Acute Pain (2007) 9, 221—227
Anaphylactic reaction after intravenous dipyrone Ulrike M. Stamer a,∗, Martin Soehle a, Tjoung-Won Park b, Matthias Fischer a,c, Frank Stuber a a
Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany b Department of Obstetrics and Gynaecology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany c Department of Anaesthesiology and Intensive Care Medicine, Klinik am Eichert, 73006 G¨ oppingen, Germany Received 27 April 2007 ; received in revised form 27 July 2007; accepted 16 August 2007 Available online 1 October 2007 KEYWORDS Dipyrone (metamizol); Anaphylaxis; Oedema; Postoperative analgesia; Cardiopulmonary resuscitation; -Blockade
Summary Dipyrone (metamizol), a non-opioid analgesic, is widely used for acute and chronic pain management. Although not marketed in all countries because of concerns of possible side effects like agranulocytosis, this potent analgesic is frequently used worldwide. A severe anaphylactic reaction without any cutaneous symptoms was observed after intravenous infusion of dipyrone 1 g. Further symptoms were a short lasting increase in airway pressure and a pronounced generalized oedema. Circulatory arrest required cardiopulmonary resuscitation. Pre-existing -blockade aggravated poor response to adrenaline. Recovery of the patient was uneventful. Previous case reports demonstrated that symptoms of allergic reaction after dipyrone might vary considerably. Erythema, bronchospasm and eyelid-/angio-oedema might present alone or in combination. Sole cardiovascular collapse produced by extreme generalized oedema and consecutive hypotension occurred after i.v. administration during anaesthesia. Risk factors for severe dipyrone induced allergy are: allergies/intolerability of dipyrone and other non-opioids and bronchial asthma. However, allergic reaction after previous intake of dipyrone without side effects has been described. © 2007 Elsevier B.V. All rights reserved.
1. Introduction
∗
Corresponding author. Tel.: +49 228 287 14114; fax: +49 228 287 14125. E-mail address:
[email protected] (U.M. Stamer).
The pyrazolone derivate dipyrone (metamizol) belongs to the non-opioid analgesics and is used for acute and chronic pain management [1]. This drug can be administered orally as tablets or drops, intravenously, intramuscularly or rectally in
1366-0071/$ — see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2007.08.025
222 children and adults and provides analgesic, antipyretic and spasmolytic properties. Therefore, it covers a broad spectrum of indications. In Germany, dipyrone is a widely prescribed drug for acute and chronic pain management. In the postoperative setting, it is one of the most powerful non-opioid analgesics marketed up to date. Its opioid sparing effect has been demonstrated in several investigations [2,3]. Since it lacks side effects on the gastrointestinal tract and has no clinically significant influence on the coagulation pathway, it is well tolerated by patients. However, dipyrone is banned in some countries because of its association with incidents of agranulocytosis [4]. The frequency of this adverse effect is still controversial [5—8]. Nevertheless, dipyrone has remained very popular (e.g. in Austria, Belgium, France, Germany, Italy, the Netherlands, Turkey, Spain, Switzerland, South Africa, Latin America, Russia) since it is efficacious at low cost and can be administered by different routes. However, like in other non-opioid analgesics, allergic and anaphylactic reactions may occur. A case report with detailed documentation of the anaphylactic event and a review of cases presenting a comparable adverse drug reaction are reported.
2. Case report A 75-year-old woman (67 kg, 168 cm) was scheduled for gynaecologic laparotomy because of a cystic adnex tumor. A history of endocarditis in 1983, a liver cirrhosis Child A of unknown origin, and a partial thrombosis of the portal vein was reported. Regular medication consisted of propanolol 2× 10 mg, furosemide 50 mg and jodid 200 g/day. The patient suffered from an insulin dependent type II diabetes mellitus and during preoperative evaluation she mentioned an allergic reaction with urticaria following ‘‘atropine intake’’ some 20 years ago. Chest X-ray was normal and preoperative physical evaluation showed no abnormalities. General anaesthesia was performed according to a standard protocol with remifentanil, propofol, cis-atracurium and desflurane. A central venous line was placed in the internal jugular vein for continuous CVP measurement. Further standard monitoring consisted of ECG, automatically measured noninvasive blood pressure, pulse oximetry (SaO2 ) and endtidal pCO2 . Pressure-controlled ventilation (10 breaths/min, minute ventilation 4.0—4.5 l/min, peak pressure: 20, PEEP: 5 cm H2 O) was adjusted to maintain the endtidal pCO2 at 35 mmHg.
U.M. Stamer et al. The gynaecologist performed a laparotomy with bilateral adnectomy for large serous cystadenomas of the ovary. Surgery was uneventful and the patient’s vital parameters remained within the normal range (heart rate 60—75/min, systolic blood pressure: 90—130 mmHg, diastolic blood pressure 60—80 mmHg, SaO2 = 97—98%, central venous pressure: 13—15 mmHg). Blood loss was negligible and a total of 1500 ml crystalloid and 500 ml of colloid fluids were administered. After starting with abdominal closure dipyrone 1 g, tramadol 200 mg and metoclopramide 10 mg were infused for prophylactic pain management. About 5 min later, blood pressure dropped to 75/45 mmHg. A colloidal infusion was started, the patient was moved into Trendelenburg position, and increments of a vasopressor (Akrinor® = cafedrine + theodrenaline) up to a total amount of 2 ampules (=cafedrine 400 mg + theodrenaline 20 mg) were injected repeatedly (details in Table 1). Remifentanil infusion was reduced to 400 g/h, exspiratory desflurane concentration to 2.4 vol.%. However, blood pressure did not increase. In parallel, mechanical ventilation became insufficient as tidal volume decreased due to increasing airway pressure. As ventilation deteriorated further, manual ventilation using oxygen 100%, allowing peak airway pressure of 40 cm H2 O was started. Tidal volume increased as well as minute ventilation. These problems in ventilation were interpreted as insufficient depth of anaesthesia at this time point and gas flow and desflurane concentrations were increased (5.7 vol.%) for some few minutes. As vasopressor treatment was without effect, remifentanil infusion and desflurane was discontinued and escalating doses of adrenaline (epinephrine) were administered repeatedly (Table 1). However, the effect on blood pressure was short lasting and did not sustain, whereas ventilation improved. Auscultation about 10 min after the cardiovascular failure only revealed very distinct crackles, although from retrospective analysis of the documented respiratory variables it can be concluded that pulmonary manifestation of anaphylaxis shock had occurred. Sudden increase in airway pressure allowed only very small tidal volumes. No erythema was visible and an allergic reaction was not considered probable at this time. A decline of pulse oxygen saturation to 90%, later to 56% became obvious. Carotide pulse was not palpable; therefore, circulatory arrest was confirmed and external chest compression was started with a compression rate of about 100 compressions per minute. Further bolus doses of adrenaline (total 5 mg) were injected and a continuous infusion of
Time
Monitoring data and resuscitation measures
Heart rate (min−1 )
SaO2 %
BP (mmHg)
CVP (mm Hg)
etCO2 (mmHg)
P peak (mbar)
PEEP (mbar)
Respiratory rate (min−1 )
Ventilation (l/min)
CPR
10:23 10:28 10:30 10:33
65 61 58 60
97 97 97 97
105/64 95/57 89/51 75/45
13 12 13 12
34 33 31 32
17 17 17 17
6 6 6 6
10 10 10 9
4.6 5.0 5.5 4.5
10:35 10:37 10:39 10:40 10:42
61 66 77 86 96
97 96 94 93 89
65/38 65/35 n.m. 75/44 n.m.
12 13 15 13 11
32 35 38 37 29
17 17 16 21 30
6 7 2 2 1
9 6 8 8 9
3.8 2.4 1.9 1.6 2.9
10:44 104
84
58/31
11
19
36
4
20
5.7
10:46
91
76
n.m.
3
12
37
3
29
7.5
X
10:48
74
79
n.m.
3
8
33
6
34
8.1
X
10:50
67
71
n.m.
7
9
34
4
32
8.0
X
10:52 74 10:54 95 11:00 95 11.03 115 11:05 116 11:10 121
78 56 67 99 99 98
n.m. n.m. n.m. n.m. 93/48 85/40
8 10 13 13 — 6
8 10 13 25 23 24
39 38 25 25 24 36
3 6 1 1 1 6
31 37 12 12 12 12
10.5 14.2 7.5 6.6 6.6 6.6
X X X X
b b
Drugs Dipyrone 1 g i.v.
Colloid 500 ml, Akrinor® , Trendelenburg position Crystalloid 500 ml Akrinor® , colloid 500 ml Crystalloid 500 ml Colloid 500 ml Manual ventilation, FiO2 = 1, call for help Repeated doses of adrenaline, total 1 mg Adrenaline 1 mg, remifentanil + desflurane discontinued Crystalloid 500 ml, colloid 500 ml, adrenaline 1 mg, calcium 1 g Adrenaline 1 mg, starting continuous infusion of adrenaline 10 g/min + noradrenaline 6 g/min, adrenaline 1 mg, crystalloid
Anaphylactic reaction after intravenous dipyrone
Table 1
Hb 14.6 g/dl Arterial line, gas analysis, Hb 14.5 g/dl
SaO2 : arterial oxygen saturation (pulse oximetry), BP: non-invasive blood pressure, b: invasive blood pressure (arterial line), CVP: central venous pressure, n.m.: not measurable, etCO2 : endtidal CO2 , CRP: X: compression rate about 100/min, without pause for ventilation.
223
224 adrenaline and noradrenaline (norepinephrine) was started (Table 1). As sufficient spontaneous circulation was restored an arterial line was inserted and a gas analysis revealed the following results: pH 7.22; paO2 = 29.98.5 kPa (225.4 mmHg); paCO2 = 7.59 kPa (57.1 mmHg); BE = −5.5 mmol/l; potassium = 3.7 mmol/l; calcium = 1.01 mmol/l; glucose = 85 mg/dl; Haemoglobin had increased from 9.0 g/dl 1 h before to 14.6 g/dl. Pupil size remained always narrow. After wound closure was finished and sterile sheets were removed a generalized oedema became obvious, however, no erythema or urticaria was visible. The patient was transferred to the intensive care unit for prolonged postoperative ventilation. Postoperative laboratory analysis, ECG, X-ray and trans-oesophageal echocardiography revealed no pathologies, specifically no ischemic cardiac event and no pulmonary embolism. Further recovery was uneventful and neurological outcome was good. A postoperative interview with the patient revealed that her previously mentioned allergy was not caused by atropine, but by dipyrone drops which she tried only once some 20 years ago for low back pain. However, at that time she reacted with an urticarial exanthema and after this event dipyrone had never been prescribed to her again. This mistake in names was possible, since the German words ‘‘Atropin’’ and ‘‘Novalgin’’ (brand names of atropine and dipyrone in Germany) sound very similar to patients, each consisting of three syllables and ending on ‘‘-in’’. Consultation of a dermatologist was arranged for an allergic testing (prIck-test, tryptase) and the patient was handed out an allergy pass with dipyrone listed as triggering agent.
3. Discussion In a Swiss investigation the rate of severe lifethreatening anaphylaxis with circulatory signs was found to be 7.9—9.6/100,000 inhabitants per year [9]. Focussing on hospital admissions only, anaphylactic and anaphylactoid reactions are estimated to occur at a rate of 1:5000 [10]. For most non-opioid analgesics, the incidence of anaphylaxis was in the range of 5—15 cases/100,000 exposed patients [11]. Among the individual analgesics, the estimates ranged from 2.1/100,000 for oral aspirin to 16/100,000 for diclofenac suppository, with oral and parenteral dipyrone lying between 7 and 8 episodes/100,000 exposed patients [11]. Other agents commonly reported to cause anaphylaxis are contrast media (up to 71/100,000), antibi-
U.M. Stamer et al. otics (parenteral penicillin 32/1,000,000), dextran (36/100,000) and streptokinase (284/100,000) [11]. A French survey revealed that drugs mainly involved in perioperatives anaphylaxis are muscle relaxants (69.2% of the cases), latex (21.1%), antibiotics (8.0%) and hypnotics (3.7%) [12]. Several cases describe anaphylaxis after dipyrone administration (Table 2; [13—20]), however, this rare, potentially severe adverse event also can occur after intake of other non-opioid analgesics like aspirin and ibuprofen [18,21]. Furthermore, cross-reactivity between NSAIDs and dipyrone exists [18]. Risk factors for an allergic reaction are pre-existing (severe) bronchial asthma [17,19], allergic reaction to other non-opioid analgesic [18], as well as previous allergic reaction to dipyrone [19]. The history of the present patient revealed that dipyrone intake producing allergic side effects was 20 years ago. Unfortunately, no allergic testing was performed at that time. The cardiovascular collapse might have been preventable if an allergy pass had been issued or a correct patient’s history had been documented. In case of an allergic reaction to a NSAID, allergic testing for alternative non-opioid analgesics which are tolerated by the patient is strongly recommended. However, allergic reaction is also possible after previous dipyrone intake without any side effects [13,16,17]. In the four cases needing CPR (Table 2), dipyrone was administered intravenously during anaesthesia. Janke et al. [17] reported of an anaphylactic shock without initial cutaneous symptoms and bronchospasm. The case showed some parallels to the present report. However, whereas bronchospasm was not observed, our patient had a transient increase in airway pressure which resolved with initial adrenaline. Since patients are under drapes, unconscious or sedated during anaesthesia diagnosis of anaphylactic shock might be delayed [22]. Increased peak respiratory pressure and cardiovascular collapse were the first signs of anaphylaxis. As this severe adverse event during anaesthesia is rare and, in general, unexpected, documentation is often lacking [22]. In some of the cases reported up to now detailed information of the symptoms and treatment is sparse due to publication in foreign languages and missing abstracts. On the other hand, severe anaphylactic shock during anaesthesia has several advantages for treatment: The patient is already intubated during general anaesthesia, a venous line and monitoring are in place and drugs for resuscitation are promptly available. It is questionable, whether the present case would have a favourable outcome, if it had taken place on a peripheral ward.
Case reports of anaphylaxis after dipyrone
Eckle et al. [13]
Patients’ history
Anaesthesia
Symptoms
Measures
Outcome/allergy test
58 year man: previous dipyrone
General anaesthesia, dipyrone 2.5 g i.v. General anaesthesia, dipyrone 2.5 g i.v.
Bronchospasm, hypotension, erythema Bronchospasm, hypotension, erythema
CPR
Survived prick test, tryptase Survived allergy test
52 year man: previous dipyrone Molto et al. [14]
59 year man
Spinal anaesthesia, dipyrone i.v.
Respiratory failure, ventricular fibrillation
Hernandez et al. [15] Janke et al. [16]
Two cases 46 year woman intake of dipyrone p.o. no side effects. No allergy/atopy known 22 year woman bronchial asthma repeated dipyrone before, no side effects 32 year woman family history of drug reaction. After aspirin laryngeal oedema, bronchial asthma 16 year man severe bronchial asthma
Dipyrone after surgery General anaesthesia, dipyrone
