Anaphylaxis to Patent Blue V. I. Clinical aspects

Allergy

ORIGINAL ARTICLE

ANAPHYLAXIS

Anaphylaxis to Patent Blue V. I. Clinical aspects A. S. Hunting1, A. Nopp2, S. G. O. Johansson2,3, F. Andersen4, V. Wilhelmsen5 & A. B. Guttormsen4,6 1

Division of Anaesthesiology and Intensive Care Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway; 2Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet, Stockholm, Sweden; 3Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; 4Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway; 5Department of Pulmonology, Oslo University Hospital, Ulleva˚l, Oslo, Norway; 6Section of Anaesthesiology and Intensive Care, Department of Surgical Sciences, University of Bergen, Bergen, Norway

To cite this article: Hunting AS, Nopp A, Johansson SGO, Andersen F, Wilhelmsen V, Guttormsen AB. Anaphylaxis to Patent Blue V. I. Clinical aspects. Allergy 2010; 65: 117–123

Keywords anaphylaxis; general anesthesia; sentinel node; skin prick test; tryptase. Correspondence S. G. O. Johansson, Department of Medicine, Clinical Immunology and Allergy Unit Karolinska University Hospital, L2:04 S-171 76 Stockholm Sweden. Accepted for publication 2 August 2009 DOI:10.1111/j.1398-9995.2009.02192.x Edited by: Marek Kowalski

Abstract Background: The dye Patent Blue V (PBV) is increasingly used for staging procedures in operable breast cancer, but is reported to cause adverse reactions. The aim of this study was to present the clinical features and the results of follow-up examinations in patients with such reactions. Methods: We studied nine patients with hypersensitivity reactions to PBV between 1999 and 2006 who were identified through the Norwegian network for reporting and investigating allergic reactions during anesthesia. Results: We observed incidences of 0.5% (7/1418) for all kinds of PBV reactions and 0.4% (5/1418) for anaphylaxis. Typical clinical features included: (i) cardiovascular and/or cutaneous symptoms, (ii) a delay in symptoms, compared to the time of dye injection, (iii) poor response to ephedrine and intravenous fluid, and (iv) need for adrenaline administration, sometimes prolonged, for circulatory stabilization. Cutaneous manifestations were noted in five of the seven patients with anaphylaxis and two additional patients without circulatory instability. During anaphylactic reactions, serum tryptase was increased in six patients and normal in one. Serum tryptase was normal in one patient with skin symptoms only. Skin prick tests to PBV were positive in all eight patients tested, including the two with skin manifestations only. Conclusion: The clinical features and the results of follow-up studies strongly suggest that these reactions are IgE mediated.

Sentinel lymph node biopsies (SLNB) are performed for staging of breast cancer, malignant melanoma, and several other malignancies. The primary draining lymph node of the tumor site, the sentinel node (SLN), is removed and examined for tumor cells. Further lymphatic spread is unlikely if no malignant cells are found in the SLN. Complete lymph node dissection is therefore not needed. The method reduces the risk of distressing sequelae, such as lymphedema (1). The popularity of the technique has increased rapidly. The SLN is identified by the peritumoral injection of markers, usually a radioactive tracer and a blue dye (1). These are transported with the lymph to the SLN, which is identified by its radioactivity as detected with a gamma probe, and by its blue color. The increased use of Patent Blue V (PBV) and Isosulfane Blue (IB) for this purpose has, how-

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ever, been accompanied by numerous reports of serious adverse reactions to these dyes. Although commonly assumed to be IgE mediated, the underlying mechanisms of these reactions are still unclear (2). Studies trying to elucidate their nature are scarce (3–5). Mertes et al. (2) recently reported 14 cases of dye-induced anaphylaxis, including the results of histamine and tryptase measurements and skin testing. Except for these patients follow-up studies of tryptase (5–10) and skin tests (5–7, 10–15) have only been published for a few additional cases. In Norway, a national network for reporting and investigating allergic reactions during anesthesia was established in 1997 (16), adapting a French model described by Laxenaire and co-workers (17, 18). The aim of the network is that all referred patients shall have a follow-up according to a stan-

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dardized protocol. Nine patients with suspected reactions to PBV were identified through this network. The purpose of this report is to present the clinical features and the results of routine follow-up examinations for this group of patients, and, in another study, to investigate the possible mechanisms involved in their reactions (19).

Material and methods Patients The nine women were operated with SLNB procedures for breast cancer between 1999 and 2006 at four different Norwegian hospitals. They all gave consent to participate in this study. The study was approved by the Regional Committee for Medical Research Ethics, Western Norway. Cases 1–5 were operated at Oslo University Hospital-Rikshospitalet (OUH-R), Cases 6–7 at Haukeland University Hospital (HUH), Bergen, Case 8 at Sørlandet Hospital Arendal (SHA), and Case 9 at Oslo University Hospital-Ulleva˚l (OUH-U). The reactions were graded according to Ring and Messmer (20). Patient characteristics and some anesthesia details are listed in Table 1. Following ordinary procedure (1) all patients received peritumoral injections of technetium-99 colloidal human serum albumin (Nanocoll, Nycomed Amersham, Sorin, Soluggia, Italy) prior to the operation, and PBV sodium (CAS 20262-76-4, Laboratoire Guerbet, Cedes, France) a few minutes before the start of surgery. Information about the reactions is based on patient interviews and on information provided by the referring anesthesiologists. Diagnostic investigations In accord with the protocol, blood samples were taken when the patients showed signs of allergic reactions. If available, blood samples drawn preoperatively and on the first postoperative day were collected for comparison. Serum tryptase

was determined by fluorescent immunoassay (UniCap; Phadia AB, Uppsala, Sweden). All samples were examined by the Laboratory of Clinical Biochemistry, Haukeland University Hospital. Levels above 24 lg/l or increased by a factor of three or more from baseline are described as increased. Skin prick tests (SPT) were performed weeks to years after the reactions at the OUH-U (by VW), at the HUH (by ABG) and at OUH-R (by ASH). The tests were performed in duplicate, according to the guidelines of the European Academy of Allergy and Clinical Immunology (21). A standardized SPT panel was used, consisting of histamine chloride 10 mg/ml, negative control solution, and vial concentration of suxamethonium, rocuronium, vecuronium, pancuronium, atracurium besylate, fentanyl, pentothal, propofol, latex, and chlorhexidine. Remifentanil sodium was included for patients exposed to it. SPT was performed with undiluted vial PBV (2.5%) as recommended (2, 10, 11, 15).

Results Reaction frequency Seven of the nine patients were operated at OUH-R (Cases 1–5) and HUH (Cases 6–7). Totally 1418 SLNB patients were operated at these hospitals during the study period (1999–2006). The pooled data (7/1418 patients) suggest an incidence of 0.5% for PVB-reactions during SLNB and 0.4% for anaphylactic reactions (5/1418 patients). Clinical description As shown in Table 2, seven patients had hypotension of severity Grade III (Cases 1–3 and 7–9) or IV (Case 6). Cases 4 and 5 had cutaneous manifestations only (Grade I). The seven patients with anaphylactic reactions had stable pulse and blood pressure for 5–25 min after the PBV injections. An abrupt or more insidious fall in blood pressure and a pronounced increase in heart rate marked the onset of the

Table 1 Nine patients with 10 reactions* to Patent Blue V (PBV): patient characteristics and anesthesia Age, years

Previous allergies

Case 2

56 56 67

None None None

Asthma, hypertension

Oxazepam Oxazepam Oxazepam, midazolam

Case 3 Case 4 Case 5

54 50 59

None None None

Healthy Healthy Gastric reflux

Oxazepam, midazolam Oxazepam Oxazepam

Case Case Case Case

62 67 39 40

None None Unknown None

Healthy Healthy Healthy Healthy

Valdecoxib, paracetamol Diclofenac, paracetamol Midazolam Rofecoxib, paracetamol, dexamethasone

Patients Case 1*

6 7 8 9

1 2

Medical history Ovarian carcinoma

Premedication

Anesthetic drugs Fentanyl, propofol, atropine, nitrous oxide Remifentanil, propofol, nitrous oxide Fentanyl, thiopentone, cisatracurium, nitrous oxide, sevoflurane Remifentanil, propofol, nitrous oxide Remifentanil, propofol, nitrous oxide Fentanyl, thiopentone, cisatracurium, nitrous oxide, sevoflurane Remifentanil, propofol Remifentanil, propofol Fentanyl, propofol, sevoflurane Remifentanil, propofol

*Two separate reactions reported for Case 1.

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Anaphylaxis to Patent Blue

reactions (Table 2). In addition, cutaneous symptoms were noted in five of these patients: Case 3 developed generalized urticaria (Fig. 1), Cases 2 and 6 had generalized and upper body erythema, while Cases 7 and 8 developed blue-colored urticaria. Two patients developed skin manifestations without cardiovascular instability 67 (Case 4) and 48 min (Case 5) after the PBV-injections. Case 4 had blue hives localized to both eye lids and shoulders, while the area around the operation field was affected in Case 5 (Fig. 2). The response to intravenous ephedrine, rapid fluid infusions, reduction of anesthetic depth, and Trendelenburg positioning was poor in all the anaphylactic patients. All but Case 1 needed adrenaline for reversal of the shock. Cases 6 and 7 received postoperative adrenaline infusion. All operations were completed as planned after the patients were stabilized. All patients woke up normally without any recollection of what had happened, and made a normal recovery thereafter. Case 6 had the most severe reaction, starting 5 min after the PBV injection. A few minutes later the blood pressure became nonrecordable, and cardiopulmonary resuscitation was performed for 4 min. Normal circulation was restored after 10 min. ECG showed sinus rhythm with a rate from 40 to 140 beats/min throughout this period. Resuscitation included adrenaline titrated to 4 mg and continued as infusion for a total of 22 h, as well as 4 h of postoperative ventilator treatment.

Figure 1 Case 3: Cutaneous reaction during anaphylactic reaction to Patent Blue V.

For Case 1, an anaphylactic reaction to PBV was suspected during the second of two separate SLNB-procedures. The anesthesia chart from the first operation, however, showed a pronounced hypotension of almost identical severity, duration and time of occurrence to that observed during

Table 2 Nine patients with 10 reactions* to Patent Blue V (PBV): symptoms and drugs administered Before PBVi 

During reactionà

Interval PBV to reaction (min)

Heart rate (beats/min)

Blood pressure (mmHg)

Heart rate (beats/min)

Blood pressure (mmHg)

Case 2

10 10 20

55 45 60

100/72 85/55 90/60

128 125 106

55/40 55/35 50/35

Case 3

8

43

86/54

136

43/30

Case 4 Case 5 Case 6

67 48 5

68 47 52

108/65 110/70 85/53

60 50 40–140

110/70 135/60 Nonrecordable

Case 7

25

60

128/52

95

68/30

Case 8 Case 9

Un-known 10

Normal Normal

Normal Normal

165 85

55/40 52/25

Patients Case 1*

1 2

Treatment Ephedrine Ephedrine 40 mg Ephedrine 50 mg, adrenaline 40 lg, hydrocortisone, prometazin Ephedrine 50 mg, adrenaline1,5 mg, hydrocortisone, deschlorpheniramine Hydrocortisone, deschlorfeniramine Hydrocortisone Ephedrine 30 mg, adrenaline 4 mg + infusion 22 h, hydrocortisone 200 mg, deschlorfeniramine 5 mg Ephedrine 30 mg, phenylephrine 200 lg, adrenaline 80 lg + infusion 4 h, hydrocortisone 200 mg, deschlorfeniramine 5 mg Adrenaline, dopamine infusion Adrenaline 10 lg, Clemastine 2 mg, hydrocortisone 250 mg

*Two separate reactions reported for Case 1.  Values during anesthesia before PBV injection. àHighest heart rate and lowest blood pressure during the reaction.

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tryptase value (75.4 lg/l). One patient with anaphylaxis (Case 7) and one patient with skin reaction only (Case 4) had normal serum tryptase. SPT to PBV was positive in all tested patients (Table 3) and negative to the other specimens. Reactions to PBV were still positive in Cases 1–5 when SPT was performed 3–6 years after the reactions. Case 9 did not consent to being tested with SPT. Discussion

Figure 2 Case 5: Blue rash, cutaneous adverse reaction to Patent Blue V.

the second procedure. No cardiovascular instability was observed during a previous operation for ovarian carcinoma. Allergological examinations Results of serial serum tryptase measurements in eight of the nine patients are presented in Table 3. Six of seven patients with anaphylaxis had increased serum tryptase during the reaction, as their peak levels were 3–15 times higher than on the preceding (Cases 1–3, 6, 8) or following days (Case 9). Only three had peak values above the reference level of 24 lg/l. Case 6 had the most severe reaction and the highest

Based on data, from two participating hospitals, we observed incidences of 0.5% (7/1418) for all kinds of PBV reactions and 0.4% (5/1418) for anaphylaxis. This compares to earlier reported incidences of 0.3% (1/300) and 0.8% (3/370) for PBV reactions during sentinel lymph node biopsy (SLNB) (10, 15). At OUH-R all the six reactions (in five patients) occurred during the first 198 SLNB procedures performed there, initially suggesting a much higher frequency of reactions. In contrast, no cases were observed at HUH for about five years, before their first reaction occurred in 2004. At neither hospital any changes in the PBV handling routines were performed. Similar examples of an un-even distribution have been reported (22) and the most likely explanation is that these rare reactions occur randomly, sometimes causing clustering and other times the opposite. Published reports of similar reactions to Isosulfan blue (IB) by far outnumber those for PBV. A recent compilation of nine studies (22), showed an incidence of anaphylaxis of 0.2% (28/15 260) for IB, but frequencies varied between 0% and 1.1% in individual publications. Of the nine patients with adverse reactions to PBV reported here seven had anaphylaxis of severity Grade III– IV, while two had skin reactions only (Grade I). Symptoms from the skin and circulation also dominate in previously published dye reactions, but bronchospasm has been described (2, 4, 6, 8, 11, 23). Itching, nasal congestion,

Table 3 Serum tryptase (ref. value: