Anaphylaxis is a rare complication of anesthesia (estimated incidence 1/13,000) that can be severe and life threatening.1 In more than 58% of cases, the causal agent is a neuromuscular blocking agent, and the specific drugs most frequently involved are succinylcholine and rocuronium.1,2 Several case reports in the literature describe a possible reversal of the signs and symptoms of rocuronium-induced anaphylaxis by the injection of sugammadex.3-9 The pathophysiology of the attenuation of this phenomenon remains uncertain; however, in most cases described, there was a relatively long interval between the first symptom and injection of sugammadex, which was administered only after failure of standard treatment (14-60 min). Moreover, the doses of sugammadex varied widely (range 3.4-18 mg·kg−1), with relatively low doses being administered; only one case in seven received a dose > 10 mg·kg−1.

We report a recent case of rapid recovery from the hemodynamic signs of rocuronium-induced anaphylactic shock with a very early injection of a large dose of sugammadex (only four minutes from first symptom to sugammadex injection).

Case report

A 22-yr-old female patient was scheduled for an elective laparoscopic cholecystectomy. She was overweight (height, 170 cm; weight, 87 kg; body mass index, 30 kg·m−2), an active smoker, and had already undergone two anesthetics for an exploratory laparoscopy and the insertion of an intra-uterine contraceptive device. No adverse events had occurred during these procedures. As a premedication, the patient received hydroxyzine 100 mg po the evening and the morning before surgery. No prophylactic antibiotic was administered. Induction of anesthesia consisted of sufentanil 10 μg (0.12 μg·kg−1), ketamine 20 mg (0.23 mg·kg−1), and propofol 200 mg (2.3 mg·kg−1), followed by rocuronium 50 mg (0.57 mg·kg−1). Tracheal intubation was performed within two minutes after rocuronium injection.

The patient developed a skin rash immediately after tracheal intubation, noninvasive blood pressure measurements were unobtainable, and her heart rate increased to 165 beats·min−1. Simultaneously, end-tidal CO2 (EtCO2) decreased markedly. No bronchospasm was detected on auscultation and airway pressure was normal. The initial treatment consisted of ventilation with 100% oxygen, fluid loading with hydroxyethyl starch 500 mL, and repeated epinephrine boluses of 100 μg and 200 μg (total 700 μg). In spite of all these endeavours, the patient’s blood pressure measurement was still unobtainable. The patient’s condition deteriorated to a grade IV anaphylaxis (EtCO2 = 1 mmHg). A bolus of sugammadex 1,200 mg (13.8 mg·kg−1, the total dose immediately available in the operating theatre) was administered six minutes after the onset of symptoms. Within one minute, a complete recovery of hemodynamic parameters was observed, and within three minutes, the patient’s skin rash disappeared. The time course of acute events, as retrieved from an electronic database, is summarized in Table 1. The procedure was cancelled and the patient was allowed to emerge from anesthesia. The tracheal tube was removed 29 min after the appearance of the first signs of anaphylaxis. The patient stayed in hospital for 24 hr and was discharged the next morning.

Table 1 Time course of events

Laboratory results obtained from blood samples drawn 30 min after the beginning of the anaphylactic reaction showed a blood histamine level at 62.1 μMol·L−1 (Normal < 10 μMol·L−1), a tryptase level at 53.9 μg·L−1 (Normal < 11.4 μg·L−1). The fixation level of quaternary ammonium-specific immunoglobulin E (IgE) (Fluoro enzymo immuno assay, Gueant’s technique, Nancy, France) was at 31.2% (positive value > 2%) with an inhibition percentage of 95.98% for rocuronium (positive value > 15%). The patient was referred for an allergo-anesthesia consultation six weeks later. She missed the first appointment but was seen eight months later before a new procedure was planned. The test results excluded all other drugs used for anesthesia and latex as potential causes of anaphylaxis. The skin prick tests were negative for propofol, sufentanil, and ketamine. There was a very strong skin reaction on the test for rocuronium (1/10,000 dilution), whereas no reaction was induced from all other neuromuscular blockers at dilutions up to 1/100 (suxamethonium, vecuronium, atracurium) and 1/10 (cisatracurium). The cholecystectomy was rescheduled 13 months after the event. General anesthesia was induced with propofol, sufentanil, and cisatracurium and maintained with sevoflurane: there were no complications.

Discussion

This case report shows resolution of grade IV anaphylactic shock due to rocuronium soon after administration of a large dose of sugammadex (approximately 14 mg·kg−1).

The present case report supports the findings of several previous reports suggesting the possibility of using sugammadex to reverse signs of anaphylactic shock induced by steroid neuromuscular blocking agents. Previous case reports described recovery from a grade II anaphylaxis reaction responsive to catecholamine3-6 or, as presented here, a complete reversal of grade IV anaphylactic shock resistant to well-conducted resuscitation measures and catecholamine administration.7-9 In all cases, a sugammadex injection was followed by a rapid hemodynamic improvement, usually within two minutes. The case with the lowest dose of sugammadex was resolved in ten minutes.8 Nevertheless, although all case outcomes were positive, it is important to remain cautious given that negative case reports are published less frequently than positive cases. Randomized controlled trials are lacking, which, for obvious reasons, would be very difficult to organize.

Two objectives motivated our decision to administer a large dose of sugammadex: 1) to reverse neuromuscular blockade (and thus stop anesthesia and its unwanted hemodynamic effects) and 2) to obtain the potential direct beneficial effects of sugammadex. The mechanism of reversal of rocuronium-induced anaphylactic shock is debated. The triggering event leading to anaphylactic shock is the binding of quaternary ammonium allergens to specific membrane IgEs. This provokes mast cell degranulation and the release of mediators, the most important of which is histamine (type I immediate hypersensitivity reaction). When this type of reaction occurs, removal of the causing allergen is recommended.10 Sugammadex is a cyclodextrin with high binding affinity for steroid-type neuromuscular blocking agents. The main hypothesis for the effect of sugammadex on anaphylactic shock, which is offered as the explanation in case reports of hemodynamic recovery, is that sugammadex is also able to encapsulate quaternary ammonium allergens. This makes the binding and blocking of the IgE allergen impossible at the onset of histamine release, which occurs early in the course of an anaphylactic reaction.8 Nevertheless, the ability of sugammadex to alter the course of a fully developed anaphylactic reaction solely by removal of the trigger allergen remains a matter of debate. In a report by Clarke et al., patients known to be allergic to rocuronium had no skin reactions when exposed to a mixture of rocuronium and sugammadex.11 They also reported that administering sugammadex after exposure to rocuronium reduces the skin reaction without stopping it completely. Leysen et al. show that adding sugammadex to a solution of rocuronium-activated basophils does not reverse the activation, even at high doses.12 The key may be early administration of a large dose of sugammadex, thus stopping the anaphylactic cascade before it is self-enhanced.

The present report is a novel case of early administration of a large dose of sugammadex (14 mg·kg−1, six minutes after the rocuronium injection and four minutes after the first manifestations) without waiting for the hypothetic efficacy of standard management (Table 2). Interestingly, early treatment allowed a very rapid recovery. The effectiveness and rapidity of using sugammadex to reverse the signs of anaphylaxis lead us to think that the effectiveness of sugammadex depends on rapid administration. Nevertheless, caution must be used because sugammadex can also lead to anaphylaxis: two cases of sugammadex-induced anaphylaxis have been reported.13,14

Table 2 Previous case reports with duration of resuscitation before sugammadex injection, and sugammadex dosage

Conclusion

A series of case reports have been published detailing the effectiveness of sugammadex in reversing rocuronium-induced anaphylactic shock. The pathophysiology of this action remains unclear. A well-conducted blind comparison trial, impossible for ethical reasons, would be necessary to confirm this hypothesis. In the absence of scientific proof, the use of sugammadex should be limited to the most severe cases of rocuronium-induced anaphylaxis after failure of well-conducted initial management. Nonetheless, very early administration (within five minutes of the first symptoms) of a high dose of sugammadex (> 10 mg·kg−1) should be considered as a possible key component of effective case management.