylaxis⁴ (Table 1), anesthesia induction agent–induced anaphylaxis was suspected, so the continuous administration of propofol was discontinued, and 375 mg of methylprednisolone was administered by rapid infusion. We simultaneously obtained a blood sample. Manual mask ventilation was smooth, and there were no abnormal respiratory sounds. Sugammadex 200 mg (∼4 mg/kg) was administered as an antagonist of rocuronium, upon which cutaneous symptoms were alleviated and heart rate decreased to 90 beats/min. Blood pressure was 110/50 mm Hg, and it did not decrease thereafter. After restarting spontaneous respiration, the surgery was suspended, and the patient awakened rapidly without hemodynamic instability. Because of concerns of possible biphasic anaphylaxis, the patient was transferred to a third-party medical institution. However, no abnormalities were observed, and the patient was discharged the following day. Two months later, a drug-induced lymphocyte stimulation test was performed. Propofol and rocuronium tested negative, but Urografin Inj 60% and fentanyl were positive.

Table 1. Clinical Criteria for Diagnosing Anaphylaxis*

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DISCUSSION

Anaphylaxis is roughly divided into immunologic (IgE-mediated) and nonimmunologic (non–IgE-mediated) types. The nonimmunologic type has been referred to in the past as “anaphylactoid” reaction, but in recent years, this name is less used and tends to be bundled with anaphylaxis. In case 1, the contrast injection was the first exposure for the patient, and in both cases 1 and 2, general anesthesia agents were first-time administrations for these patients. It is thought that the cause of allergies to muscle relaxants is due to their quaternary ammonium structure. This structure is also included in some cosmetics, toothpastes, shampoos, and other common products. It is possible that one might first be sensitized by being exposed to them in our daily lives. Thus, initial use of rocuronium could trigger anaphylaxis.⁵

During general anesthesia, there are numerous opportunities for patients to come into contact with potential allergens such as drugs, blood components contained in transfusions, and latex. Although anaphylactic shock can occur at any stage of general anesthesia, 90% of cases occur during induction of anesthesia.⁶ As multiple drugs are administered almost simultaneously during the induction of anesthesia, it is difficult to identify the causative drug. However, muscle relaxants are the most common causative drugs, followed by latex and antibacterial drugs (Table 2). Rocuronium has been shown to have the highest frequency of allergy among the muscle relaxants.³ Rocuronium was suspected to be the cause of anaphylaxis in both cases 1 and 2, considering the time course.

Table 2. Substances Responsible for IgE-Mediated Perioperative Hypersensitivity Reactions in France (Results in Percentages From 7 Consecutive Surveys)*

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In case 1, intra-articular contrast agent was used before induction of anesthesia. In Japan, cancer chemotherapy drugs are the most common cause of drug-induced anaphylaxis, followed by radiologic contrast agent.⁷ Therefore, the contrast agent should also be considered as the cause of anaphylaxis in case 1. The frequency of allergic reaction by intravenous ionic contrast agent and hyperosmolarity is high. However, the rate of anaphylactic shock from intra-articular contrast administration is only 0.003%,⁸ and allergic reaction by administering Urografin Inj 60% to a joint has not been reported so far. Also, in drug-induced anaphylaxis, the median time from antigen exposure to circulatory collapse is 5 minutes.⁹ In case 1, about 10 minutes elapsed from completion of the contrast examination until induction of anesthesia, and anaphylaxis occurred 2 minutes after administration of rocuronium. Because of the time course, we felt that the contrast agent was an unlikely cause of the anaphylactic shock.

As a result of blood collection very shortly after onset of symptoms, an increase in plasma tryptase (22.9 μg/L) and hematocrit (40.3%) and a disappearance of basophils were observed. Furthermore, the regression of the symptoms was confirmed 1 minute after sugammadex administration. Therefore, we presumed that rocuronium was the causative drug. However, from the results of a drug-induced lymphocyte stimulation test at a later date, the possibility of involvement of delayed type hypersensitivity reaction by fentanyl and/or Urografin Inj 60% was also considered. It should be noted that not all cases of rocuronium sensitivity are diagnosed with the drug-induced lymphocyte stimulation test, and a drug provocation test would be required to rule out rocuronium allergy.¹⁰

Improving hemodynamics is one of the most important treatments in anaphylactic shock, and any signs of imminent circulatory collapse should be treated immediately by administering epinephrine.³ Park et al¹¹ also recommended epinephrine as the first-choice drug. Indications for epinephrine administration are based on the severity of anaphylaxis symptoms (eg, hypotension, unconsciousness, respiratory symptoms or compromise, cyanosis, arrhythmia, cardiac arrest, dysphagia, intolerable persistent abdominal pain, and repeated vomiting).

The symptoms of case 1 were cutaneous symptoms and sustained tachycardia, whereas respiratory symptoms and hypotension were not observed. Therefore, epinephrine was not administered, and the second-line agent, methylprednisolone, was administered instead. When the rocuronium antagonist sugammadex was then administered, the cutaneous symptoms were alleviated, and the patient's heart rate decreased immediately following administration. Therefore, we presumed that rocuronium-induced anaphylaxis had occurred. Respiratory symptoms are observed in 70% of anaphylactic shock cases.¹² Fortunately, respiratory symptoms did not appear at the onset of anaphylaxis in this case, and manual ventilation with a mask was unremarkable. However, if respiratory symptoms had appeared, manual ventilation by a mask was difficult, or hypotension developed, simultaneous administration of sugammadex and epinephrine would have been chosen.

The reddening in case 2 appeared on the anterior thorax immediately after intubation. We assumed that the high dose of opioids in combination with propofol at the induction of anesthesia caused hypotension, with tachycardia probably occurring as compensation. The continuous administration of remifentanil was interrupted, and an attempt was made to increase blood pressure with ephedrine. However, as the low blood pressure was not alleviated and the redness spread to the whole body, the patient was diagnosed with anaphylactic shock induced by anesthesia induction agents. Cutaneous symptoms, sustained tachycardia, sustained hypotension, and decreased SpO₂ were also observed. It is possible that in this case, epinephrine should have been administered as the first-choice drug. However, we were concerned that it could cause excessive cardiovascular stimulation, and manual ventilation was not difficult with rapid return of normal oxygenation. Furthermore, as rocuronium is the causative drug associated with the highest rates of perioperative anaphylactic shock,³ and based on our experiences with case 1, we thought that symptoms might improve with administration of sugammadex. Therefore, we administered sugammadex rather than epinephrine. After administering sugammadex, the cutaneous symptoms were alleviated immediately, and the patient's hemodynamics also stabilized. Therefore, we presumed that this was a case of rocuronium-induced anaphylactic shock. If respiratory symptoms were more severe and manual ventilation were difficult, epinephrine would have been administered first.

Rapid volume expansion is also one of the initial treatments for anaphylaxis, as vasodilatation and hyperpermeability of capillary vessels occur simultaneously in anaphylaxis. This can rapidly decrease circulating blood volume. For this reason, rapid volume infusion according to circulatory dynamics is important.¹³ In case 2, we secured another peripheral vein route for more rapid volume infusion.

In both cases, we were also concerned with biphasic anaphylaxis, so the patients were hospitalized after anesthesia. Biphasic anaphylaxis occurs in about 23% of adult cases. It is reported to occur up to 72 hours after the first reaction.¹³ There is no clear standard, however, for the postevent monitoring period at present.

Some previous reports have described the effective use of sugammadex for rocuronium-induced anaphylactic shock.^14–17 One of these reported that circulatory symptoms did not improve despite multiple administrations of epinephrine but improved by administration of sugammadex.¹⁴ Kawano and Yokoyama¹⁸ theorized that the mechanism of sugammadex in reversing presumed anaphylaxis to rocuronium is the rocuronium molecule's quaternary ammonium group being enclosed by sugammadex, thereby eliminating the antigenicity of rocuronium. However, even if this antigenicity could be completely antagonized, it may not inhibit the anaphylactic reaction that is already in course.¹⁷ As such, it is important not to neglect the necessity of steroid administration or the use of epinephrine, which are standard treatments for anaphylactic shock, based on clinical presentation.

Interestingly, sugammadex itself can also cause anaphylaxis. Therefore, it is not yet standard practice that sugammadex should be selected for initial therapeutic use for perioperative anaphylaxis at anesthetic induction when rocuronium has been administered. The first-line drug would still be considered to be epinephrine, with supporting therapies such as intravascular fluids, corticosteroids, and antihistamines. However, if rocuronium is thought to be the likely agent of impending allergic response in a relatively stable patient, sugammadex can be considered. If symptoms do not resolve, standard therapy should not be deferred. For serious signs of anaphylaxis, when response to epinephrine treatment according to guidelines is not satisfactory, sugammadex should be considered an option.

In conclusion, we treated 2 cases in which anaphylaxis/anaphylactic shock occurred upon induction of anesthesia. Considering the possibility that rocuronium was the causative drug, we administered sugammadex, which improved symptoms in both cases. These results suggest that the administration of sugammadex may be effective for rocuronium-induced anaphylaxis and that it may also be effective for identifying the cause of such cases.