Gadolinium-induced anaphylaxis: a case presentation and review of anaphylaxis treatment December 5, 2013 Jocelyn Chaing, PharmD PGY1 Pharmacy Practice Resident UW Medicine [email protected] Case 31 y/o F presents to UWMC for outpatient MRI of abdomen Past Medical History Crohns disease s/p 2 colectomies
Allergies Gadolinium containing compounds Iodinated radiocontrast dye Medications Folate Methotrexate Effexor Case (continued) Patients 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 Crohns 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:
Temp 36.0C 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 I II III IV Classification Anaphylactic hypersensitivity Cytotoxic hypersensitivity Immune complex hypersensitivity Delayed-type hypersensitivity Mechanism
IgE Cytotoxic Ab (IgM, IgG) IgG 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;110:341348 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 Histamine Roles 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 Cellular immunity; produce interferon gamma Humoral immunity; produce cytokines (interleukin) T-Helper 1
T-Helper 2 Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110:341348 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 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;101:3337 Simons et al. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871873 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, cushings, 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;110:341348 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 pts 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:
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 Pts 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 als 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 Tramr et al. Tramr et al. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review, BMJ 2006;333:675 Pretreatment Tramr 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
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