Administration of Intravenous Radiocontrast to patients with asthma

History
Iodinated contrast media were first introduced in 1929 as sodium Iodide (1,2). In the 1950’s tri-iodinated benzoic acid salts were introduced and then in the 1970’s, the currently used low osmolarity non-ionic contrast media were developed.

Pathophysiology
Iodine has a high atomic number of 53, similar to that of barium.(1) After intravenous injection, 70% of the dose diffuses into the extracellular space within 5 minutes and complete equilibrium is achieved by 2 hours. It is filtered by the renal glomerulus and has no tubular reabsorption having a half life of 2 hours if normal renal function.(2) Iodine salt is found readily in modern food and drinking water.(1) Although Iodine allergy does occur, it would result in allergy to common salt and true allergy is very rare.

ADVERSE DRUG REACTIONS
Intravenous contrast is the commonest drug used in Radiology and every contrast examination is performed at some risk to the patient.

Adverse reactions to contrast media can result by multiple different mechanisms
Drug allergy
Pseudoallergic “anaphylactoid”
Drug Intolerance
Overdose
Drug Interaction
Reactions may be dose dependent or idiosyncratic.

Most Adverse Drug Reactions (ADR) are not allergic in nature but rather due to the chemical composition and are directly related to the osmolarity. The exact mechanism is not clear however the osmotic contrast bolus interrupts homeostasis with the degree of disruption directly relating to the risk of adverse event.( 1 ,2, 3,4) Use of low osmolarity non-ionic contrast significantly decreases the physiologic disturbances.(4)


Osmolarity
Plasma
300
Ionic
1000-2400
Non-ionic
750

Allergic type reactions are usually unpredictable and involve multiple mediators.(2)
Anaphylactoid reactions are more common than true IgE mediated anaphylactic reactions and there is no anti-contrast antibody detected in the majority of cases making predictive skin testing unhelpful.(2,3)

Most adverse reactions will occur within the first 60 minutes with the greatest risk in the first 5 minutes. Delayed contrast reactions do occur with some events recorded up to 7 days post contrast. These are often not reported and sometimes difficult to relate directly to the contrast injection and although reported at 2-8%, the exact incidence is unknown.(2,5)

Ionic versus Non-ionic contrast
There is no doubt from the literature that non-ionic contrast is significantly safer than ionic contrast when considering ADR's of all levels of severity. (1,2, 4,6,7,8,9,10,11,12,13) Fatal reactions are very rare and there is less of a statistically significant difference between the two types of contrast. (7) A detailed review of this topic is beyond the scope of this paper however a brief review of the major studies in the literature is included. Non-ionic contrast is the standard in this institution.

There is some variation in the literature between quoted incidence of ADR’s. This is due to a number of reasons but mostly to the fact that there is no standard definition of an ADR or its severity. Many studies do not separate the osmolality related ADR’s from anaphylactoid or anaphylactic reactions.


Ionic
Non-ionic
Total


Mild
8-15%
0.2-3%
Moderate
1-2%

Severe
0.1-0.22%
0.04%
Life threatening
0.04%
0.004%
Fatal
0.0006% 1: 170,000
0.0006% 1:170000
(1,2,4,7,11)
The risk of fatal reaction does not differ between contrast types. The risk of death from contrast is similar to that of the risk of death from exposure to penicillin. (1)

History of allergy or atopy
A history of allergy in some form is associated with a 1.5-3 fold relative risk increase for an ADR. (2,4,11) Despite the long held belief, there is no proven association between seafood allergy and reaction to non-ionic intravenous contrast. Seafood allergy results from hypersensitivity to a protein within the seafood and has no association with iodine. As such there is no higher relative risk in a patient with seafood allergy than with allergy to any other food product. (1,8)

Anxiety as a risk factor
There appears to be an association between the level of patient anxiety and the risk of an allergic type ADR. (1,2) This should be considered when interacting with patients prior to contrast administration.

ASTHMA AND INTRAVENOUS CONTRAST

The issue of administration of intravenous contrast to patients with a history of asthma arises frequently. There does not appear to be a standard approach within the Royal Brisbane Hospital (RBH).
A history of asthma is associated with a 5-6 fold increase in relative risk of ADR to contrast.( 2,4,14) Despite this, although the incidence of childhood asthma is double that of adults at 13-20%, children have a much lower rate of ADR to contrast media.(14)


Role of pretreatment
The risk of recurrent anaphylactoid reaction after intravenous contrast is variably quoted from 17-35%.(15) There are many case reports regarding ADR to contrast despite pretreatment regimes and there is no doubt that steroid pretreatment does not exclude the potential for life threatening allergic ADR’s.( 1 ,2,3,6,16) The quoted figures for breakthrough reactions despite steroid pretreatment range from 6-40%.(9,16)
Patients with a previous history of contrast related allergy have a 5 fold increase relative risk for recurrent adverse event.(2)

There is no support in the literature for the use of antihistamines or adrenaline for pretreatment.(2,15)

Current American College of Radiology Guidelines recommend the use of non-ionic contrast but describe no role for pretreatment. (6)

At the Great Ormond Street Hospital for Children, there is an established protocol for asthmatic patients receiving non-ionic contrast. Pretreatment is administered only if there is a history of previous contrast reaction, chronic steroid dependent asthma or active wheeze on presentation. Asthmatic patients on bronchodilators or inhaled steroids do not receive pretreatment.(14)

LANDMARK STUDIES

There is a noticeable paucity of literature addressing the issue of Adverse Drug Reaction (ADR) to intravenous contrast in the last two decades since the introduction of non-ionic contrast. Most studies relate to the use of ionic contrast and have little relevance to current clinical practice.

Lasser et al 1987 The New England Journal of Medicine(11)
Prospective multi-institutional randomised study of 6763 patients with a previous history of an immediate generalised contrast reaction. Randomised to oral methylprednisalone pretreatment at 12 and 2 hours prior, at 2 hours prior and placebo groups. Patients were given ionic contrast only. The single dose pretreatment regime showed no benefit at interim analysis and was subsequently discontinued.

Conclusion
- No difference between placebo and steroid pretreatment at 2 hours prior.
- Statistical benefit of dual dose steroid pretreatment for overall, minor and severe reactions but not for moderate reactions.
- Non-ionic contrast without pretreatment is safer than ionic contrast with pretreatment BUT cheaper to pretreat and use ionic contrast than use non-ionic contrast.


Limitations
- Looked at ionic contrast only – not relevant in current practice.
- Too small study group for statistical difference between moderate ADR.
- Asthma was inadvertently not assessed due to an error in the data sheet.


Palmer et al 1988 Australasian Radiology (4,12)
A recommended guideline for selective use of non-ionic contrast in high risk patients was issued by the Royal Australasian College of radiologists in 1986. A prospective survey of ADR was performed between 1986 and 1988.

Reactions graded
Mild – skin reaction / not require treatment
Moderate – require treatment but not admission
Severe – required urgent treatment and admission

109,546 patients included in the survey.


IONIC CONTRAST

NON-IONIC CONTRAST

ADR
High risk patient
Low risk patient
High risk patient
Low risk patient
Mild
7.2%
3.2%
1.1%
.97%
Moderate
2.7%
0.3%
.1%
.09%
Severe
0.36%
.09%
.03%
0
Death
0
.0025%
0
0
Incidence Mod-severe

1:32

1:251

1:718

1:1084

Conclusions
- non-ionic contrast is safer in all groups

Lasser et al 1993 American Journal Radiology(17)
Prospective randomised multi-institutional study of 1411 patients requiring intravenous contrast for CT or IVP over a 3 year period. Assessed with intention to treat
All patients received non-ionic contrast. The study group received oral methylprednisalone at 6-24 hours and at 2 hours prior and was compared with placebo. Reactions were graded as mild, moderate and severe and were not restricted to allergic type symptoms or signs.

Conclusion
- Overall reaction rate fell from 5% to 2% with predominant effect seen in mild reactions.
- There was no significant reduction in moderate and severe reactions.

Limitations
- small study number despite the duration of the study and multiple institutions.
- study ceased early due to lack of funds.
- Because Moderate and Severe reactions are very uncommon, a very large study group would be required to see a significant difference.





Katayama et al 1990 Radiology(13)
Nationwide Japanese prospective study to compare the use of ionic and non-ionic intravenous contrast. 352,817 contrast injections with equal percentage of ionic and non-ionic contrast used.

ADR
Ionic
Non-ionic
Total
21428 (12.66%)
5276 (3.13%)
Severe
367 (0.22%)
70 (0.04%)
Very Severe
63 (0.04%)
6 (0.004%)
Fatal
1 - ? association
1 - ? association
All differences had P < 0.01

No difference was found with age and sex.

Past history of contrast reaction:

Ionic
Non-ionic
Overall recurrence rate
44%
11.2%
Recurrence of severe reaction
0.73%
0.18%

History of allergy or atopy:

Ionic

Non-ionic


All ADR
Severe ADR
All ADR
Severe ADR
Hx of allergy
23.3%
0.53%
6.8%
0.1%
No Hx allergy
11.7%
0.13%
2.7%
0.03%

History of asthma:
Ionic – 1.88% have severe reactions
Non-ionic – 0.23% have severe reactions

Effect of pretreatment:
Hx Allergy
PreRx
Ionic

Non-ionic



ADR
Severe
ADR
Severe
With
PreRx
34.5%
0.28%
14%
0.1%

Not
22.2%
0.56%
6.3%
0.1%
Without
PreRx
17.8%
0.36%
4.7%
0.06%

Not
11.3%
0.17%
2.6%
0.03%

Conclusions
- Non-ionic contrast reduces prevalence of ADR’s at all levels of risk
- Patients with a history of allergy and given non-ionic contrast had less ADR than patients without a history of allergy and given ionic contrast.
- Steroid pretreatment is beneficial only for ionic contrast and history of allergy
- There is no benefit of steroid pretreatment when non-ionic contrast is used



REFERENCES

1. Shymko, M.: Reactions to iodinated contrast. Radiologic Technology72(4): 381-2.
2. Morcos, S., Thomsen, H.: Adverse Reactions to Iodinated contrast media. European Radiology (2001)11: 1267-75.
3. Dewachter, P., Mouton-Faivre, F., Felden, F.: Allergy and contrast media. Allergy (2001) Mar 56(3): 250-1.
4. Palmer, F. The R.A.C.R. Survey of Intravenous Contrast Media Reactions. A preliminary report. Australasian Radiology 1988 32: 8-11.
5. Newman, B. Delayed Adverse reaction to non-ionic contrast agents. Paediatric Radiology (2001) 31: 597-9.
6. Taragin, B., Newhouse, J. Question and Answer. American Journal of Roentgenology (2001) 177: 1211-2.
7. Cochran, S., Bomyea, K., Sayre, J. Trends in Adverse Events after IV Administration of Contrast Media. American Journal of Roentgenology (2001) 176: 1385-8.
8. Leder, R. The safe administration of intravenous contrast material for urologists and radiologists. Current opinion in Urology 2000 10: 95-7.
9. Dunnick, N., Cohan, R. Cost, Corticosteroids and Contrast Media. American Journal of Roentgenolegy 1994 162: 257-9.
10. Federle, M., Willis, L., Swanson, D. Ionic versus Non-ionic contrast media: A prospective study of the effect of rapid bolus injection on nausea and anaphylactoid reactions. Journal of Computed Assisted Tomography 22(3): 341-5.
11. Lasser, M., Berry, C. et al. Pretreatment with corticosteroids to alleviate reactions to Intravenous Contrast Material. The New England Journal of Medicine 1987 317(14): 845-9.
12. Palmer, F. The R.A.C.R. Survey of Intravenous contrast media reactions. Final Report. Australasian Radiology 1988 32: 426-8.
13. Katayama, H., Yagamuchi, K. Adverse Reactions to Ionic and Non-ionic Contrast Media. Radiology (1990) 175(3): 621-8.
14. McHugh, K., Shaw, M. Prophylaxis in asthmatic patients prior to intravenous contrast. Paediatric radiology (1990) 29(1): 78.
15. Greenberger, P., Patterson, R., Tapio, C. Prophylaxis against repeated radiocontrast Reactions in 857 cases. Archives of Internal Medicine (1985) 145: 2197-200.
16. Freed, K., Leder., et al, Breakthrough adverse reactions to low-osmolar contrast media after steroid premedication. American Journal of Roentgenology (2001) 176: 1389-92.
17. Lasser, E., Berry. et al. Pretreatment with corticosteroids to prevent adverse reactions to non-ionic contrast media. American Journal of Roentgenology (1994) 162: 523-6.




SUMMARY OF LITERATURE REVIEW

The incidence of severe or life threatening Adverse Drug reaction (ADR) to contrast is very low.

Most ADR's are due to osmotically induced physiologic disturbances.
True allergic reactions are uncommon and anaphylactoid reactions predominate.
Non anaphylactoid reactions (nausea, vomiting and flushing) are significantly less common with non-ionic contrast and not associated with an increase risk of anaphylactoid reaction.

There is no doubt regarding the safety of non-ionic contrast relative to ionic contrast.

Patients with an allergic history have a 3 fold increase relative risk for allergic type ADR.
Allergy to seafood is NOT directly related to risk of contrast ADR.

Pretreatment

Patients with a previous anaphylactoid contrast reaction have up to a 40% risk of recurrent contrast reaction.
Pretreatment with corticosteroids is associated with a breakthrough rate of up to 40% and breakthrough reactions may be lifethreatening.

There is no evidence base for pretreatment with antihistamine or adrenaline.

Contrast in asthmatics

Patients with asthma have a 5 fold increase in relative risk for allergic type ADR.
If non-ionic contrast is used, pretreatment has no significant effect on the risk of anaphylactoid reaction.

There is no evidence in the literature to support routine premedication of asthmatics prior to administration of intravenous non-ionic contrast.
Patients on bronchodilators and inhaled steroids do not benefit from steroid pretreatment.

TAKE HOME MESSAGE

Most adverse drug reactions will occur unexpectedly despite risk assessment.
Pretreatment will not prevent severe adverse drug reactions
All staff should be skilled in the detection and immediate management of anaphylaxis.