Advertisement
ADVANCED SEARCH

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hill, M. D. Articles by Buchan, A. M. Search for Related Content PubMed PubMed Citation Articles by Hill, M. D. Articles by Buchan, A. M. Related Collections Allergy Drugs: central nervous system (not psychiatric) Stroke

Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke

From the Department of Clinical Neurosciences, University of Calgary, Calgary, Alta.
Drs. Hill and Buchan received grants from the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada and the Alberta Heritage Foundation for Medical Research. Dr. Feasby is funded by a grant from the Heart and Stroke Foundation of Canada.

	Abstract

Top Abstract Case reports Comments Addendum References

 
Among 105 patients given recombinant tissue plasminogen activator (rt-PA, alteplase) intravenously for acute stroke, 2 (1.9%) had lingual angioedema, which progressed to a fatal anaphylactoid reaction in 1. The authors review the 2 cases and possible mechanisms responsible. They warn that patients who are taking an angiotensin-converting-enzyme inhibitor may be at increased risk for angioedema with concomitant alteplase therapy.

	Case reports

Top Abstract Case reports Comments Addendum References

 
Case 1

A 74-year-old woman with known coronary artery disease, adult onset type 2 diabetes mellitus, hypertension and congestive heart failure collapsed. She was taking ASA, losartan, furosemide, diltiazem, digoxin, atorvastatin, acarbose and glyburide and was wearing a nitroglycerine skin patch. She was in atrial fibrillation but was not taking anticoagulants. On arrival at the hospital she was awake, globally aphasic and had a right homonymous hemianopia. Her eyes were tonically deviated to the left with a dense right hemiplegia. She had no sensation of painful stimuli on the right side. Her plantar response was extensor on the right. Her National Institutes of Health Stroke Scale (NIHSS) score was 24 (a score over 15 indicates severe stroke). A CT brain scan performed 90 minutes following stroke onset showed a hyperdense left middle cerebral artery sign and early signs of infarction in the left lentiform nucleus and insular ribbon. Her platelet count, international normalized ratio (INR) and activated partial thromboplastin time were normal, and her blood pressure was 180/70 mm Hg. The patient met the criteria for intravenous alteplase treatment of acute ischemic stroke and was given 0.9 mg/kg alteplase - a 10% bolus initially and the remaining drug infused over 60 minutes.

The patient began to improve within 30 minutes of treatment initiation, with some fluent speech and spontaneous movement in her right arm and leg. However, 15 minutes later she was noted to be in some discomfort and was attempting to scratch her left arm. The first signs of an urticarial rash were noted, and it subsequently spread from her legs to large areas of her abdomen and chest. The alteplase infusion was stopped; the patient had received a total of 38 mg of the drug.

Extensive bilateral swelling of her tongue and periorbital region developed, and her blood pressure dropped to 90/40 mm Hg. Hydrocortisone (100 mg), diphenhydramine (50 mg), ranitidine (50 mg) and crystalloid were administered intravenously. Stridor developed, and there was massive swelling of the epiglottis, uvula and tongue; a traumatic intubation resulted in some oropharyngeal hemorrhage. It was unclear whether her oropharyngeal swelling was complicated by the hemorrhage in addition to angioedema. Fresh frozen plasma (8 units), cryoprecipitate (20 units) and red blood cells (4 units) were given for possible retropharyngeal hematoma. A follow-up CT scan of the neck showed swelling but no hematoma. The patient suffered a small midline brainstem hemorrhage and petechial hemorrhage into the area of infarction (left middle cerebral artery territory). She was admitted to the intensive care unit and was making moderate neurological improvement. However, 14 days after stroke onset the patient experienced ventricular arrhythmia and, despite attempts to resuscitate, died. An autopsy was not performed.

On the day the patient was admitted to the hospital her serum glucose level was 29 mmol/L, perhaps partly explaining her intraparenchymal cerebral hemorrhage.² Levels of complement C3 and C4 were normal the day after her stroke. She was not taking an angiotensin-converting-enzyme (ACE) inhibitor. Additional history obtained from the family revealed that the woman had experienced 8 episodes of angioedema in the previous 14 years - 1 while she was taking a ß-blocker and another while she was taking an ACE inhibitor.

Case 2

A 76-year-old woman with chronic atrial fibrillation (treated with digoxin but not anticoagulants or ASA), coronary artery disease, a previous transient ischemic attack and hypertension presented to the hospital with sudden onset of right-gaze preference, left hemiplegia and left hemispatial neglect. On arrival she was awake and oriented but drowsy and easily rousable. She had a left hemianopia and left visual hemineglect. Sensation on her left side was altered but not absent. A brain CT scan revealed a hyperdense left middle cerebral artery sign and early signs of infarction in the lentiform nucleus and anterior middle cerebral artery territory. Her NIHSS score was 18, blood pressure 165/96 mm Hg, serum glucose 8.1 mmol/L, INR 1.0 and platelet count 154 x 10⁹/L. She had slight microcytic anemia, with a hemoglobin concentration of 105 g/L, but an otherwise normal blood smear. She was taking an ACE inhibitor. Intravenous alteplase (0.9 mg/kg, 10% initial bolus dose and the remaining drug infused over 60 minutes) was initiated 110 minutes after stroke onset.

Thirty minutes after the alteplase infusion was finished, the patient had unilateral swelling of her tongue and lips on the left side, but she had no rash or hypotension. She was treated with methylprednisolone (80 mg), diphenhydramine (50 mg) and ranitidine (25 mg), and her symptoms resolved over several hours.

	Comments

Top Abstract Case reports Comments Addendum References

 
Allergic reactions to thrombolytic agents can occur but are most commonly seen with streptokinase administration; anaphylaxis is uncommon.^3,4 Angioedema has been reported in association with alteplase treatment of myocardial ischemia^5,6 and deep vein thrombosis,^7,8 but very rarely in association with alteplase treatment of acute ischemic stroke.^9-12 Anaphylactoid reactions or angioedema have been reported to occur in less than 0.02% of patients treated with alteplase for acute myocardial infarction. However, over a 3-year period we observed these adverse reactions in 2 (1.9% [95% confidence interval 0.2%-6.7%]) of the 105 patients given alteplase for acute ischemic stroke. Fayad and colleagues¹¹ reported similar reactions in 4 (1.5%) of 260 patients.

Anaphylaxis and angioedema during alteplase infusion are likely caused by the activation of the complement and kinin cascades.¹³ Although anti-alteplase antibodies have been reported, alteplase is an endogenous protein and thus has low antigenicity in humans.^10,14 IgG or IgM antibodies have been found in serum only days to weeks after alteplase treatment.^15-17 However, IgE antibodies to alteplase were detected in one case of anaphylaxis without angioedema.¹⁰ Activation of the complement system is likely direct, rather than through the binding of complement C1 to antigen-antibody complexes containing IgG or IgM.

Plasminogen activator is a serine protease that cleaves plasminogen to plasmin (Fig. 1). Plasmin cleaves thrombus-bound fibrin, which results in the fibrinolytic effect, and can also activate the complement cascade and kinin pathway. Bradykinin is a potent vasodilator with a short half-life due to the action of plasma kininases. Plasma kininases may be inhibited by ACE inhibitors, but angioedema secondary to ACE inhibitors in some patients may be associated with a genetic defect in bradykinin metabolism.¹⁹

View larger version (19K): [in this window] [in a new window]   Fig. 1: In addition to activating fibrinolysis, plasmin may activate the complement cascade by directly cleaving C1 and C3. The release of each of the anaphylotoxins, C3a, C4a, C5a and C2-kinin, contributes to angioedema. Plasmin may also directly activate the kinin pathway, leading to the production of bradykinin, a potent vasodilator. Kininases may be inhibited by angiotensin-converting-enzyme (ACE) inhibitors, providing a putative mechanism for the observed association between angioedema after alteplase treatment and ACE inhibitors. - indicates inhibition.

The activation of complement C3 results in an amplification of the complement cascade via the alternate pathway; C3a, the cleavage product of C3, is a potent anaphylotoxin that activates mast-cell degranulation and histamine release. C4a and C5a also activate mast-cell degranulation. Experimental evidence suggests that anaphylaxis results in an upregulation of endogenous t-PA levels,^20,21 and C3a, C4a and C5a show a marked increase after alteplase administration.¹³ Activation of angioedema in this fashion may not necessarily lead to complement consumption and low C3 and C4 levels. Plasmin may also directly activate C1 in the classic pathway with the release of C2-kinin, another potent vasodilator thought to be responsible for angioedema in both hereditary and acquired C1 esterase inhibitor deficiency.¹⁹

Each vial of alteplase used in North America contains 100 mg of alteplase, 3.5 g of L-arginine, 1 g of phosphoric acid and 8 mg of polysorbate-80. It contains no preservatives and is reconstituted with sterile water. The concentration of L-arginine may be enough to stimulate endothelial nitric oxide synthase (eNOS); both the kinins and the eNOS may have contributed to the adverse reactions and hypotension we documented. Using nitroarginine as the carrier might reduce risk and prevent nitric-oxide-induced neurotoxicity.²²

In hindsight, our first patient may have had an undiagnosed hereditary or acquired C1 esterase inhibitor deficiency. C1 esterase inhibitor is a member of the 2-macroglobulin family and has antiplasmin activity. A deficiency in this patient may have resulted in an overwhelming activation of the complement cascade and severe oropharyngeal angioedema. The second patient's angioedema was milder, and we suspect that ACE inhibition made her susceptible.

An intriguing aspect of these and other cases is that the angioedema of the tongue or lips began unilaterally and if severe enough progressed to involve the entire tongue and oropharynx. Several others^23-25 have investigated the role of the insular cortex in sympathetic and parasympathetic control. We speculate that infarction of the contralateral insular cortex, leading to autonomic dysregulation and changes in vasomotor tone on the hemiparetic side of the body, interacted with the angioedema cascade and resulted in the apparent initial localization of the angioedema on the symptomatic side.

Physicians treating acute ischemic stroke with alteplase should be aware of this infrequent complication. We routinely inspect the tongue and oropharynx in patients 30-45 minutes after the start of an alteplase infusion and pay particular attention to patients taking ACE inhibitors. A history of ACE inhibitor use should always be obtained before treatment with alteplase is initiated.

Our treatment with antihistamines and corticosteroids has been empirical and is based on the treatment of angioedema associated with hereditary or acquired deficiency in C1 esterase inhibitor. Infusion of C1 esterase inhibitor has been reported in the treatment of acute myocardial ischemia²⁶ for its possible myocardial-protective effect, and an infusion of C1 esterase inhibitor may be an effective therapy in this situation as well. We avoided the use of epinephrine because of the possibility of increasing the risk of intracerebral hemorrhage with a sudden rise in blood pressure.

	Addendum

Top Abstract Case reports Comments Addendum References

 
Since the submission of this article we have observed 2 other cases of hemilingual angioedema of the tongue (each ipsilateral to the hemiplegia) in patients treated with alteplase for acute ischemic stroke. Both cases were mild and resulted in symptoms of dysphagia in the first patient and no symptoms in the second patient. Both patients were taking an ACE inhibitor and both were treated with ranitidine (50 mg) and diphenhydramine (50 mg) intravenously; the angioedema was resolved in both cases within 60 minutes.

Competing interests: None declared for Drs. Takahashi, Feasby and Demchuk. Drs. Hill and Buchan have received speaker fees from Hoffman-La Roche Canada Limited, and Dr. Barber has received travel assistance from Knoll Pharmaceutical Company.

	Acknowledgments

 
For the leadership and management skills necessary to function effectively

Approved for RCPSC, CFPC and AAFP study credits

PMI-1/PMI-2

June 4-6/June 7-9, 2000 Château Laurier, Ottawa Sept. 24-26/Sept. 27-29, 2000 The Queen Elizabeth Montréal

Nov. 5-7/Nov. 8-10, 2000 Sutton Place Hotel, Vancouver

PMI Refresher

Oct. 20-22, 2000 Sutton Place Hotel, Vancouver

In-house PMI

A practical, cost-effective and focused training opportunity held on site for leaders and managers

For information: tel 800 663-7336 or 613 731-8610; x2319 (PMI) or x2261 (In-house PMI); michah{at}cma.ca; www.cma.ca/prodev/pmi

Canadian College of Health Service Executives Collège canadien des directeurs de services de santé

	Footnotes

 
This article has been peer reviewed.

Reprint requests to: Dr. Michael D. Hill, Department of Clinical Neurosciences, University of Calgary, MRG 005, Foothills Hospital, 1403 29th St. NW, Calgary AB T2N 2T9; fax 403 670-1602; michael.hill{at}crha-health.ab.ca

	References

Top Abstract Case reports Comments Addendum References

 

1. Canadian Pharmacists Association. Compendium of pharmaceuticals and specialties. 34th ed. Ottawa: The Association; 1999. p. 31.
2. Demchuk AM, Morgenstern LB, Krieger DW, Chi TL, Hu W, Wein TH, et al. Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999;30:34-9.[Abstract/Free Full Text]
3. Tsang TS, Califf RM, Stebbins AL, Lee KL, Cho S, Ross AM, et al. Incidence and impact of on outcome of streptokinase allergy in the GUSTO-1 trial. Global Utilization of Streptokinase and t-PA in Occluded Coronary Arteries. Am J Cardiol 1997;79:1232-5.[Medline]
4. White HD, Cross DB, Williams BF, Norris RM. Safety and efficacy of repeat thrombolytic treatment after acute myocardial infarction. Br Heart J 1990;64:177-81.[Abstract/Free Full Text]
5. Purvis JA, Booth NA, Wilson CM, Aggi JAA, McClusky DR. Anaphylactoid reaction after injection of altepase. Lancet 1993;341:966-7.
6. Massell D, Gill JB, Cairns JA. Anaphylactoid reaction during infusion of recombinant tissue-type plasminogen activator for acute myocardial infarction. Can J Cardiol 1991;7:298-302.[Medline]
7. Francis CW, Brenner B, Leddy JP, Marder VJ. Angioedema during therapy with recombinant tissue plasminogen activator. Br J Haematol 1991;77:562-3.[Medline]
8. Marder VJ, Brenner B, Totterman S, Francis CW, Rubin R, Rao AK, et al. Comparison of dosage schedules of rt-PA in the treatment of proximal deep vein thrombosis. J Lab Clin Med 1992;119:485-95.[Medline]
9. Pancioli A, Brott T, Donaldson V, Miller R. Asymmetric angioneurotic oedema associated with thrombolysis for acute stroke. Ann Emerg Med 1997;30:227-9.[Medline]
10. Rudolf J, Grond M, Prince WS, Schmulling S, Heiss WD. Evidence of anaphylaxy following alteplase infusion. Stroke 1999;30:1142-3.[Abstract/Free Full Text]
11. Fayad PB, Albers GW, Frey JL, Raps EC. Orolingual angioedema complicating rt-PA therapy for acute ischemic stroke [abstract]. Stroke 1999;30:242.
12. Felberg RA, Wein TH, Demchuk AM, Hickenbottom SL, Malkoff M, Morgenstern LB, et al. Oropharyngeal angioedema: a clinically important complication of intravenous recombinant tissue plasminogen activator [abstract]. 124th Annual Meeting of the American Neurological Association; 1999 Oct 9-13; Seattle.
13. Bennett WR, Yawn DH, Migliore PJ, Young JB, Pratt CM, Raizner AE, et al. Activation of the complement system by recombinant tissue plasminogen activator. J Am Coll Cardiol 1987;10:627-32.[Abstract]
14. Reed BR, Chen AB, Tanswell P, Prince WS, Wert RM Jr, Glaesle-Schwarz L, et al. Low incidence of antibodies to recombinant human tissue-type plasminogen activator in treated patients. Thromb Haemost 1990;64:276-80.[Medline]
15. Topol EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, Nishikawa A, et al. A multi-centre randomized placebo controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator in acute myocardial infarction. J Am Coll Cardiol 1987;9:1205-13.[Abstract]
16. Cugno M, Cicardi M, Colucci M, Bisiani G, Merlini PA, Spinola A, et al. Non-neutralizing antibodies to tissue-type plasminogen activator in the serum of acute myocardial infarction patients treated with the recombinant protein. Thromb Haemost 1996;76:234-8.[Medline]
17. Reed BR, Chen AB, Tanswell P, Prince WS, Wert RM, Glaesle-Schwarz L, et al. Low incidence of antibodies to recombinant human tissue-type plasminogen activator in treated patients. Thomb Haemost 1990;64:276-80.
18. Blais C Jr, Rouleau JL, Brown NJ, Lepage Y, Spence D, Munoz C, et al. Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema. Immunopharmacology 1999;43:293-302.[Medline]
19. Markovic SN, Inwards DJ, Frigas EA, Phyliky RP. Acquired C1 esterase inhibitor deficiency. Ann Intern Med 2000;132:144-50.[Abstract/Free Full Text]
20. Van der Linden PWG, Hack E, Struyvenberg A, Roem D, Brouwer MC, de Boer JP, et al. Controlled insect-sting challenge in 55 patients: correlation between activation of plasminogen and the development of anaphylactic shock. Blood 1993;82:1740-8.[Abstract/Free Full Text]
21. Shimaya K, Sumi H, Maruyama M, Mihara H. A rapid and strong increase of plasminogen activator induced by experimental anaphylaxis in rabbits. Enzyme 1992;46:204-12.[Medline]
22. Buchan AM, Gertler SZ, Huang ZG, Li H, Chaundy KE, Xue D. Failure to prevent selective CA1 neuronal death and reduce cortical infarction following cerebral ischemia with inhibition of nitric oxide synthase. Neuroscience 1994;61:1-11.[Medline]
23. Zamrini EY, Meador KJ, Loring DW, Nichols FT, Lee GP, Figueroa RE, et al. Unilateral cerebral inactivation produces differential left/right heart rate responses. Neurology 1990;40:1408-11.[Abstract/Free Full Text]
24. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727-32.[Abstract/Free Full Text]
25. Yoon BW, Morillo CA, Cechetto DR, Hachinski V. Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 1997;54:741-4.[Abstract/Free Full Text]
26. Bauernschmitt R, Bohrer H, Hagl S. Rescue therapy with C1-esterase inhibitor concentrate after emergency coronary surgery for failed PTCA. Intensive Care Med 1998;24:635-8.[Medline]

This article has been cited by other articles:

				M. Rucker, T. Schafer, C. Scheuer, Y. Harder, B. Vollmar, and M. D. Menger Local Heat Shock Priming Promotes Recanalization of Thromboembolized Microvasculature by Upregulation of Plasminogen Activators Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1632 - 1639. [Abstract] [Full Text] [PDF]

				M. D. Hill, A. M. Buchan, and for The Canadian Alteplase for Stroke Effectivenes Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study Can. Med. Assoc. J., May 10, 2005; 172(10): 1307 - 1312. [Abstract] [Full Text] [PDF]

				M. D. Hill, T. Lye, H. Moss, P. A. Barber, A. M. Demchuk, N. J. Newcommon, T. L. Green, C. Kenney, A. Cole-Haskayne, and A. M. Buchan Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke Neurology, May 13, 2003; 60(9): 1525 - 1527. [Abstract] [Full Text] [PDF]

				G. Molinaro, M. Cugno, M. Perez, Y. Lepage, N. Gervais, A. Agostoni, and A. Adam Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema Is Characterized by a Slower Degradation of des-Arginine9-Bradykinin J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 232 - 237. [Abstract] [Full Text] [PDF]

				G. Molinaro, N. Gervais, and A. Adam Biochemical Basis of Angioedema Associated With Recombinant Tissue Plasminogen Activator Treatment: An In Vitro Experimental Approach Stroke, June 1, 2002; 33(6): 1712 - 1716. [Abstract] [Full Text] [PDF]

				M. D. Hill, P. A. Barber, A. M. Demchuk, N. J. Newcommon, A. Cole-Haskayne, K. Ryckborst, L. Sopher, A. Button, W. Hu, M. E. Hudon, et al. Acute Intravenous-Intra-Arterial Revascularization Therapy for Severe Ischemic Stroke Stroke, January 1, 2002; 33(1): 279 - 282. [Abstract] [Full Text] [PDF]

				M. D. Hill, P. A. Barber, J. Takahashi, A. M. Demchuk, T. E. Feasby, and A. M. Buchan Reactions to alteplase in patients with acute thrombotic stroke Can. Med. Assoc. J., August 1, 2000; 163(4): 388 - 389. [Full Text] [PDF]

				W. B. Chodirker Reactions to alteplase in patients with acute thrombotic stroke Can. Med. Assoc. J., August 1, 2000; 163(4): 387 - 388. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hill, M. D. Articles by Buchan, A. M. Search for Related Content PubMed PubMed Citation Articles by Hill, M. D. Articles by Buchan, A. M. Related Collections Allergy Drugs: central nervous system (not psychiatric) Stroke

HOME	CURRENT ISSUE	PAST ISSUES	COLLECTIONS	HELP	SEARCH
Copyright 1995-2000, Canadian Medical Association. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p) All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.