Dl-3-n-butylphthalide induced anaphylactic shock: a case report

Abstract

Dl-3-n-butylphthalide (DL-NBP) has good neuroprotective function and is safe for use in patients with acute ischaemic stroke. DL-NBP induced anaphylactic shock is rarely reported. Here we describe the case of a 75-year-old woman who received an injection of DL-NBP (25 mg/100 mL intravenously guttae, twice daily) for acute ischaemic stroke. Approximately 5 min after the DL-NBP injection was administered, the patient developed a decrease in blood pressure and an increase in heart rate along with skin pruritus, mottlement of the lower limbs, discomfort, and the desire to defecate, following which DL-NBP was discontinued immediately. The patient recovered with antiallergic therapy and could tolerate further treatment. We emphasise that the increased use of DL-NBP in recent year raises the importance of attention to potential allergies in clinical use, especially in patients with a history of allergies to multiple drugs.

Background

Dl-3-n-butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, antioxidative and antiapoptotic activities.^{1 2} Current treatment guidelines recommend that DL-NBP could be widely used for improving neurological deficit in patients with acute ischaemic stroke.³

Although treatment with DL-NBP is generally well tolerated, it has been reported that some patients experience drug induced adverse effects, including an increase in liver enzymes.^4–6 Cutaneous reactions induced by DL-NBP were also found in phases III and IV of a multicentre clinical trial on the use of DL-NBP.^{6 7} To date, case reports on DL-NBP associated anaphylactic shock have rarely been reported. Therefore, given the extensive use of DL-NBP in clinical practice in the People’s Republic of China, close monitoring of DL-NBP associated adverse drug reactions is critical. Here we present a case of DL-NBP induced anaphylactic shock that occurred in a patient with acute ischaemic stroke.

Case presentation

A 75-year-old woman experienced sudden dizziness with marked loss of vision. She was admitted to the emergency department of our hospital 10 hours after the initial symptoms. According to her medical records, she had a history of hypertension for 10 years, rheumatoid arthritis for 10 years, and type 2 diabetes mellitus for 1 year. She was currently being treated with amlodipine, telmisartan, metformin, and voglibose to control blood pressure and blood sugar, but they were not well controlled. She had no history of food allergies but had allergies to levofloxacin injection, oxiracetam injection, and gastrodin injection. An emergency cranial CT scan showed right cerebellar infarction, bilateral parietal and occipital infarction, lacunar infarction and brain atrophy. The patient was transferred to the neurology department for treatment. Her vitals on admission were temperature 36.1°C, blood pressure 149/77 mm Hg, pulse rate 84 beats/min and respiratory rate 18 breaths/min. A physical examination revealed decreased response, mental exhaustion and memory/comprehension/calculation deficits. The National Institutes of Health Stroke Scale score was 8. The modified Rankin Scale score was 2. The patient was diagnosed with acute ischaemic stroke.

After admission, she was received medication treatment with amlodipine (5 mg orally, once daily), telmisartan (40 mg orally, once daily), insulin, clopidogrel (75 mg orally, once daily), atorvastatin (20 mg orally, once daily), xueshuantong injection (lyophilised) (300 mg intravenously guttae, once daily), and DL-NBP injection (25 mg/100 mL intravenoulsy guttae, twice daily). The patient received the first dose of DL-NBP injection at about 09:10 without discomfort. However, approximately 5 min after the second dose of intravenous DL-NBP injection was administered at 15:35, the patient developed a decrease in blood pressure and an increase in heart rate along with skin pruritus, mottlement of the lower limbs, discomfort and the desire to defecate. At this time, the patient was indifferent.

Investigations

The condition was considered an anaphylactic shock. The severity of anaphylaxis was assessed as grade 3, according to the grading criteria for anaphylaxis.⁸ Therefore, the DL-NBP injection was discontinued immediately. The clinical pharmacist examined the patient’s medication list and assessed causality of the adverse drug reaction using the Naranjo algorithm.⁹ This yielded a probability score of +5 for DL-NBP (table 1), suggesting that it was the probable cause of anaphylactic shock.

Table 1.

Naranjo scale for assessing the likelihood of Dl-3-n-butylphthalide induced anaphylactic shock

Question	Yes	No	Don't know	Score
1. Are there previous conclusive reports on this reaction?	+1	0	0	0
2. Did the adverse event occur after the suspected drug was administered?	+2	-1	0	+2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	+1
4. Did the adverse reaction reappear when the drug was re-administered?	+2	-1	0	0
5. Are there possible alternative causes that could have caused the reaction? Are there alternative causes (other than the drug) that could have solely caused the reaction?	-1	+2	0	+2
6. Did the reaction reappear when a placebo was given?	-1	+1	0	0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	0
Total score				＋5

Treatment

The DL-NBP injection was discontinued as it was suspected to have caused anaphylactic shock. The patient was administered intramuscular epinephrine (1 mg), promethazine (25 mg), and intravenous dexamethasone (10 mg). However, the patient’s blood pressure was not restored to normal levels. The patient was then transferred to the intensive care unit. ECG monitoring was immediately conducted and showed that respiratory rate was 20 breaths/min, pulse rate 139 beats/min and blood pressure 58/31 mm Hg. To treat the patient’s hypotension, dopamine (100 mg) was intravenously administered, and norepinephrine (0.1 µg/min/kg) was infused.

Outcome and follow-up

After treatment, the patient’s consciousness improved. ECG monitoring showed that respiratory rate was 18 breaths/min, pulse rate 110 beats/min and blood pressure 138/76 mm Hg. As her circulation gradually stabilised, the dose of norepinephrine was gradually decreased until it was stopped. Later, the DL-NBP injection was switched to citicoline (0.1 g orally, three times daily). She was transferred to the neurology department and stayed for another day without exhibiting any abnormalities. During the following 1 month, the patient received citicoline (0.1 g orally. three times daily) and xueshuantong (200 mg orally, three times daily) and no further anaphylaxis occurred.

Discussion

DL-NBP has been widely used for treating acute ischaemic stroke in China and shows a good clinical effect. Here we describe the case of a patient who developed anaphylactic shock after DL-NBP injection was administered for 5 min. The DL-NBP injection was then discontinued immediately. The patient recovered with antiallergic therapy and could tolerate further treatment.

To rule out alternative causes that could induce anaphylactic shock, the clinical pharmacist examined the patient’s medication list. A xueshuantong injection (lyophilised) was administered at 08:30. According to the instructions for xueshuantong injection (lyophilised), it could induce anaphylaxis or anaphylactic shock. There were also other case reports of anaphylactic shock caused by xueshuantong.^{10 11} However, the cause and mechanism of xueshuantong induced anaphylactic shock are relatively clear.¹² Notoginsenoside, the active ingredient of xueshuantong, directly stimulates mast cells/basophils. Then, the mast cells/basophils are triggered to release bioactive mediators, such as histamine, prostaglandin 2, leukotrienes, and platelet activation factor, which provoke local or systemic allergic responses. Therefore, the anaphylactoid reaction is the main mechanism of xueshuantong induced anaphylactic shock, which occurs rapidly but is not driven by IgE.¹² However, during administration of the xueshuantong injection (lyophilised), the patient had no discomfort. Therefore, we believed that the xueshuantong injection (lyophilised) was less likely to have caused the anaphylactic shock.

For drugs, the part of the molecule known as the epitope is responsible for the anaphylactic reaction. A DL-NBP injection is composed of two components, DL-NBP and the pharmaceutical adjuvant, hydroxypropyl-β-cyclodextrin (HP-β-CD). These two components are the main factors that cause anaphylactic shock. DL-NBP, a small molecular substance, is extracted from the seeds of Apium graveolens Linn (Chinese celery).¹ The chemical structure of DL-NBP is dl-3-butyl-1(3 H)-isobenzofuranone, which can be used as a complete antigen, thereby leading to an anaphylactic reaction. Although celery induced anaphylaxis has not been reported to date, a detailed inquiry of the patient’s allergic history is of crucial importance because of cross allergic reactions. HP-β-CD is a pharmaceutical adjuvant, which may provoke severe reactions resulting from the presence of high titres of cyclodextrin reactive antibodies. Although there have been no reports of anaphylactic reactions induced by HP-β-CD, many cases have reported that sugammadex, a cylodextrin derivate, induced anaphylaxis or anaphylactic shock.^{13 14} Luke et al ¹⁵ also found that sulfobutylether-β-cyclodextrin, a solubilising agent, could induce in vitro basophil activation to release histamine and leukotriene where the reactions were dose related. In addition, cyclodextrin found in food additives and cosmetics could potentially be sensitising.¹⁶ Therefore, the exact aetiology of DL-NBP induced anaphylactic shock has not been clearly defined and requires further investigation in future research.

In this case, because anaphylactic shock occurred rapidly, this response was considered immediate hypersensitivity. Immediate hypersensitivity includes type I hypersensitivity reactions and anaphylactoid reactions, which have similar clinical manifestations and are not easily distinguished. However, they have different mechanisms. Type I hypersensitivity reactions are mediated by IgE, while anaphylactoid reactions are not driven by IgE. Unfortunately, no further drug specific serum IgE immunoassays were conducted, so we hypothesise that DL-NBP injection induced anaphylactic shock. The mechanism of anaphylactoid reactions is that drugs directly activate mast cells/basophils or act on the complement system, resulting in the release of anaphylactic mediators, thereby triggering an acute response of local or systemic allergic symptoms. Hence anaphylactoid reactions may occur after the first dose.¹⁷ A previous study has shown that anaphylactoid reactions are also related to the rate at which the drug is infused, such as vancomycin.¹⁷ In this case, the patient received the first dose of DL-NBP injection without discomfort and the infusion rate of DL-NBP injection remained unchanged, so the likelihood of an anaphylactoid reaction with the second dose was low.

Induction of an antigen specific IgE response is a prerequisite for the development of type I hypersensitivity reactions. Our patient had allergies to levofloxacin injection, oxiracetam injection and gastrodin injection, which may be regarded as multiple drug hypersensitivity syndromes.¹⁸ Because T cells are more responsive to allergens, patients with multiple drug hypersensitivity syndromes are at higher risk of developing allergic reactions to unrelated medications.^19–22 In addition, although DL-NBP injection does not have cross reactivity with levofloxacin, oxiracetam or gastrodin based on their chemical structures, potential pharmaceutical adjuvants may be cross reactive. Moreover, a wide range of substances with similar structures to DL-NBP and HP-β-CD, such as drugs, Chinese celery, food additives and cosmetics could increase the titre of specific IgE to DL-NBP or HP-β-CD, thereby increasing the risk of allergic reaction to DL-NBP injection.

Interestingly, although cross reactivity could induce an antigen specific IgE response, our patient did not experience discomfort during the first dose of DL-NBP injection. We hypothesised that the underlying reason was that the generation of a specific immune response requires time, and sensitisation seems to go along with a transient and selective unresponsiveness of mast cells/basophils to the drug administered.²³ Moreover, previous studies have also shown that allergic reactions could be regarded as an antigen specific IgE threshold effect.²⁴ Therefore, we also hypothesised that the allergen further stimulated the antigen specific IgE response rapidly during the first dose of DL-NBP injection. This resulted in sufficient IgE antibodies and an asymptomatic state of sensitivity. When the second dose of DL-NBP injection was administrated, the allergen was recognised by the IgE antibodies bound to mast cells/basophils and led to the triggering of these cells. This resulted in the immediate release of histamine and tryptase as well as the rapid generation of leukotrienes and prostaglandins.^{18 25} However, as multiple pathways may be involved in allergic reactions, the exact mechanism of DL-NBP injection induced anaphylactic shock is complex and needs further investigation.

Of note, we emphasise that the clinical use of DL-NBP should involve a detailed inquiry of the patient’s allergic history, including drug and food allergies, thereby enhancing monitoring. Moreover, the skin prick test and intradermal skin test can also be used to identify the risk of anaphylaxis. Once anaphylactic shock occurs, drug administration should be discontinued immediately, and the patient should be treated in a timely manner.²⁶

In summary, we reported a case of clinically suspected anaphylactic shock induced by DL-NBP injection in a patient with acute ischaemic stroke. Although the exact aetiology and mechanism of DL-NBP induced anaphylactic shock remain unknown, attention should be paid to potential allergies in clinical use, especially in patients with a history of allergies to multiple drugs.

Learning points.

• Dl-3-n-butylphthalide is generally considered to be safe, but it can cause anaphylactic shock in patients with acute ischaemic stroke.

• The exact aetiology and mechanism of Dl-3-n-butylphthalide induced anaphylactic shock have not been clearly defined and require further investigation in future research.

• Attention should be paid to potential allergies in the clinical use of Dl-3-n-butylphthalide injection, especially in patients with a history of allergies to multiple drugs.

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Ethics approval

This study involves human participants but was not approved. This case report does not contain personal medical information about an identifiable individual and does not have to approved by an ethics committee or institutional board. Participants gave informed consent to participate in the study.