1. Management of Orolingual Angioedema Post-Alteplase Treatment in Stroke Patients
Oumaima Sahbani, PharmD
PGY1 Pharmacy Resident
John Dempsey Hospital at UCONN Health
May 8th, 2018

2. Conflicts of Interest I have no conflicts of interest to report
I intend to reference unlabeled/unapproved uses of drugs or products in my presentation

3. Objectives
Describe the mechanism of action behind post-alteplase angioedema
Understand the difference between allergic and non-allergic angioedema
Describe the treatment and medical management of angioedema post-alteplase
Orolingual angioedema post-alteplase therapy is a rare occurrence that is not frequently encountered by a majority of pharmacists

4. Alteplase (Activase )
Fibrinolytic effect: activates plasmin, which cleaves thrombus-bound fibrin
Used in treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarction
Contraindication: hypersensitivity
ADRs
Bleeding
Orolingual angioedema
Cerebral edema
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

5. Orolingual Angioedema Post-Alteplase
Rarely occurs ~1.3-5% in patients treated for ischemic stroke
0.02% in patients treated for myocardial infarction
Most patients respond well to medical management
Potentially life threatening if not recognized immediately and treated accordingly
Only well-known risk factor is prior use of an ACE inhibitor
O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3),

6. Mechanisms of Orolingual Angioedema
Allergic
Type I hypersensitivity
Antigen cross links with immunoglobulin E antibody bound on the surface of mast cells
Results in release of histamine
Non-allergic
Mediated by bradykinin
Three types:
Hereditary
Acquired
Drug-induced
Antigen cross links with immunoglobulin E antibody bound on the surface of mast cells – results in release of histamine
Important to understand the mechanisms between both because they differ in their mediator, clinical presentations, and their management
Non-allergic:
Onset is more progressive – symptoms may subside in 3-5 days
Symptoms are resistant to antihistamine and corticosteroid treatment, symptoms resolve only after drug discontinuation
Kalambay J, Ghazanfar H, Martes pena K A, et al. (August 23, 2017) Pathogenesis of Drug Induced NonAllergic Angioedema: A Review of Unusual Etiologies. Cureus 9(8): e1598.

7. Mechanism of Allergic Orolingual Angioedema
Angioedema results as a consequence of the underlying mechanism of alteplase
Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):

8. Mechanism of Allergic Orolingual Angioedema
Alteplase activates plasmin, which can activate complement cascade and kinin pathway
Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):

9. Mechanism of Allergic Orolingual Angioedema
Results in activation of mast-cell degranulation and histamine release
Which leads to anaphylactoid reactions
Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):

10. Mechanism of Non-Allergic Orolingual Angioedema
KKS is a cascade of proteolytic enzymes that release vasoactive peptides
Plasma kallikrein cleaves human high molecular weight kininogen and releases bradykinin
Bradykinin stimulates beta-2 adrenergic receptors, which results in the release of nitric oxide and prostacyclin
Nitric oxide and prostacyclin
Drugs can target three different sites of actions in the KKS to cause bradykinin mediated angioedema:
Synthesis of bradykinin with C1 INH suppression
Response to bradykinin: Bradykinin
Metabolism of bradykinin and substance P with ACE and DPP-IV suppression
Icatibant:
Bradykinin 2 (B2) receptor antagonist
FDA approved for treatment of hereditary angioedema
Used off-label for ACE-I induced angioedema
Studies show that resolution of angioedema occurs significantly sooner with Icatibant than with conventional therapy
Kalambay J, Ghazanfar H, Martes pena K A, et al. (August 23, 2017) Pathogenesis of Drug Induced NonAllergic Angioedema: A Review of Unusual Etiologies. Cureus 9(8): e1598.

11. Fresh frozen plasma (FFP) – provides the patient with kinase II which acts as an ACE thus allowing for the break down of bradykinin
C1 esterase inhibitor – inhibit kallikrein conversion of kininogen thus preventing the production of bradykinin
Scalese MJ, Reinaker TS. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health-System Pharm 2016; 73(12):
Scalese MJ, Reinaker TS. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health-System Pharm 2016; 73(12):

12. C1 Inhibitors Blood product derivatives Berinert® Cinryze®
Play a role in regulating the complement and intrinsic coagulation pathway
As well as the fibrinolytic and kinin pathways
Inactivate plasma kallikrein and factor XIIa, thus preventing bradykinin production
Make sure to know ADRs for these drugs as well as price
HAE = hereditary angioedema
Unregulated bradykinin production is thought to contribute to the increased vascular permeability and angioedema observed in HAE
Berinert®
Cinryze®
Main role: hereditary angioedema (HAE)
Case reports have shown that C1 inhibitors are a safe and effective addition to standard of therapy, and further exploration is encouraged

13. Clinical Presentation: Allergic
Important to quickly recognize symptoms and have treatment algorithm in place
Transient, self-limiting swelling of the tongue and lips
Caused by increased vasodilation and vascular permeability
Can potentially cause airway obstruction and respiratory compromise requiring emergent intubation
Localized, nonpitting edema involving the mucosa of the upper respiratory tract
Caused by increased vasodilation and vascular permeability
Drug induced allergic – rapid onset of swelling of mucosa and submucosa tissues, urticarial rash – responds to antihistamine, epinephrine, and corticosteroid treatment
O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3),

14. Onset of Orolingual Angioedema
Occurs quickly and unexpectedly after thrombolytic therapy
Can occur at any time after starting the infusion of the medication
Close monitoring required for the duration of administration of alteplase
Typically occurs towards the end of the alteplase infusion
The clinical presentation of non-allergic angioedema is very similar – but the symptoms are resistant to antihistamine and corticosteroids, symptoms only resolve after drug discontinuation
O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3),

15. Medical Management: Allergic
Guidelines for a specific treatment protocol do not exist
Discontinue remaining alteplase infusion if any signs of tongue or lip swelling
Promptly administer IV antihistaminergic medications
If swelling persists, administer corticosteroids
Guidelines for a specific treatment protocol do not exist: Many institutions use the protocol developed by the University of Cincinnati
O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3),

16. Medical Management: Allergic
Antihistaminergic:
H1 blockade
Diphenhydramine
10-50 mg IV per dose every 4-8 hours
100 mg per single dose; max 400 mg/day
H2 blockade
Famotidine 20 mg IV every 12 hours
Ranitidine 50 mg IV every 6 to 8 hours
Histamine is the primary mediator of anaphylaxis and can trigger a cascade of inflammatory mediators that modulate its own release, so in order to achieve total histamine blockage we use an h1 blocker like diphen and an h2 blocker like famotidine or ranitidine at their standard doses for anaphylaxis
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

17. Medical Management: Allergic
Glucocorticoids:
Methylprednisolone once
125 mg IV (low dose)
250 mg (moderate dose)
>500 mg (high dose)
Dexamethasone 2 to 6 mg IV every 6 to 12 hours
If the histamine blockage was not providing adequate response, glucocorticoids are the next option
IV methyl or IV dexa, with the standard doses for anaphylaxis listed here
Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

18. UCONN Health Clinical Care Guidelines for Stroke
Included here is our protocol at uconn health, this is in our guideline for stroke management if the team encounters angioedema during an alteplase infusion
This is here to show that it’s a good idea for institution to have a plan in place to know which teams to call such as ENT, in case if patient needs cricothyrotomy
UConn John Dempsey Hospital. (2014). Clinical Care Guidelines. Ischemic and Hemorrhagic Stroke. Farmington, CT.

19. Follow-up Treatment Consider in patients: Required intubation
With extensive edema
Refractory to initial doses of medications
Short course of maintenance corticosteroids
Prednisone taper
A specific taper is up to what the patient required for management and up to the provider
O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3),

20. Which of the following corticosteroid dosing regimens would you recommend for the treatment of orolingual angioedema during alteplase infusion?
A. Methylprednisolone 12.5 mg IV once
B. Prednisone 20 mg IV every 4 hours
C. Methylprednisolone 125 mg IV once
D. Dexamethasone 125 mg IV every 6 hours

21. Which of the following corticosteroid dosing regimens would you recommend for the treatment of orolingual angioedema during alteplase infusion?
A. Methylprednisone 12.5 mg IV once
B. Prednisone 20 mg IV every 4 hours
C. Methylprednisolone 125 mg IV once
D. Dexamethasone 125 mg IV every 6 hours

22. Patient MTM is brought to the ED for symptoms of stroke and is determined as a candidate for alteplase. Twenty minutes into her alteplase infusion, her lips start to swell and complains of difficulty breathing. What is the mediator of her reaction?
A. Bradykinin
B. Histamine
C. Kininogen
D. None of the above

23. Patient MTM is brought to the ED for symptoms of stroke and is determined as a candidate for alteplase. Twenty minutes into her alteplase infusion, her lips start to swell and complains of difficulty breathing. What is the mediator of her reaction?
A. Bradykinin
B. Histamine
C. Kininogen
D. None of the above

24. Summary
Clinical presentation and management of non- allergic vs. allergic angioedema differs
Orolingual angioedema post-alteplase therapy rarely occurs
Close monitoring of patients required
Treatment involves management of symptoms
Post-stroke follow up
Consider maintenance treatment
At the patient’s post-stroke follow up appointment, its important to assess for symptoms and counsel patients to watch out for these symptoms and go to the hospital if they notice OA
Consider maintenance in patients with more severe symptoms
Clinical presentation and management of non-allergic vs. allergic angioedema differs
Orolingual angioedema post-alteplase therapy rarely occurs
Requires close monitoring of patients
Treatment involves management of symptoms
Post-stroke follow up
Consider maintenance treatment

25. Management of Orolingual Angioedema Post-Alteplase Treatment in Stroke Patients
Oumaima Sahbani, PharmD
PGY1 Pharmacy Resident
John Dempsey Hospital at UCONN Health