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Patient Safety & Free Iodine

Tiara Ratna WMedical PT. Bayer Indonesia

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General Safety Allergy Like

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Types of Adverse ReactionOverview

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Distinction by pathophysiologyAnaphylactoid, dose-independent reactions (allergy-like)Organotoxic, dose-dependent reactions (e.g. CIN), including physiological reactions

or by timepoint of occurrence after injectionsAcute reactions (up to 1 h after the administration of CM)Delayed (late) reactions (The majority of the late reactions occur between 3 and 72 hours after the application of contrast media. Subsequently occurring reactions are rare; the maximum interval is 7 days)Very late reactions – occurring more than 1 week after the CM injection (ESUR V9.0)

Sidhu and Dawson, Adverse reactions: cause, prophylaxis and management in Textbook of Contrast Media, 1999

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ACR 2020 Categories of Acute Reaction

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MILD• Limited urticaria / pruritis • Limited Cutaneous Edema • Limited “itchy”/“scratchy” throat • Nasal congestion • Sneezing / conjunctivitis / rhinorrhea

MODERATE• Diffuse urticaria / pruritis • Diffuse erythema, • Facial edema without dyspnea • Throat tightness or hoarseness without dyspnea• Wheezing / bronchospasm, mild or no hypoxia

SEVERE• Diffuse edema, or facial edema with dyspnea • Diffuse erythema with hypotension • Laryngeal edema with stridor and/or hypoxia • Wheezing / bronchospasm, significant hypoxia • Anaphylactic shock (hypotension + tachycardia)• ACR Manual On Contrast Media 2020

MILD• Limited nausea / vomiting • Transient flushing / warmth / • Headache / dizziness / anxiety / altered taste • Mild hypertension • Vasovagal reaction that resolves spontaneously

MODERATE• Protracted nausea / vomiting • Hypertensive urgency • Vasovagal reaction that requires and is responsive

to treatment

SEVERE• Vasovagal reaction resistant to treatment• Arrhythmia • Convulsions, seizure • Hypertensive emergency

Allergylike Physiologic

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ESUR V10.0 Categories of Acute Reactions allergy-like/Hypersensitivity vs. chemo toxic

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ACR Contrast Media Manual 2020

6ACR Manual On Contrast Media 2020

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Histamine Release – Acute Reactions to CM

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Strong evidence that histamine plays an important, if not dominant role in CM reactionsHistamine can cause many of the symptoms of CM reactionCM injection increases the level of histamine in the bloodMight be direct impact of CM on mast cells and basophilsIn patients with allergies a higher proportion of histamine may be releasedAdditionally, histamine might be released via the complement system (next slides)Histamine release can also explain why IV CM causes more allergy-like reactions than IA (mast cells might be activated via the lung passage of the CM)Many symptoms can be prevented or treated by the administration of antihistamines

But: Histamine levels correlate poorly with symptoms

Schild HH: To see or not to see;

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Complement Activation and CM

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Strong evidence that histamine plays an important, if not dominant role in CM reactions, but other pathways might be relevantActivation of the Complement system involves a cascade of eventsThe sequence in which the components are activated can varyC3a and C5a (activated forms of C3 and C5) are also called anaphylatoxins. Cleavage product of C3a and C5a increase capillary and venular permeability (explaining the loss of intravascular volume which occurs in anaphylactoid reactions)Exact role of the C system in CM reactions is still under discussion. Maybe the C system can influence other factors which play a part in the CM reactions (e.g. histamine release)The complement system involves peptides. CM protein binding correlates with the ability to activate complement

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Histamine release of Iodinated Contrast Media

Krause, Invest Radiol. 1994 May;29 Suppl 1:S21-32 Krause Acad Radiol. 1996 Aug;3 Suppl 2:S235-7.);Pinet Invest Radiol. 1988 Sep;23 Suppl 1:S174-7);

Ioversol

Histamine Release 100 mg l/mL)*

Iomeprol

Iopentol

Ultravist®

Iopamidol

Iotrolan

Ioxaglate

77.5±7.0

80706050403020100

11.7±1.6

9.8±1.4

9.1±2.3

6.7±2.8

5.4±3.5

3.4±1.0

3.0±0.6

Iohexol

Iodixanol

2.7±0.5

1.3±1.2

* Tested concentrations between 30 and 150 mg l/mL

Diatrizoate

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Hypersensitivity Reactions to Iodinated Contrast Media : A Multicenter Study of 196.081 patients (Korea)

Design : Multicenter, prospective of 7 center in Korea

Purpose : Identify prevalence, pattern, risk factor and preventive measure for ICM related hypersensitivity reactions (HSRs)

Material & Method : Between Marc 2017 – October 2017, a total 196.081 patients who underwent Iodinated Contrast Media (ICM) administration were enrolled from 7 institution. Theoccurrence of HSRs and baseline patient information were recorded.

ICM used : 22 brands with generic profile (Iobitrol, Iohexol, Iomeprol. Iopamidol. Iopromide,Ioversol & Iodixanol

HSRs : Was define based on ACR guidance

Cha M.J., et al 2019. Radiology: 293:117-124

Prevalence is compared the HSRs with Contrast Media used – more reliable information

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Prevalence and Severity of HSRs based on Generic Profile

MildModerateSevere

0.61

0.76

0.56

0.52

0.81

0.11

0.16

0.36

0.09

0.120.94

0.62

0.99

0.93

0.73

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90

0.700.60

0.65

0.370.27

0.51

0.09

0.10

0.14

0.01

0.01

0.07

0.01

0.01

0.01

0.00

0.00

Total

Iobitridol

Iodixanol

Iohexol

Iomeprol

Iopamidol

Iopromide

Ioversol

% HSRs

Cha M.J., et al 2019. Radiology: 293:117-124

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Risk Factor for the Occurrence and Recurrence of ICM related HSRs

1. Previous history of ICM related HSRs

2. Patient’s previous history of hyperthyroidism

3. Drug Allergy

4. Asthma

5. Other Allergic Disease

6. Family history of ICM related HSRs

Cha M.J., et al 2019. Radiology: 293:117-124

Premedication & a changed of ICM were associated with a lower risk of HSR recurrence

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Premedication regimen

• Mild HSRs : 4 mg of intravenous chlorpheniramine 30 minutes before ICM administration

• Moderate HSRs : 40 mg of intravenous methylprednisolone and 4 mg of intravenous chlorpheniramine 1 hour before ICM administration

• Severe HSRs : 40 mg of intravenous methylprednisolone 4 hours and 1 hour before ICM administration and 4 mg of intravenous chlorpheniramine 1 hour before ICM administration via the intravenous cannula inserted for ICM injection

Physicians were allowed to modify the premedication regimen at their own discretion

Cha M.J., et al 2019. Radiology: 293:117-124

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12.6

16.6

10.7

26.9

31.1

24.3

9

12

7.6

0

5

10

15

20

25

30

35

Total No Premedication Anti Histamine

% ADR Recurrence rate after apply prevention method

Total Same Contrast Different Contrast

Under the condition of given pre-medication:

• ADR recurrence rate was 24.3% when same contrast media was given

• ADR recurrence rate decreased to 7.6% when different contrast media was given

Under the condition of no pre-medication:

• ADR recurrence rate was 31.1% when same contrast media was given• ADR recurrence rate decreased to 12% when different contrast media was given

Cha M.J., et al 2019. Radiology: 293:117-124

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“Right Pair” for different contrast

/// Bayer 16:9 Template /// June 201815

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Thyroid Safety

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Very Late Adverse Reactions

Definition: An adverse reaction which usually occurs more than 1 week after contrast agent injection.E

ESURReaction (by ICM) E • Thyrotoxicosis

• Iodinated contrast medium solutions contain small amounts of free Iodide and excess free iodide in the blood (ingested or injected) may cause thyrotoxicosis in patients at risk.

Risk factors for thyrotoxicosis E

• Patients with untreated Graves’ disease.• Patients with multinodular goiter and thyroid autonomy, especially if they are elderly and/or live in

area of dietary iodine deficiency.

Clinical presentations of thyrotoxicosis

• Weight loss, nervousness, easy fatigability, intolerance to heat, hyperkinesia, palpitations andcardiac arrhythmias.

• Cardiovascular- Most important manifestations of thyrotoxicosis- Palpitations are the most common cardiac symptom- Tachycardia is the most common sign of thyrotoxicosis at physical examination, occurring in more than 40% of patients on initial presentation.

EESUR Guidelines on Contrast Media Version 10.0J. van der Molen et al 2004 (by ESUR Contrast Media Safety Committee)

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Prevalence of Thyroid Dysfunction and Effect of CM

Free Iodide Concentration in CM Solution

Aim To assess the presence and type of thyroid dysfunction in patients admitted for coronaryangiography (CA), to assess the concentration of free-iodide in five non-ionic CM, and to evaluate changes in thyroid function after CA in patients with low T3 syndrome.

Design Single centre randomized clinical study

Patients Patients referred for coronary CT angiography (n=1752) divided into 4 groups based on thyroid hormone analysis. • Group 1: Euthyroid (n=1045; normal values of TSH, fT3, fT4)• Group 2: Low T3 syndrome (n=492; fT3 3.8 uIU/mL)• Group 4: Hyperthyroid (n=34; TSH

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Free Iodide Concentration in CM Solution

Marraccini et al 2012

Prevalence of Thyroid Dysfunction in Cardiac Patients Undergoing Coronary Angiography

The presence of a thyroid dysfunction (low-T3), has retained independent prognostic value both for total mortality and for the composite end-point (nonfatal myocardial infarction and cardiac death).

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Evaluation of Free Iodide in CM Solution

Marraccini et al 2012

Free Iodide Concentration in CM Solution

Iodixanol showed the highest iodide concentration (7.27 ug/mL), about seven times greater than the other CM.

Iopromide had the lowest level of iodide (0.11 ug/mL) High contrast media purity

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Summary

Free Iodide Concentration in CM Solution

Iopromide has been shown to have a high purity level with low free iodide level

High contrast media purity is important to minimise the risk of inadvertently exposing patients with undiagnosed thyroid conditions to significant free iodide levels. High levels of free iodide can place patients with undetected thyroid disease at risk of developing subclinical thyrotoxicosis.

Iodine-induced thyrotoxicosis is relevant in patients with previous thyroid disease or in patients at risk, especially in areas of iodine deficiency and in the geriatric population

J. van der Molen et al 2004(by ESUR Contrast Media Safety Committee)

Marraccini et al 2012

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New Data

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• In July 2015 US FDA reported rare cases of hypothyroidism in infants (premature or with other serious underlying medical condition) after iodinated contrast media (ICM)

• FDA asked ICM manufacturers to conduct a clinical study to assess risk of ICM-associated hypothyroidism in children up to the age of 3 years

CM injection leads to a transient decrease in hormone production, which recovers after a few

days.In pediatric - hormone production, could not return

to normal, leading to hypothyroidism

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Materials & Methods

Aim 1. To investigate the incidence of hypothyroidism after exposure to ICM in young children from birth to 3 years of age

2. To critically review the relevant literatureDesign Observational retrospective cohort study (Jan 1, 1998 till Dec 31, 2015); Maccabi

Healthcare Database (2 million members), IsraelPatients N= 843 (0-3 years exposed to ICM)

Drugs Iodinated contrast media (not further specified with respect to brand and dose)

Endpoints 1. Incidence of hypothyroidism (Diagnosis: TSH above OR T3/T4 below norm, diagnosis of hypothyroidism: Thyroid hormone replacement therapy), one year follow-up

ICM = Iodinated contrast media

Rosenberg et al., PedEndRev 2018 23

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Results (1) – Children with ICM administration (n=843)

The incidence rate per 1000 person years: 13.28 (95% CI: 6.63-23.77).

Completed 1 year follow up

24 Rosenberg et al., PedEndRev 2018

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Results (2) – Children with ICM-induced Hypothyroidism (n=8/11)

Eight cases were classified as ‘probable ICM induced hypothyroidismThe incidence rate per 1000 person-years was 9.66 (95% CI: 4.17- 19.04).

#9 and 10: Myxedema(hypothyreodism)

#11: Secondaryhypothyroidism (pituitary gland)

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Authors’ Overall Conclusions

‘’ …the risk of ICM induced hypothyroidism needs to be considered especially in young children

with low weight, undergoing cardio-angiography examinations…

…The most common pattern found was that of subclinical hypothyroidism, with elevated

TSH, but normal levels of thyroid hormones T3/T4….

Systematic monitoring of thyroid function should be conducted in this focused patient

population to avoid potential adverse consequences on child development….’’

26 Rosenberg et al., PedEndRev 2018

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Impact of Free Iodide in Very Low Birthweight Infant

Dembinski J., et al. Arch Dis Child Fetal Neonatal Ed 2000;82:F215–F217 27

Method :

• Thyroid function was analyzed in 20 very low birthweight infants of gestational age less than 30 weeks after injection of Iopromide

• Levels of free thyroxine and thyroid stimulating hormone were compared with those in 26 control infants.

Results :

1. Free T4 values for the infants who had received iopromideshowed no statistically significant differences from those for the control infants on days 14–21 and 35–49

2. Slightly increased TSH levels were observed at 14–21 days of age after iopromide treatment, but the difference did not reach statistical significance. TSH levels in the two groups were not statistically significantly different on days 35–49

Conclusion :

The risk of transient hypothyroidism or hyper-thyrotropinaemiamay be reduced with the use of Iopromide compared with other contrast media

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Important how to keep the Iodinated Contrast Media – avoid additional free Iodide

All contrast media contain iodide (I-), During storage free iodide levels increase.

To reduce more free iodide in contrast media during storage :

1. Avoid sun light & X-ray

2. Keep in their box

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Summary

• Allergic-like contrast reactions are classified as “anaphylactoid”, “allergic-like”, or “idiosyncratic”. Are likely independent of dose and concentration above a certain unknown threshold

• ICM are known to directly cause histamine release from basophils and mast cells. Activation of the Complement system involves a cascade of Allergic-like contrast reaction

• In study by Cha M, et al, Prevalence and severity Allergic-like (hypersensitive reaction) of LOCM almost similar. Iopromide tend to have lower Allergic-like compared to others ICM

• Premedication & a changed of contrast media were associated with a lower risk of HSR recurrence

• Iopromide has been shown to have a high purity level with low free iodide level.

• Study Iopromide on Very Low Birthweight infant shows that no differences of level T4 & TSH compared to control

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