Art. 1.1475/ringraziamenti

European Review for Medical and Pharmacological Sciences
2015; 19: 149-153 Treatment with icatibant in the management
of drug induced angioedema

G. BERTAZZONI, E. BRESCIANI1, L. CIPOLLONE1, E. FANTE1, R. GALANDRINI Research Center on Evaluation and Promotion of Quality in Medicine (CEQUAM), "Sapienza"University of Rome, Rome, ItalyEmergency Medicine Unit, "Sapienza" University of Rome, Umberto I Polyclinic, Rome, Italy Abstract. Acute, drug-induced angioedema
There are no specific laboratory analyses that may not respond to standard therapies, because
can be performed in these patients to better de- the pathogenetic mechanism that induces the
fine the mechanism behind the drug-induced an- pathology is not always mediated by histamine
gioedema. It has also been pointed out3,4 that oth- but, in certain instances, by bradykinin. A case
of angioedema is reported here, in which allergic

er investigations (i.e. complement fraction, trip- etiology was excluded by the non-response to
tase) are not performed in a routine emergency antihistamines. Considering the clinical history
room setting.
(repeated use of drugs) and the ineffectiveness
This situation of diagnosis, unsupported by of standard therapy, it was decided to administer
laboratory data, poses a serious problem of thera- a beta2 receptor antagonist, icatibant. After 20
py and the clinical case reported below highlights minutes, the patient reported a subjective im-
provement. The only form of angioedema for

this fact. The patient came to the Emergency De- which this type of medication is licensed is the
partment of the Policlinico Umberto I of Rome in hereditary deficiency of C1 inhibitor. The use of
the spring of 2013.
icatibant for the treatment of other types of an-
gioedema (which can also be life-saving if the

Clinical Case airway is involved) is off label. The off-label use
P.C., female, aged 72, arrived at the Emergency of a drug is allowed in the absence of a viable al-
ternative therapy, if there is scientific evidence in

Room at 6.00 p.m., presenting an edema of the the literature and if the prescriber takes respon-
tongue and mouth; the condition had started at 2.00 sibility. The case here reported draws attention
pm and had become increasingly more serious.
to this therapeutic problem and underlines the
Only a minimal passage of air was possible and the fact that a life-threatening emergency can justify
patient could not swallow or speak. She had eup- the use of icatibant.
noea, the vital signs were normal and stable (96% Key Words: O Sat, BP 150/70 mmHg, 70/min HR, 20/min Drug induced angioedema, Icatibant, Life saving RR); however, her condition was a cause of con- cern owing to the possibility of a further, rapid de-terioration of respiratory function (Figure 1).
The Table I summarizes the clinical data and medical history.
The blood gas analysis, performed in ambient Acute, drug-induced angioedema is not always air, showed slight hypoxemia (PO 79 mmHg) responsive to standard therapies, such as antihista- without hypercapnia, or pH changes. Other respi- mines, steroids and epinephrine. This could be be- ratory (P/F, SaO ) and metabolic parameters (lac- cause the pathogenetic mechanism that induces tate and bicarbonate) were within the norm.
the angioedema effect of a drug is not mediated by Antihistamine drug was administered (chlor- histamine, but by bradykinin1. The diagnosis of phenamine 10 mg, i.m.), steroids (hydrocortisone non-histaminergic angioedema is based on the 1000 mg, e.v.) and, subsequently, epinephrine (1 clinical picture and on clinical suspicion: it is an fl 1 mg/ml, solution 1:1000, aerosol), given the angioedema that is not related to urticaria, pruri- persistence of the symptoms; all without im- tus, erythema, rash, flushing or bronchoconstric- tion, and is not related to food ingestion or insect After 45 minutes of this triple therapy, the clin- stings2, which breaks out and disappears more ical situation remained unchanged and steroid slowly than histaminergic angioedema.
therapy was repeated to no avail. An anesthetist, Corresponding Author: Giuliano Bertazzoni, MD; e-mail: G. Bertazzoni, E. Bresciani, L. Cipollone, E. Fante, R. Galandrini It was given subcutaneously at a dose of 30 mg.
After 20 minutes, the patient reported a subjec-tive improvement. This was also documented bythe image (Figure 2) taken 45 minutes after ad-ministration of the drug, which showed a reduc-tion in edema of the tongue and mouth. She waskept under observation overnight as a precautionand discharged the next morning with completeremission of the symptoms. Specific blood tests(tryptase, C3 and 4) were negative (Table II).
The angiotensin receptor blockers (ARB) ther- apy was suspended and the patient, in a follow-up of 10 months, has no had any more episodesof angioedema Figure 1. The figure shows the edema of tongue and
A case of angioedema has been reported here, mouth at access to the Emergency Room.
in which allergic etiology was excluded by thenon- response to antihistamines, administered as called in for a consultation, was prepared to per- standard therapy. The laboratory tests did not form a tracheotomy as soon as there was evidence show any increase in tryptase, despite the lack of of desaturation. It was impossible to carry out en- specificity of the results. Angioedema did not ap- dotracheal intubation owing to the very small oral pear to be hereditary, since the crises were of re- space available, which did not allow the introduc- cent onset in a patient of a mature age, there was tion of the tube.
no family history and the laboratory tests showed Meanwhile, the clinical history of the patient no reduction in the level of C4. Given the recent was reconstructed with help from relatives.
use of different drugs, it was possible to compre- The patient was under gabapentin therapy for hend that the angioedema had been induced by neuralgic amyotrophy of the brachial plexus and such treatment. It was necessary, therefore, to venlafaxine treatment for depression. In addition, identify which of the drugs taken, might have she had recently suffered an infection of thoracic been responsible.
herpes zoster, which was mainly neurologicalrather than dermatologic. For these reasons, shewas taking paracetamol and aciclovyr; irbesartanand also furosemide for hypertension. In her re-cent history, the patient tooks NSAIDs, occasion-ally, for spondylolisthesis treated by stabilizationwith a metal plate.
Two months before presenting at our Emer- gency Department there had been an episode ofswelling of one half of the tongue; the swellingsubsided after a few hours. A month after, therewas a further episode of swelling of the entiretongue, extending under the jaw and chin, whichsubsided after 12 hours. The latest incident thatprompted her visit to the Emergency Room wasmore severe than the others and was in progressfor about 4 hours before hospitalization.
At this point, considering the clinical history with repeated use of drugs and given the ineffec-tiveness of the standard therapy, it was decided to Figure 2. The figure shows a reduction of edema of tongue
administer a beta2 receptor antagonist, icatibant.
and mouth after adminstration of icatibant.
Treatment with icatibant in the management of drug induced angioedema Table I. Clinical data and medical history.
Table II. Specific blood test.
G. Bertazzoni, E. Bresciani, L. Cipollone, E. Fante, R. Galandrini A study reported that gabapentin may induce The only class of drugs for which there is evi- angioedema in 0.14% of 34,020 patients fol- dence, even though limited, for the indication to lowed for 6 years5; angioedema generally occurs treat angioedema with bradykinin antagonists is within the second year of therapy, with a peak in ACE inhibitors. A number of case reports15,16 and the first month. The study stated that the popula- a series of cases17 have appeared in the literature tion followed was not on monotherapy.
over the past three years (2010/12), but currently Venlafaxine can induce angioedema, as well as the only form of angioedema that is licensed to serotonin reuptake inhibitors. The angioedema receive this type of medication is the hereditary found is described with histaminergic features deficiency of C1 inhibitor1. The use of icatibant (skin rash and urticaria)6.
for the treatment of an attack of angioedema Paracetamol was responsible for 8% of the re- (which can also be life saving if it involves the ported drug-induced angioedema in our series7.
airway) is off label. The use of an off label drug Acyclovir may give allergic reactions, such as is permitted (1) in the absence of a viable alterna- urticaria, pruritus, angioedema8.
tive therapy, (2) if there is scientific evidence in Extensive scientific literature shows that thera- the literature, (3) if the prescriber takes responsi- pies with ACEIs and ARBs can induce angioedema bility and (4) if there is the informed consent of as an adverse event9, although a lower occurrence is the patient, as soon as the clinical condition al- reported for ARBs compared with ACE -I. Trials lows. These issues are currently reported in the (2002 and 2004) on angiotensin II receptor blockers literature as cases of angioedema that might not (ARBs), have shown an appearance of 0.13% with be linked to the production of histamine.
the use of valsartan (Value study10) and between 0.1and 0.2% with losartan (Life study11) in a popula-tion followed for 5 years. ARBs interfere with the renin-angiotensin system, by blocking the effect ofangiotensin II12 and this can lead to an accumula- The case reported above draws attention to the tion of bradykinin with vasodilatation and increased problem of having a treatment option available in vascular permeability, (as shown by the fact that the such acute situations. Currently, only a life- symptoms respond to treatment with an anti- threatening emergency can justify the use of icat- bradykinin, such as icatibant); but the mechanism ibant; if, however, it expects that angioedema of action of ARBs, is different from that the ACE – does not respond to standard therapy, the use of I, and may be indirect. Other mechanisms of action icatibant may be late.
that do not involve the bradykinin system are lesslikely. It is also possible hypothesize that a drug, Conflict of interest
such as ARB, can lead to an adverse reaction suchas angioedema in which other drugs, including The Authors declare that they have no conflict of interests, nor any sponsorship.
those used by the patient, are involved. This is aninteresting hypothesis, but requires demonstration.
It is striking, however, is the fact that the patientwho has suspended the ARB has not had any more episodes of angioedema.
There are no reports of angioedema after the 1) CICARDI M, BELLIS P, BERTAZZONI G, CANCIAN M, CHIESA M, CREMONESI P, MARINO P, MONTANO N, MORSELLI C, use of furosemide in the literature or medical OTTAVIANI F, PERRICONE R, TRIGGIANI M, ZANICHELLI A. Guidance for diagnosis and treatment of acute In the case described above, more than one angioedema in the emergency department: con- drug may be responsible for the onset of the an- sensus statement by a panel of Italian experts. In-tern Emerg Med 2014; 9: 85-92.
gioedema seen and drugs together may have a synergistic action. Therefore, it is difficult to as- ERTAZZONI G, SPINA MT, SCARPELLINI MG, BUCCELLETTI F, DE SIMONE M, GREGORI M, VALERIANO V, PUGLIESE F, cribe to one drug only the responsibility of hav- RUGGIERI MP, MAGNANTI M, SUSI B, MINETOLA L, ZULLI ing induced angioedema.
L, D'AMBROGIO F. Drug-induced angioedema: ex- The most important point is that, in such a perience of Italian emergency departments. Intern case of angioedema, the indication for anti- Emerg Med 2014; 9: 455-462.
bradykinin treatment is off label. The case de- 3) BERNSTEIN JA, MOELLMAN J. Emerging concepts in the diagnosis and treatment of patients with undif- scribed here shows a clinical situation similar to ferentiated angioedema. Int J Emerg Med 2012; that reported by Manders et al14.
Treatment with icatibant in the management of drug induced angioedema 4) WILKERSON RG. Angioedema in the emergency de- MS, OMVIK P, OPARIL S, WEDEL H, LIFE STUDY GROUP. partment: an evidence-based review. Emerg Med Cardiovascular morbidity and mortality in the Pract 2012; 14: 1-21.
Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial IN CE, CHEN CL. Angioedema following adminis- tration of venfaxine and mirtazapine. Gen Hosp against atenolol. Lancet 2002; 359: 995-1003.
Psychiatry 2010; 32: 341.e1-2.
11) ABDI R, DONG VM, LEE CJ, NTOSO KA. Angiotensin II receptor blocker-associated angioedema: on the ANCHABHAI TS, GOGTAY NJ, BAVDEKAR SB. Paraceta- mol induced angioedema. Indian J Med Sci 2008; heels of ACE Inhibitor angioedema. Pharma- 62: 420-422.
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EN SP, SHARMA R, KOCHAR S. Probable acyclovir-in- THOMSONHC.COM, TRUVEN HEALTH ANALYTICS; London duced angioedema in a patient with HIV infection 2011-13 Available from: and suspected varicella-zoster virus encephalitis.
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A. Bradykinin-receptor antagonist icatibant: possi- ble treatment for ACE inhibitor-related angioede- AKANI H, MESSERLI FH, ROMERO J, WEVER-PINZON O, ma. Neth J Med 2012; 70: 386-387.
ORNIYENKO A, BERRIOS RS, BANGALORE S. Meta- analysis of randomized trials of angioedema as 14) SCHMIDT PW, HIRSCHL MM, TRAUTINGER F. Treatment an adverse event of renin-angiotensin system in- of angiotensin-converting enzyme inhibitor-relat- hibitors. Am J Cardiol 2012; 110: 383-391.
ed angioedema with the bradykinin B2 receptor antagonist icatibant. J Am Acad Dermatol 2010; ULIUS S, KJELDSEN SE, WEBER MA, BRUNNER HR, EK- 63: 913-914.
MAN S, HANSSON L, HUA T, LARAGH J, MCINNES GT,MITCELL L, PLAT F, SCHORK A, SMITH B, ZANCHETTI A; 15) GALLITELLI M, ALZETTA M. ICATIBANT: a novel approach VALUE Trial Group. Outcomes in hypertensive pa- to the treatment of angioedema related to the use tients at high cardiovascular risk treated with regi- of angiotensin-converting enzyme inhibitors. Am J mens based on valsartan or amlodipine: the VAL- Emerg Med 2012; 30: 1661-1662.
UE randomized trial. Lancet 2004; 363: 2022- 16) BAS M, GREVE J, STELTER K, BIER H, STARK T, HOFF- MANN TK, KOJDA G. Therapeutic efficacy of icati- 10) DAHLOF B, DEVEREUX RB, KJELDSEN SE, JULIUS S, BEEV- bant in angioedema induced by angiotensin-con- ERS G DE FAIRE U, FYHRQUIST F, IBSEN H, KRISTIANSSON verting enzyme inhibitors: a case series. Ann K, LEDERBALLE-PEDERSON O, LINDHOLM LH, NIEMINEN Emerg Med 2010; 56: 278-282.


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