Gadolinium-induced anaphylaxis:
a case presentation and review of
anaphylaxis treatment
December 5, 2013
Jocelyn Chaing, PharmD
PGY1 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)
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
Case (continued)
• Vital signs the ED:
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Temp 36.0°C
HR 136
RR 31
BP 98/57 mmHg
O2 Sat 77% on room
air
• Physical Exam
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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 lifethreatening
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 3060 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,
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)
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
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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 q515min 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;101:33–37
Simons 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
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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
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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:
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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
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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 treatmentrefractory 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 (calciumdependent 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:
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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
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
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