1. How to Minimize Radiographic Contrast Reactions: Anaphylactoid & Acute Renal Injury How to Minimize Radiographic Contrast Reactions: Anaphylactoid & Acute Renal Injury Charles E. Chambers, MD, FSCAI, FACC VP, Society of Cardiovascular Angiography and Interventions Professor of Medicine and Radiology Pennsylvania State University College of Medicine Charles E. Chambers, MD, FSCAI, FACC VP, Society of Cardiovascular Angiography and Interventions Professor of Medicine and Radiology Pennsylvania State University College of Medicine

2. Radiographic Contrast Media (RCM) First introduced in 1923 (SrBr) to study the urinary tract, with NaI introduced in 1924. First introduced in 1923 (SrBr) to study the urinary tract, with NaI introduced in 1924. RCM makes fluid visible by increasing x-ray (60-125 photon kVp) absorbance based on elemental atomic number and density with iodine best. RCM makes fluid visible by increasing x-ray (60-125 photon kVp) absorbance based on elemental atomic number and density with iodine best. Minimum iodine concentrations are 300 mg/ml (normal range 320-400 mg/dl). Minimum iodine concentrations are 300 mg/ml (normal range 320-400 mg/dl). Classification is based upon an agents ability to dissociate (ionic) or not dissociate (nonionic) into ionic particles when introduced into blood. Classification is based upon an agents ability to dissociate (ionic) or not dissociate (nonionic) into ionic particles when introduced into blood.

3. Criteria for “Ideal” Radiographic Contrast Media Must be liquid at room temperature with viscosity similar to blood. Must be liquid at room temperature with viscosity similar to blood. It must contain an element with sufficiently high atomic number in a concentration adequate to provide an x-ray absorbance that is 10 percent greater than blood. It must contain an element with sufficiently high atomic number in a concentration adequate to provide an x-ray absorbance that is 10 percent greater than blood. It’s components must be biocompatible, with the lowest side effect profile, and easily eliminated from the body. It’s components must be biocompatible, with the lowest side effect profile, and easily eliminated from the body. Hirshfeld JW. Radiographic Contrast Agents. In Cardiac Imaging, ed Marcus, Schelbert, Skorton, Wolf, 1991

4. Ionic Monomer Nonionic Monomer Ionic Dimer Nonionic Dimer Radiographic Contrast Media Classification is based upon the agent’s ability to dissociate (ionic) or not dissociate (nonionic) into ionic particles

5. Radiographic Contrast Media Product Type I Concentration Osmolality (mgI/mL) (mOsm/kg H 2 O) ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ -------------------------------------------------- Monomers iohexol (Omnipaque) non-ionic 350 844 iopamidol (Isovue) non-ionic 370 796 ioxilan (Oxilan) non-ionic 350 695 iopromide (Ultravist) non-ionic 370 774 ioversol (Optiray) non-ionic 350 792 Dimers iodixanol (Visipaque) non-ionic 320 290 ioxaglate (Hexabrix) ionic 320 600 __ Kozak M, Chambers, CE. Cardiac Catheterization Laboratory: In: Kaplan, JA, ed. Kaplan's Cardiac Anesthesia. 6th ed., 2011 Kozak M, Chambers, CE. Cardiac Catheterization Laboratory: In: Kaplan, JA, ed. Kaplan's Cardiac Anesthesia. 6th ed., 2011

6. “Allergic” Reactions to RCM Differentiate Chemotoxic from Anaphylactoid Differentiate Chemotoxic from Anaphylactoid Anaphylactoid not anaphylactic since non-IgE medicated, therefore no skin tests are available or invitro tests to detect potential allergic rxns Anaphylactoid not anaphylactic since non-IgE medicated, therefore no skin tests are available or invitro tests to detect potential allergic rxns Allergy to “fish” is unrelated to RCM allergy since the presence of iodine in fish and contrast media is not a common antigenic factor. Allergy to “fish” is unrelated to RCM allergy since the presence of iodine in fish and contrast media is not a common antigenic factor. A trial administration of a small dose of contrast may well not detect potential reactions to the therapeutic dose. A trial administration of a small dose of contrast may well not detect potential reactions to the therapeutic dose. Incidence of Repeat Anaphylactoid Contrast Reactions Incidence of Repeat Anaphylactoid Contrast Reactions Without prophylaxis- 44% Without prophylaxis- 44% With steroid and diphenhydramine-5% With steroid and diphenhydramine-5% With steroids, diphenhydramine, and non-ionic contrast-0.5% With steroids, diphenhydramine, and non-ionic contrast-0.5% Reisman RE. Anaphylaxis, in Allergy and Immunology, AM Coll of Physicians, 1998

7. Prednisone: 50 mg po 6pm, midnight, and 6 AM prior to catheterization. Prednisone: 50 mg po 6pm, midnight, and 6 AM prior to catheterization. Most important dose likely the one >12 hrs prior. Most important dose likely the one >12 hrs prior. Diphenhydramine: 50mg, given IV on call Diphenhydramine: 50mg, given IV on call Non-ionic contrast used. Non-ionic contrast used. Limited role for H 2 blockers and ephedrine. Limited role for H 2 blockers and ephedrine. Should not use H 2 without H 1. Should not use H 2 without H 1. Ephedrine not proven beneficial in the cardiac pt. Ephedrine not proven beneficial in the cardiac pt. Emergent procedures, limited data: Emergent procedures, limited data: Hydrocortisone, 200 mg IV q 4 hrs, until procedure. Hydrocortisone, 200 mg IV q 4 hrs, until procedure. Goss JE, Chambers CE, Heupler. Systemic Anaphylactoid Rxns to RCM/ CCD 1995. 34: 88-104. Anaphylactoid Reaction Prophylaxis

8. Therapy for Anaphylactoid Reactions Minor-Uticaria, with or without Skin Itching Minor-Uticaria, with or without Skin Itching No therapy No therapy Diphenhydramine, 25-50mg IV Diphenhydramine, 25-50mg IV Epinephrine 0.3 cc of 1:1,000 solution sub- Q q 15 min up to 1 cc Epinephrine 0.3 cc of 1:1,000 solution sub- Q q 15 min up to 1 cc Cimetadine 300 mg or ranitadine 50 mg in 20 cc NS IV over 15 mins Cimetadine 300 mg or ranitadine 50 mg in 20 cc NS IV over 15 mins Bronchosapsm Oxygen Mild- albuterol inhaler, 2 puffs Moderate-Epinephrine 0.3 cc of 1:1,000 sub-Q up to 1 cc Severe-Epinephrine IV as bolus 10 micrograms/min then infusion 1 to 4 micrograms/min Diphenhydramine 50 mg IV Hydrocortisone 200-400mg IV Consider H2 blocker Facial/Laryngeal Edema Call anesthesia Assess airway O2 mask, Intubation, Tracheostomy tray Mild-Epinephrine sq Moderate/Severe: Epi-IV 0.3 cc of 1:1,000 solution sub-Q q 15 min, 1 cc Diphenhydramine 50 mg IV Hydrocortisone 200-400 mg IV Optional: H2 blocker Hypotension/Shock Epinephrine IV boluses Large volumes 0.9% NS (1-3 l) CVP, PA catheter Airway, intubation as needed Diphenhydramine 50 mg IV Hydrocortisone 400mg IV If unresponsive… H2 blocker Dopamine/nor epinephrine

9. 2011 PCI Guidelines 3.3 Anaphylactoid Reactions Recommendations Class I Class I 1. Patients with prior evidence of an anaphylactoid reaction to contrast media should receive appropriate steroid and antihistamine prophylaxis prior to repeat contrast administration. (Level of Evidence B) Class III: No Benefit Class III: No Benefit 1. In patients with prior history of allergic reactions to shellfish or seafood, anaphylactoid prophylaxis for contrast reaction is not beneficial. (Level of Evidence: C)

10. Delayed Contrast Reaction Uncommon Uncommon Exclude Exclude Clopidogrel Clopidogrel Other drugs Other drugs Consider Consider Steroids Steroids Other Dx. Other Dx.

11. Contrast Induced Nephropathy (CIN) Contrast Induced Acute Kidney Injury Definition: an increase in serum Cr from baseline of >25%, or absolute >0.25 or 0.5 mg/dl. Definition: an increase in serum Cr from baseline of >25%, or absolute >0.25 or 0.5 mg/dl. Baseline renal disease increases risk as assessed by eGFR or CrCl; age, sex, and obesity factors in estimating eGFR/CrCl. Baseline renal disease increases risk as assessed by eGFR or CrCl; age, sex, and obesity factors in estimating eGFR/CrCl. Renal dysfunction is identifiable by 48 hrs and most often returns to baseline by 7-10 days. Renal dysfunction is identifiable by 48 hrs and most often returns to baseline by 7-10 days.

12. Pre-procedural Clinical Risk Factors for Contrast Induced Nephropathy Modifiable Risk Factors Modifiable Risk Factors Contrast volume Contrast volume Hydration status Hydration status Concomitant nephrotoxic agents Concomitant nephrotoxic agents Recent contrast administrations Recent contrast administrations Non-modifiable Risk Factors Diabetes/Chronic kidney disease Shock/hypotension Advanced age (> 75 yrs) Advanced congestive heart failure Klein LW, Sheldon MA, Brinker J, Mixon TA, Skeldiong K, Strunk AO, Tommaso CL, Weiner B, Bailey SR, Uretsky B, Kern M, Laskey W. The use of radiographic contrast media during PCI: A focused review. Cathet Cardiovasc Int 2009; 74: 728-46

13. Multi-factorial Predictors of CIN VariableScoreOdds RatioP Value Hypotension52.537 <0.0001 Hypotension52.537 <0.0001 IABP use52.438 <0.0001 IABP use52.438 <0.0001 CHF52.250 <0.0001 CHF52.250 <0.0001 SCR>1.542.053 1.542.053 <0.0001 Age.7541.847 <0.0001 Age.7541.847 <0.0001 Anemia31.601 <0.0001 Anemia31.601 <0.0001 DM31.508 <0.0001 DM31.508 <0.0001 Contrast Volume 1/100 1.290 <0.0001 Contrast Volume 1/100 1.290 <0.0001 Mehran R J. Am Coll Cardiolo. 2004;44:1393-99.

14. Multi-factorial Predictors of CIN

15. Cardiac Complication in Patients with CIN Post PCI Mayo Clinic Registry of 7,586 pts post PCI Mayo Clinic Registry of 7,586 pts post PCI Patients with CIN had increased rates of: Patients with CIN had increased rates of: CABG p=0.004 CABG p=0.004 Q-MI p< 0.001 Q-MI p< 0.001 CK Risep<0.001 CK Risep<0.001 Low BPp<0.001 Low BPp<0.001 Shockp<0.001 Shockp<0.001 Cardiac Arrestp<0.001 Cardiac Arrestp<0.001 Rihal CS. Circ. 2002; 105:2259-64.

16. Mortality with CIN

17. Non- RCM Related Procedural Complications Resulting In Renal Injury Cholesterol Emboli Cholesterol Emboli Renal Insufficiency identified week(s) later Renal Insufficiency identified week(s) later Livedo reticularis Livedo reticularis Necrotic toes Necrotic toes Eosinophilia Eosinophilia Crystals on bx Crystals on bx Cholesterol Emboli

18. Reducing CIN Risk Not Prevention Pre-Procedure Pre-Procedure Hydration Hydration Normal Saline preferred over D5 ½ normal Normal Saline preferred over D5 ½ normal Sodium Bicarbonate, mixed reviews Sodium Bicarbonate, mixed reviews Medications Medications NSAID stop if possible NSAID stop if possible N-acetylcysteine, mixed reviews, no clear benefit N-acetylcysteine, mixed reviews, no clear benefit Procedure Procedure Contrast to CrCl ratio Contrast to CrCl ratio Contrast Contrast Volume, repeat studies Volume, repeat studies Type-non-ionic/isoosmolar Type-non-ionic/isoosmolar Post Procedure Post Procedure Hydration: Normal Saline & PO Hydration: Normal Saline & PO Identify Risk Low risk: eGFR > 60 ml/1.73 m2 Optimize hydration status. High risk: eGFR <60 ml/1.73 m2 Schedule outpatient for early arrival and/or delay procedure time to allow time to accomplish the hydration.

19. 2011 PCI Guidelines 3.2 Contrast-Induced Acute Kidney Injury Recommendations Class I 1. Patients should be assessed for risk of contrast-induced AKI before PCI. (Level of Evidence: C) 2. Patients undergoing cardiac catheterization with contrast media should receive adequate preparatory hydration. (Level of Evidence: B) 3. In patients with chronic kidney disease (creatinine clearance <60cc/min), the volume of contrast media should be minimized. (Level of Evidence: B) Class III: No Benefit 1. Administration of N-acetyl-L-cysteine is not useful for the prevention of contrast- induced AKI. (Level of Evidence: A )

20. Contrast Dose Maximal Allowable Contrast Dose (MACD) Maximal Allowable Contrast Dose (MACD) 5 cc contrast x body wgt (kg)/ baseline Cr 5 cc contrast x body wgt (kg)/ baseline Cr Brown et al, Circ Interv, 2010. Brown et al, Circ Interv, 2010. Volume to Creatinine Clearance Ratio Volume to Creatinine Clearance Ratio Contrast volume/ CrCl Contrast volume/ CrCl Laskey, JACC 2007, unselected population, 3.7 ratio Laskey, JACC 2007, unselected population, 3.7 ratio Gurm et al, JACC, 2011, 3 concern Gurm et al, JACC, 2011, 3 concern

21. Contrast Type Low osmolar or Iso-osmolar better than high osmolar contrast Low osmolar or Iso-osmolar better than high osmolar contrast Iso-osmolar may be better than certain low osmolar contrast (iohexol) but has not consistently been proven for all low osmolar agents. Iso-osmolar may be better than certain low osmolar contrast (iohexol) but has not consistently been proven for all low osmolar agents. Keys Keys Low-osmolar or iso-osmolar Low-osmolar or iso-osmolar Limit dose Limit dose Repeat studies>72 hrs, if clinically possible Repeat studies>72 hrs, if clinically possible

22. Gadolinium Gadolinium chelates used extensively in MR imaging. Gadolinium chelates used extensively in MR imaging. Once Considered a potential “substitute” for iodonated RCM in pts with renal insufficiency and anaphylactoid reactions. Once Considered a potential “substitute” for iodonated RCM in pts with renal insufficiency and anaphylactoid reactions. Advantages have not been documented and visualization is an issue compared with iodonated RCM. Advantages have not been documented and visualization is an issue compared with iodonated RCM. Nephrotic Systemic Fibrosis (NSF) or Nephrotic Fibrosing Dermopathy (NFD) identified in patients with baseline renal dysfunction following gadolinium. Nephrotic Systemic Fibrosis (NSF) or Nephrotic Fibrosing Dermopathy (NFD) identified in patients with baseline renal dysfunction following gadolinium.

23. N-acetylcysteine: a Meta-analysis of 20 Randomized Trials 20 Random Trials, N=2195, CI 95%; Nallamothu BK et al. Am J Med. 2004; 117:938-47

24. Other Considerations Carbon Dioxide Alternative Contrast Agent Used in conjunction with small dose of iodinated contrast Potential Neurotoxicity Recommended only below diagram Volume: Hydration Diuretics not of benefit mannitol may be detrimental Sodium Bicarbonate: inconsistent data, unclear benefit 0.9 NS better than 0.5 NS IV better than oral Pre and post hydration preferred, CHF patient dependent. Rudnick. Prevention of Contrast-induced Nephropathy, 2013

25. Other Considerations Hemofiltration and Hemodialysis Neither can be recommended routinely In Stage 5 CKD, more information is needed Drugs Atrial natriuretic peptide Statins Ascorbic Acid Trimetazidine Renal Guard System Fluid management device that guides fluid replacement. More information required before routinely recommended.

26. Manage Medications Manage Medications Withhold, if clinically appropriate, potentially nephrotoxic drugs including aminoglycoside antibiotics, anti-rejection medications and nonsteroidal anti- inflammatory drugs (NSAID). Withhold, if clinically appropriate, potentially nephrotoxic drugs including aminoglycoside antibiotics, anti-rejection medications and nonsteroidal anti- inflammatory drugs (NSAID). Manage Intravascular Volume (Avoid Dehydration) Manage Intravascular Volume (Avoid Dehydration) Administer a total of at least 1L of isotonic (normal) saline beginning at least 3 hrs before and continuing at least 6-8 hrs after the procedure. Administer a total of at least 1L of isotonic (normal) saline beginning at least 3 hrs before and continuing at least 6-8 hrs after the procedure. i. initial infusion rate 100 to 150 ml/hr adjusted post procedure as clinically indicated i. initial infusion rate 100 to 150 ml/hr adjusted post procedure as clinically indicated Radiographic Contrast Media Radiographic Contrast Media Minimize volume Minimize volume Low- or iso-osmolar contrast agents Low- or iso-osmolar contrast agents Post-Procedure: Discharge/Follow-Up Post-Procedure: Discharge/Follow-Up Obtain follow-up SCr 48 hrs post procedure Obtain follow-up SCr 48 hrs post procedure Consider holding appropriate medications until renal function returns to normal, i.e. metformin, NSAID Consider holding appropriate medications until renal function returns to normal, i.e. metformin, NSAID Recommendations for Decreasing Risk of Contrast Induced Acute Renal Injury/CIN

27. Final Thoughts and Questions