Gadolinium-induced anaphylaxis: a case presentation and review of anaphylaxis treatment

December 5, 2013

Jocelyn Chaing, PharmDPGY1 Pharmacy Practice Resident

UW Medicine jchaing@uw.edu

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

Case (continued)

• Patient’s History • In 2009 – pt had an anaphylactic rxn to iodinated radiocontrast• In 2010 – pt had an anaphylactic reaction gadolinium• In 2012- 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

Case (continued)

• 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

Pt was scheduled for an MRI for staging of her Crohn’s Disease

Case (continued)

• Vital signs the ED: • 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

Diagnosis

UpToDate

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

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

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

Time course• Uniphasic anaphylaxis• Most common, 80% of all anaphylactic reactions• Response peaks 30-60 min• Symptoms resolve spontaneously or w/ treatment within 30-60

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

Pathophysiology

Biochemical Mediators in Anaphylaxis

Biochemical Roles

Histamine H1 receptors – pruritis, rhinorrhea, tachycardia, bronchospasmH1 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)

Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348

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

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

Epinephrine• First line agent in all cases of

anaphylaxis• Adult Dose• 0.3-0.5 mg IM x 1, may repeat q5-

15min prn• 0.3-0.5 mL of epinephrine 1:1000*

(1 mg/mL) solution • No absolute contraindications in

the setting of anaphylaxis• Onset: rapid

*NOTE CONCENTRATION

Johnson RF and Stokes Peebles R. Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Seminars in Respiratory and Critical Care Medicine. 2004:25(6);695-703.

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.

Epinephrine• IM vs. SQ vs. IV• 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 et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33–37Simons et al. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871–873

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;27:231-48.

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.

Diphenhydramine• Adjunctive agent• Dose: 25-50 mg IV, may repeat until MAX 400mg/24hr• Onset: 15-60 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

Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

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

Simons et al. World Allergy Organization Guidelines for Assessment and Management of Anaphylaxis. WAO Position Paper 2011:1-37.

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.

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

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?

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

Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341–348

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

Johnson RF and Stokes Peebles R. Anaphylactic Shock: Pathophysiology, Recognition, and Treatment. Seminars in Respiratory and Critical Care Medicine. 2004:25(6);695-703.

Glucagon• Patients taking beta-blockers have more severe or treatment-

refractory anaphylaxis• Dose: 1 mg IV q5min, then 5 -15 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);695-703.

Case (continued) • Pt started on epinephrine infusion• 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

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 0.0045% vs. spine 0.0034% (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)414-22.Prince et al. Incidence of immediate gadolinium contrast media reactions. AJR Feb 2011:196; 138-43.

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

Pretreatment

Tramèr et al. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review, BMJ 2006;333:675

Systematic Review of 9 studies by Tramèr et al.

Pretreatment• Tramèr et al conclusions: • Incidence of respiratory and hemodynamic symptoms reduced

from 0.9% to 0.2% with premedication• Need to premedicate 100-150 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

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

Questions