Two episodes of life-threatening anaphylaxis in the same patient to a chlorhexidine–sulphadiazine-coated central venous catheter

R. Stephens1, M. Mythen1, P. Kallis1, D. W. L. Davies1, W. Egner2 and A. Rickards3

1UCL Hospitals, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK. 2Supraregional Protein Reference Unit, Department of Immunology, Northern General Hospital NHS Trust, Sheffield S5 7YT, UK. 3The Heart Hospital, 50 Wimpole Street, London W1M 7DG, UK*Corresponding author

Accepted for publication: March 19, 2001


    Abstract
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Chlorhexidine allergy has been described in the literature, mainly in Japanese individuals. Most reactions have been limited to the skin, mild in severity and a result of chlorhexidine containing solutions such as ‘Savlon’ (Novartis Consumer Health, Horesham, UK). We describe what we believe is the first reported case of anaphylaxis in a European patient to a chlorhexidine- sulphadiazine-coated central venous catheter.

Br J Anaesth 2001; 87: 306–8

Keywords: allergy; complications, anaphylaxis; complications, chlorhexidine allergy; equipment, catheters central venous


    Introduction
 Top
 Abstract
 Introduction
 Case report
 Discussion
 References
 
Allergy to chlorhexidine is described in the literature, mainly in Japanese individuals. Most reactions have been limited to the skin, mild in severity and a result of chlorhexidine-containing solutions such as ‘Savlon’ (Novartis Consumer Health, Horesham, UK). In 1997, reports appeared of anaphylaxis in Japanese individuals to a chlorhexidine–sulphadiazine-coated central venous catheter.1 2

We describe what we believe to be the first reported case of anaphylaxis in a European patient to a chlorhexidine– sulphadiazine-coated central venous catheter.


    Case report
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 Abstract
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 Case report
 Discussion
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A 50-yr-old man with a history of ischaemic heart disease presented for coronary artery bypass graft surgery. He had been diagnosed with Type II diabetes in 1992 and had undergone two percutaneous coronary angioplasties for coronary artery disease. His most recent coronary angiogram showed recurrent two-vessel disease with good left ventricular function. There was no other significant past medical or surgical history and he was a non-smoker.

He had been told that he was ‘sensitive’ to penicillin and was taking diltiazem and gliclazide. On further questioning, he felt that the skin antiseptic fluid used for his angiogram, performed abroad, had resulted in an itchy rash in his groin, for which he had been prescribed an oral antihistamine, cetirizine. It was thought likely that this was the antiseptic solution ‘Savlon’ which contains chlorhexidine.

Clinical examination was unremarkable, and he was premedicated with temazepam and atenolol on the day of surgery. In the anaesthetic room large bore i.v. access and invasive monitoring was established following midazolam sedation. The patient was pre-oxygenated and 1 litre of Hartmann’s solution was infused i.v. during induction of anaesthesia. Anaesthesia was induced with midazolam, fentanyl, and propofol and maintained with an air/oxygen/isoflurane mixture. Neuromuscular paralysis was achieved with pancuronium and the airway was secured with a Portex endotracheal tube. A central venous catheter (Arrow-HowesTM Quad-lumen Central Venous Catheterization Set with ARROWg+ard Blue® Catheter, Arrow, Reading USA), was inserted in the right internal jugular vein following skin preparation with aqueous iodine (‘Betadine’, Seton Scholl Healthcare, Oldham, UK). Simultaneously, a urethral catheter was placed after cleansing the urethral meatus with ‘Savlon’ solution.

After 1–2 min the patient developed a widespread erythematous rash, periorbital oedema and became progressively hypotensive (Fig. 1), culminating in pulseless electrical activity. 100% Oxygen and external cardiac massage were commenced immediately and continued until a return of pressure was recorded on the invasive arterial trace after 10–15 min. The patient did not develop significant bronchospasm. During the cardiac arrest a total of 1 mg phenylephrine, 10 mg adrenaline (in increasing increments), 10 ml 10% CaCl2 and 4 litres of fluid were given. Subsequent treatment included 10 mg chlorpheniramine, 200 mg hydrocortisone and 50 mg ranitidine. The patient had not been given any antibiotics at this stage. Surgery was abandoned and the patient was transferred to the intensive care unit for further monitoring. At this stage, the precipitating drug was thought to be the ‘Savlon’ used before urethral catheterization. The patient was sedated and ventilated for 18 h in the Intensive Care Unit, after which the sedation was stopped and his trachea subsequently extubated uneventfully.



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Fig 1 Heat rate (HR) and arterial pressure (ART) changes during the first episode of anaphylaxsis.

 
Blood obtained 1 h post-cardiac arrest revealed a markedly elevated serum tryptase at 157 mg litre–1 (normal range 0–12 mg litre–1), C reactive protein of 7 mg litre–1 (range 0–6 mg litre–1) and normal complement levels. The patient was discharged home after 4 days observation, neurologically intact with no evidence of long term cardiovascular sequelae.

Skin testing, to propofol, fentanyl, pancuronium, natural rubber latex (three preparations), midazolam, and aqueous betadine were all negative. No reaction was seen to 0.04% chlorhexidine but a large weal with pseudopods measuring 7x7 mm with a 14x14 mm flare was seen with 0.4 and 4% dilutions. This was considered to be a positive result as no reaction was seen in two control subjects at any concentration. A provisional diagnosis was made of IgE mediated allergy to chlorhexidine, present in ‘Savlon’, and avoidance of chlorhexidine antisepsis was advised.

Three weeks later, the patient was rescheduled for a second attempt at coronary artery surgery. This time, it was decided to avoid chlorhexidine containing products, to prospectively give steroids along with H1/H2 antagonists, and to administer drugs and insert lines one by one so as to identify more easily the cause of any deterioration. Two doses of 20 mg prednisolone and three doses of 20 mg methylprednisolone were given orally at 6 h intervals in the 30 h before surgery. He also received 4 mg chlorpheniramine and 150 mg ranitidine, together with his normal medication of glicazide and diltiazem. The patient was again premedicated before surgery, but on this occasion was given morphine and hyoscine.

Two consultant anaesthetists conducted anaesthesia on this occasion. The patient was transferred to the anaesthetic room and monitored with an electrocardiograph and pulse oximetry. A radial artery was cannulated and transduced, and a large bore i.v. cannula was sited under lignocaine local anaesthesia. Anaesthesia was again induced with midazolam and fentanyl, and neuromuscular paralysis was achieved with rocuronium. A further 100 mg hydrocortisone was given at induction of anaesthesia. The airway was secured with a Portex endotracheal tube, and the arterial pressure was noted at 160/80 mm Hg, with a heart rate of 80 beats min–1, in sinus rhythm. A central venous catheter was placed in the right internal jugular vein after cleaning with aqueous iodine solution (‘Betadine’). Whilst flushing the central venous line with heparinized saline, progressive hypotension was again noticed to occur, culminating in pulseless electrical activity cardiac arrest, accompanied by facial oedema and an erythematous rash. The central venous line was removed immediately, replaced with a single lumen cannula (14G Abbocath), and 100% oxygen and external cardiac massage commenced. During the cardiac arrest, 10 mg phenylephrine, 4 mg adrenaline, and 3 mg noradrenaline were required, and 10 ml 10% CaCl2, 200 mg lignocaine (for two episodes of ventricular tachycardia), 2 M units of aprotinin (in case of C-1-esterase deficiency) and 10 mg chlorpheniramine. Atrial fibrillation was noted on the ECG. The patient again received a total of 4 litre of i.v. fluid. Surgery was further postponed and the patient transferred to the Intensive Care Unit. Two hours later, he remained in atrial fibrillation at a rate of 130 beats min–1, and his ECG showed evidence of some non-specific ST depression. He was, therefore, DC cardioverted with a single 50 J shock. The ST segments were noted to normalize on return to sinus rhythm.

Blood obtained 1 h post-operatively showed a serum tryptase level of 68 mg litre–1, total creatine kinase 33 iu litre–1 (reference range 33–186 iu litre–1) and creatine kinase MB fraction 2 iu litre–1 (range 0–24 iu litre–1). The post-operative ECG was unchanged. At 24 h, the total CK was 33 iu litre–1 and the CK-MB still normal at 5 iu litre–1. The patient’s trachea was extubated after 12 h and the patient discharged home 2 days later. He was again neurologically intact showing no physical signs of long term sequelae.

In response to further skin testing, the patient was positive to chlorhexidine at 4% and 0.4% as before, but where previously negative he was now skin test positive at 0.04%. His angina is currently being managed medically.


    Discussion
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Chlorhexidine allergy has been well described for over 30 yrs in European and Japanese individuals, mainly as a result of application to skin or mucus membranes before instrumentation. 36

Although unusual, we feel that anaphylaxis to chlorhexidine is the most likely cause for this patient’s clinical course on both occasions for a number of reasons. Sudden hypotension (which was resistant to treatment), tachycardia and widespread erythematous rash, are all features of an acute severe anaphylactic or anaphylactoid reaction.7 Elevated serum tryptase (>10 µg litre–1) is a relatively sensitive (86%), and specific (88%) indicator of anaphylaxis and anaphylactoid reactions.8 9 Skin prick testing was positive for chlorhexidine, and negative to all administered anaesthetic agents including natural rubber latex. The central venous catheter was subsequently examined and found to be chlorhexidine coated, with a warning on the packaging urging extreme caution in chlorhexidine sensitive patients.

There are several interesting features of this case. First, on both occasions (and in the case report by Oda and colleagues2), the patient was easy to ventilate—implying that there was little or no bronchospasm. Contrary to common belief, a recent review of clinical and laboratory markers of anaphylaxis and anaphylactoid reactions found that bronchospasm was a feature in only 43% of patients with allergy-proven anaphylaxis, and in 28% of those having anaphylactoid reactions.10 Second, large doses of vasopressors were needed in both episodes to restore the arterial pressure, presumably as a result of the profound vasodilatation secondary to mediator release. It was extremely fortunate that the patient was being invasively monitored at the time of anaphylaxis. Third, as it is not widely appreciated that central lines may be pre-coated with chlorhexidine and (as is routine practice) the line was handed to us already open, none of us thought to check the package insert.

Anaphylaxis has previously been reported to chlorhexidine–sulphadiazine-coated central venous catheters in two Japanese individuals, both of whom received coated central venous catheters on two occasions.1 2 Interestingly in one report2 skin prick testing after the first anaphylactic episode was negative to chlorhexidine, but the second test at 6 weeks was positive. Unfortunately, this result was not reported to the anaesthetists, resulting in a second exposure and anaphylaxis. The optimal time to skin prick test is uncertain, but most allergists wait 6–12 weeks after the episode in order to avoid false negative results.11

Products containing chlorhexidine are widely used in medicine and surgery. In our experience both doctors and nurses are often unaware that chlorhexidine is present, as we were on this occasion. This may have serious life-threatening consequences despite the warnings being marked on the product packaging.


    References
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 Terazawa E, Nagase K, Masue T, et al. Severe anaphylactic reaction due to a chlorhexidine-impregnated central venous catheter. Masui 1998; 47: 556–61[Medline]

2 Oda T, Hamasaki J, Kanda N, Mikami K. Anaphylactic shock induced by an antiseptic-coated central venous catheter. Anesthesiology 1997; 87: 1242–44[ISI][Medline]

3 Chisholm DG, Calder I, Peterson D, Powell M, Moult P. Intranasal chlorhexidine resulting in anaphylactic circulatory arrest. BMJ 1997; 315: 785[Free Full Text]

4 Okano M, Nomura M, Okada N, Sato K, Tashiro M. Four cases presenting anaphylactic reactions due to topical application of Hibitane®. Skin Res 1983; 25: 587–92

5 Harukuni I, Ishizawa Y, Nishikawa T, et al. Anaphylactic shock with ventricular fibrillation induced by chlorhexidine Masui 1992; 41: 445–59

6 Nikaido S, Tanaka M, Yamoto M, Minami T, Akatsuka M, Mori H. Anaphylactoid shock caused by chlorhexidine gluconate. Masui 1998; 47: 330–34[Medline]

7 Association of Anaesthesists of Great Britain and Ireland Guidelines on Anaphylaxis (1995) at http://www.ncl.ac.uk/~nassoca/nanap.html

8 Edston E, van Hage-Hamsten M. Beta-Tryptase measurements post-mortem in anaphylactic deaths and in controls. Forensic Sci Int 1998; 93: 135–42[ISI]

9 Fisher MM and Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 1998; 80: 26–9[ISI][Medline]

10 Gueant J-L, Aimone-Gastin I, Namour F, Laroche D, Bellou A, Laxenaire M-C. Diagnosis and pathogenesis of the anaphylactic and anaphylactoid reactions to anaesthetics. Clin Exp Allergy 1998; 28: 65–70[ISI][Medline]

11 Moneret-Vautrin DA, Laxenaire MC, Moeller R. Anaphylaxis due to succinylcholine: immunoallergological study of thirteen cases. Clin Allergy 1981; 11: 175–83[ISI]