1. PGY1 Pharmacy Practice Resident
Gadolinium-induced anaphylaxis: a case presentation and review of anaphylaxis treatment
December 5, 2013
Jocelyn Chaing, PharmD
PGY1 Pharmacy Practice Resident
UW Medicine

2. Case 31 y/o F presents to UWMC for outpatient MRI of abdomen
Past Medical History
Crohn’s disease
s/p 2 colectomies
Allergies
Gadolinium containing compounds
Iodinated radiocontrast dye
Medications
Folate
Methotrexate
Effexor

3. Case (continued) Patient’s History
In 2009 – pt had an anaphylactic rxn to iodinated radiocontrast
In 2010 – pt had an anaphylactic reaction gadolinium
In pt tolerated an MR enterography with pretreatment steroids and antihistamine prior to gadolinium injection
GI recommended pretreatment with methylprednisolone PO 32 mg 12 hours and 2 hours prior to MRI as well as diphenhydramine 50 mg PO 1 hr before the gadolinium injection

4. Case (continued)
Pt was scheduled for an MRI for staging of her Crohn’s Disease
Minutes after administration of gadolinium contrast, the pt began sneezing and coughing
Radiology tech observes the pt is tachypneic w/ labored breathing and has signs of cyanosis
Immediately, the pt is wheeled across the hall into the ER

5. Case (continued) Vital signs the ED: Physical Exam Temp 36.0°C HR 136
RR 31
BP 98/57 mmHg
O2 Sat 77% on room air
Physical Exam
Positive for cyanosis
Red rash on stomach
Somnolent
Diffuse expiratory wheezing
Swollen oropharynx

6. Diagnosis
UpToDate

7. Hypersensitivity Reactions
Gell and Coombs Classification
Type
Classification
Mechanism I
Anaphylactic hypersensitivity
IgE II
Cytotoxic hypersensitivity
Cytotoxic Ab (IgM, IgG)
III
Immune complex hypersensitivity
IgG IV
Delayed-type hypersensitivity
Cell-mediated (lymphocytes)
UpToDate

8. Anaphylaxis 50 to 2,000 episodes per 100,000 people in the U.S.
1,500 deaths per year
Type I Hypersensitivity
Immunologic reaction to foods, drugs, insect stings
Onset: seconds to 1 hr
Ranges from mild to life-threatening
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348

9. Clinical Presentation
Signs and symptoms (% of anaphylactic episodes)
Skin (90%) – urticaria, angioedema, pruritis, flushing
Respiratory (70%) – dyspnea, throat tightness, stridor, wheezing, rhinorrhea, hoarseness, and cough
GI (45%) – nausea, vomiting, abdominal cramping, diarrhea
Cardiovascular (45%) – hypotension, tachycardia, syncope
Deaths mainly due to respiratory distress or cardiovascular collapse
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341– 348

10. Time course Uniphasic anaphylaxis Biphasic anaphylaxis
Most common, 80% of all anaphylactic reactions
Response peaks min
Symptoms resolve spontaneously or w/ treatment within min
Biphasic anaphylaxis
20% of all anaphylactic reactions
Uniphasic response followed by an
asymptomatic period of >1 hr and
recrudescence of symptoms without
further exposure to the antigen
Protracted anaphylaxis
Uncommon
Lasts hours to days
UpToDate

11. Pathophysiology 1st exposure: Antigen  IgE antibody formation
2nd exposure: Antigen  IgE bound to mast cells and basophils
-Triggers degranulation of mast cells and basophils
-Degranulation = release of vasoactive amines (histamine, serotonin) and other agents (heparin, eosinophil and neutrophil chemotactic factors, platelet-activating factor, a variety of cytokines and prostaglandins and leukotrienes)
-Collectively cause contraction of smooth muscle cells, vasodilation, increased vascular permeability and platelet aggregation and degranulation  anaphylactic signs and symptoms

12. Biochemical Mediators in Anaphylaxis
Roles
Histamine
H1 receptors – pruritis, rhinorrhea, tachycardia, bronchospasm
H1 and H2 receptors – headache, flushing, hypotension
Prostaglandin D2
Bronchospasm, vascular dilatation
Leukotriene D4 and E4
Hypotension, bronchospasm, mucous secretion, chemotactic signals for eosinophils and neutroophils
T-Helper 1
Cellular immunity; produce interferon gamma
T-Helper 2
Humoral immunity; produce cytokines (interleukin)
Histamine
Prostaglandin D2 (PD2) – bronchospasm, vascular dilatation,
Leukotriene C4 (LTC4)  LTD4 and LTE4 – hypotension, bronchospasm, mucous secretion, chemo
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348

13. Anaphylactic vs. Anaphylactoid
Anaphylactic reactions
IgE mediated
Occurs after re-exposure to antigen
Examples: antibiotics, peanuts, insect venom
Anaphylactoid reactions
Identical pathophysiology as anaphylactic reactions, but NOT IgE mediated
Can occur after first exposure to antigen
Example: radiocontrast media
Non-IgE-mediated causes include factors causing marked complement activation such as plasma proteins or compounds which act directly on the mast cell membrane

14. Treatment of Anaphylaxis
Epinephrine
Maintain airway
Supplemental oxygen
IV fluids if pt is hypotensive
Consider adjunctive agents
Monitor vitals and pulse oximetry for 4-10 hrs
Identify antigen and avoid future exposure

15. Epinephrine First line agent in all cases of anaphylaxis Adult Dose
mg IM x 1, may repeat q5-15min prn
mL of epinephrine 1:1000* (1 mg/mL) solution
No absolute contraindications in the setting of anaphylaxis
Onset: rapid
Epinephrine is commercially available in several dilutions, and great care must be taken to use the correct dilution
The epinephrine dilution for intramuscular injection contains 1 mg per mL and may also be labeled as 1:1000.
Each mL of the 1:10,000 solution contains 0.1 mg epinephrine
Each mL of the 1:1000 solution contains 1 mg epinephrine
Mean maximum plasma epinephrine levels are achieved significantly faster following IM administration compared with subQ, due to delayed absorption following subQ administration. An injection of epinephrine IM into the thigh (vastus lateralis muscle) is the more effective route and site of injection when compared with IM or subQ administration into the upper arm (deltoid area). Mean peak plasma epinephrine concentrations are significantly higher after an IM injection into the thigh than after an IM or subQ injection into the upper arm
*NOTE CONCENTRATION
Johnson RF and Stokes Peebles R. Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Seminars in Respiratory and Critical Care Medicine. 2004:25(6);

16. Epinephrine Prevent/reverse airway obstruction and CV collapse
Mechanism of action
Alpha-1 adrenergic agonist -  vasoconstriction,  systemic vascular resistance,  mucosal edema in upper airway
Beta-1 adrenergic agonist -  ionotropy,  chronotropy
Beta-2 adrenergic agonist -  bronchodilation,  release of mediators from mast cells and basophils
Monitor: BP, HR
Adverse effects: anxiety, flushing, pallor, hypertension, palpitations, angina, arrhythmias, intracranial hemorrhage
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

17. Epinephrine IM vs. SQ vs. IV Deltoid vs. Vastus lateralis (thigh)
Simons et al reported epinephrine IM is superior to SQ
Delayed epinephrine absorption with SQ compared with IM
Due to the cutaneous vasoconstrictive properties of epinephrine
Deltoid vs. Vastus lateralis (thigh)
Simons et al reported superior serum levels of epinephrine in thigh compared to SQ and IM into the deltoid
Superiority of blood flow to the vastus lateralis
Simons FER, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33–37
Simons FER, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871–873
Intramuscular injection is recommended over subcutaneous injection because it consistently provides a more rapid increase in the plasma and tissue concentrations of epinephrine
Mean maximum plasma epinephrine levels are achieved significantly faster following IM administration compared with subQ, due to delayed absorption following subQ administration. An injection of epinephrine IM into the thigh (vastus lateralis muscle) is the more effective route and site of injection when compared with IM or subQ administration into the upper arm (deltoid area). Mean peak plasma epinephrine concentrations are significantly higher after an IM injection into the thigh than after an IM or subQ injection into the upper arm
Simons et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33–37
Simons et al. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871–873

18. Adjunctive Agents Do NOT substitute for epinephrine IM
No randomized double-blind, placebo-controlled trials of any of these medications in the treatment of acute anaphylaxis episodes
Doses are extrapolated from use in treatment of other disease states
Simons FER. Anaphylaxis: evidence-based long-term risk reduction in the community. Immunol Allergy Clin North Am 2007;27:

19. Albuterol
Dose: 1 Albuterol 0.083% ampule (2.5 mL) via nebulizer q15min
Onset: 5-10 minutes
Treats bronchospasm
Mechanism of action
Beta-2 agonist – bronchodilation
Monitor: HR
Adverse effects: palpitations, tachycardia, cardiac arrhythmias
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

20. Diphenhydramine Adjunctive agent
Dose: mg IV, may repeat until MAX 400mg/24hr
Onset: min (oral), unknown for IV
Treats itching and urticaria
Mechanism of action
H1 receptor antagonist – blocks histamine effects on H1 receptors of effector cells in GI, blood vessels, and respiratory tract
Adverse effects: somnolence, hypotension
H1 antihistamines relieve itch and hives. These medications DO NOT relieve upper or lower airway obstruction, hypotension or shock, and in standard doses do not inhibit mediator release from mast cells and basophils.
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

21. Ranitidine Dose: 50 mg IVPB x 1
Treats hypotension in conjunction with H1 antihistamines
Minimal evidence to support use w/ H1 antihistamines
Onset: 1 hour
Mechanism of action
H2 receptor antagonist - blocks histamine effects on H2 receptors of effector cells
Both H1 and H2 receptors mediate headache, flushing, and hypotension
Adverse Effects: less sedation than H1 antihistamines, transient local burning or itching with IV administration
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341– 348
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

22. Glucocorticoid Prevent biphasic or protracted reactions
Limited evidence to support effectiveness if anaphylaxis
Dose: methylprednisolone 1-2 mg/kg/day IV
Onset: 30 minutes
Mechanism of action
Decreased formation, release and activity of the mediators of inflammation
Adverse Effects: fluid retention, cushing’s, hyperglycemia, impaired wound healing
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.
Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

23. Case (continued) Pt showing signs of anaphylactic shock
Anesthesia and ENT paged for possible intubation
Pt Immediately received:
Epinephrine 0.3 mg IM x 1
Diphenhydramine 50 mg IV x 1
Methylprednisolone 125 mg IV x 1
Ranitidine 50 mg IVPB x 1
Vitals signs
HR 121
BP 106/71 mmHg
O2 saturation 99% with Vent Face Mask
Patient more alert and reports feeling better

24. Case (continued) 10 minutes later:
RN reports pt is having labored breathing and chest tightness
Vital signs:
HR 135
RR 26
O2 saturation 98% with Vent Face Mask
What is going on?

25. Refractory Anaphylaxis
Patients who do not respond to epinephrine IM
Biphasic or protracted anaphylaxis
Pathophysiology unknown
Possible saturation/desensitization of adrenergic receptors
Possible prolonged half-life of offending antigen
No published prospective studies on the optimal management of refractory anaphylaxis
Treatment options:
Maintain airway
Epinephrine
Glucagon
No clear superiority of dopamine, dobutamine, norepinephrine, phenylephrine, or vasopressin (either added to epinephrine alone, or compared with one another) demonstrated in clinical trials.
Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348

26. Epinephrine infusion
For patient with profound hypotension or signs of shock
Initial dose: 2-10 mcg/min
Alaris pumps in mcg/kg/min
Maintain SBP >90 mmHg, MAP>60
Requires close monitoring (HR, BP)
Adverse effects: ventricular arrhythmias, hypertensive crisis, pulmonary edema
Consider pt’s IV access
Peripheral vs. Central
Potentially fatal dose errors  ventricular arrhythmias, hypertensive crisis, pulmonary edema
Johnson RF and Stokes Peebles R. Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Seminars in Respiratory and Critical Care Medicine. 2004:25(6);

27. Glucagon
Patients taking beta-blockers have more severe or treatment-refractory anaphylaxis
Dose: 1 mg IV q5min, then mcg/min IV infusion
Increase HR and cardiac output
Mechanism
Non-adrenergic pathway
Stimulate adenylate cyclase to produce cyclic AMP (calcium-dependent stimulation)
Positive ionotropic and chronotropic effects
Adverse Effects: nausea, vomiting
Johnson RF and Stokes Peebles R. Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Seminars in Respiratory and Critical Care Medicine. 2004:25(6);

28. Case (continued) Pt started on epinephrine infusion Follow up vitals:
Initial dose 0.02 mcg/kg/min
Translates to 1.1 mcg/min, pt does not have a central line
Wt: 55 kg
Follow up vitals:
HR 108
RR 14
BP 114/71 mmHg
O2 saturation 100% with 4L of O2
Intubation was not required
Pt was admitted to MICU for close monitoring
Epinephrine was weaned off after a few hours
Pt’s course was unremarkable thereafter and discharged home

29. Anaphylactoid Reactions from Gadolinium
MR contrast considered safe alternative to CT contrast allergy
Incidence 0.079% of 141, 623 doses
Prince et al’s restrospective analysis
Abdominal MRI highest rate of adverse events 0.013% vs. brain % vs. spine % (p<0.001)
Adverse events more likely in women (3.3 female to male ratio) and pt w/ history of prior allergic reactions
Jung et al. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 2012 Aug;264(2)
Prince et al. Incidence of immediate gadolinium contrast media reactions. AJR Feb 2011:196;
Jung et al. Immediate hypersensitivity reaction to gadolinium-based MR contrast media. Radiology 2012 Aug;264(2)
Prince et al. Incidence of immediate gadolinium contrast media reactions. AJR Feb 2011:196;

30. Pretreatment Patient risk stratification (see handout)
Data supporting the use of premedication in patients with a history of allergic reactions are lacking
Many pharmacologic regimens based on observation data
Premedication Regimens at HMC/UWMC
Routine: Methylprednisolone 32 mg PO 12 hr and 2 hr before contrast injection OR prednisone 50 mg PO at 13, 7, 1 hr before contrast injection
Optional: diphenhydramine 25 mg PO 1 hr before contrast
Emergency (pt NPO): Hydrocortisone 200 mg IV or 40 mg SoluMedrol at 6 hr and 2 hr before contrast study and diphenhydramine 50 mg IV 1 hr before contrast study

31. Pretreatment Systematic Review of 9 studies by Tramèr et al.
Tramèr et al. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review, BMJ 2006;333:675

32. Pretreatment Tramèr et al conclusions:
Incidence of respiratory and hemodynamic symptoms reduced from 0.9% to 0.2% with premedication
Need to premedicate patients to prevent one potentially serious reaction
Usefulness of premedication prior to contrast is doubtful
Despite pretreatment with steroids, patients still have breakthrough anaphylactoid reaction
Physicians should not rely on the efficacy of premedication

33. Conclusion
Immediate hypersensitivity to contrast media are non-IgE mediated anaphylactoid reactions
Treatment for anaphylaxis and anaphylactoid reactions are similar
Epinephrine IM is 1st line agent for all anaphylaxis and anaphylactoid reactions
Adjunctive agents should NOT replace epinephrine IM
Breakthrough reactions can occur despite pretreatment with steroids and antihistamines
Epinephrine and glucagon infusions can be used for refractory anaphylaxis

34. Questions