This was a rare case of adrenaline-resistant anaphylactic shock induced by a contrast medium following an overdose of risperidone. The clinical course of this case showed that risperidone may have a dose-dependent effect on adrenergic responsiveness. Because adrenaline is an important rescue drug for the treatment of anaphylaxis [7], clinical evidence of the concomitant use of adrenaline and antipsychotics with α-blocking activity should be accumulated.

Several etiological mechanisms of anaphylaxis have been described, but most episodes are triggered through an immunological mechanism involving IgE [8]. However, contrast media-induced anaphylaxis, previously classified as an anaphylactoid reaction, is usually IgE-independent [9, 10] and involves the release of histamine, activation of the complement system, and inhibition of enzymatic activity by the direct stimulation of mast cells and basophils. In rare cases, contrast media-induced anaphylaxis may be mediated by specific IgE antibodies and manifest as a Type I allergic reaction [9, 10]. The PMDA reported that diagnostic agents, including contrast media, induced 3428 cases of anaphylaxis between 2005 and 2017; these account for 20.3% of all anaphylaxis cases [11]. Within these cases, diagnostic agents were responsible for 120 fatalities (28.7% of all fatalities due to anaphylaxis) [11]. Anaphylaxis induced by contrast media during clinical examinations at medical institutions can be treated more rapidly than anaphylaxis associated with food or oral drugs; however, diagnostic agents were responsible for over 20% of all anaphylactic deaths. Therefore, contrast agent-induced anaphylaxis is a pathological condition that requires the attention of researchers and clinicians alike.

Because the patient had a history of unspecified drug-induced allergies, he was premedicated with steroids prior to the administration of the contrast medium in an attempt to prevent the onset of allergic symptoms. The American College of Radiology recommends that premedication be performed at least several hours or even a day prior to contrast media administration for best results [12]. However, as the patient was urgently hospitalized, the steroid was administered just prior to the administration of the contrast medium, which may have reduced its prophylactic efficacy.

In the treatment of anaphylaxis, adrenaline is usually administered once or twice at a dose of 0.5 mg via intramuscular injection, and this has been reported to be effective for the Japanese physique [11]. However, although the patient received two doses of 0.5 mg adrenaline, his hypotension did not improve. Several factors may have contributed to the patient’s adrenergic resistance. The first was his body constitution. The patient’s body (height: 174 cm; weight: 82.4 kg) was slightly larger than that of the average Japanese adult man. However, his body build was not notably different from that of people in the Western countries. Thus, the effect of body size was considered minimal. Second, the pharmacological action of risperidone may have antagonized the α-stimulating activity of adrenaline due to its high plasma concentration. Dopamine D2 and 5-HT2 antagonists, such as risperidone, possess antipsychotic properties [1]. Furthermore, laboratory animal studies have shown that risperidone exerts strong α1 and mild α2 receptor-blocking effects [1]. Therefore, in Japan, the concomitant use of antipsychotic drugs with α-blocking activity (such as risperidone and aripiprazole) and adrenaline was contraindicated because the β-agonistic effect of adrenaline would dominate and increase the risk of hypotension. However, in 2018, this contraindication was removed only for the treatment of anaphylaxis, because adrenaline is essential in anaphylaxis treatment. In fact, there are few reports that adrenaline caused severe hypotension due to suspected adrenaline reversal by the concomitant use of adrenaline and antipsychotics except for chlorpromazine [3, 13]. Therefore, adrenaline was the best option in this case as well, even though the patient was treated with risperidone. The fact that a continuous intravenous infusion of adrenaline was required to improve the patient’s blood pressure may be due to the risperidone overdose. Risperidone and adrenaline are competitive antagonists of α1 receptors; thus, their relative effects are dependent on the drug concentration. In a Japanese male adult, the Cmax, Tmax, and T1/2 of risperidone after a dose of 2 mg are 13.6–16.0 ng/mL, 0.9–1.7 h, and 3.1–3.4 h, respectively [14, 15]. In this case, the time elapsed between ingestion and hospitalization was estimated to be 1–2 h. As this is closer to the Tmax range than the T1/2 range reported above, we inferred that the blood concentration of risperidone in this patient would also be close to the peak value after ingestion. As the concentration of risperidone measured in the patient was over twice the Cmax values obtained after ingestion of the standard 2 mg dose, we believe that the patient required multiple doses and a continuous intravenous infusion of adrenaline because of the high concentration of risperidone in his body. Meanwhile, complications such as metabolic acidosis and hemorrhagic shock may also have contributed to adrenergic resistance. A high H+ concentration in the blood, acidemia, affects the exchange of H+/Ca2+ and attenuates muscular contraction [16]. However, in this patient, the arterial blood pH was 7.36, indicating mild acidemia. Therefore, it was considered that acidemia did not contribute to adrenaline resistance. Because the patient also experienced bleeding due to pelvic fractures and other injuries, the abnormal body hemodynamics caused by blood loss may have prolonged his state of shock. Thus, the patient was administered with fresh frozen plasma considering the complications of a hemorrhagic shock prior to the initiation of the continuous intravenous infusion of adrenaline. Meanwhile, the patient did not present with tachycardia, which is often observed during a hemorrhagic shock, except for transient increase due to administration of adrenaline. Moreover, FAST findings were negative, no evidence of extravasation or retroperitoneal hematoma formation was observed, and his pelvic fracture did not require transcatheter arterial embolization. Based on these findings, the adrenaline-resistant nature of his anaphylactic episode was considered to be more likely due to risperidone overdose than hemorrhagic shock. However, based on the patient’s clinical course alone, we were unable to demonstrate that the high blood concentration of risperidone was associated with the adrenaline resistance observed during treatment of the anaphylaxis, and no other potential explanation could be identified. Further investigation of this phenomenon will require additional case reports and clinical data related to the concomitant use of adrenaline and risperidone.

Adrenaline is critical for the treatment of anaphylaxis due to its ability to increase the blood pressure and cardiac contractility by stimulating α1 and β1 receptors; it promotes bronchodilation by β2 receptor stimulation. Therefore, the role of adrenaline in the treatment of anaphylaxis will continue to be of utmost importance in the future, and its use should be recommended without hesitation. However, our case showed that the effects of adrenaline may be muted in patients receiving treatment with α-blocking antipsychotics such as risperidone; the dosage and time elapsed since administration may change the required minimum effective dose of adrenaline. In our case, the patient did not show hypotension induced by a dominance of the β2 agonistic effects by adrenaline reversal. However, if the blood concentrations of α-blocking drugs are higher, the adrenaline requirement would also increase; therefore, the reaction to adrenaline administration requires special attention.