Safe use of contrast media - part 2

Prophylaxis of hypersensitivity reactions after contrast administration

Question

Which prophylactic measures should be taken in patients with increased risk of hypersensitivity reactions after contrast administration?

Recommendation

I Patients with a previous (acute) hypersensitivity reaction to a known ICM or GBCA

A Elective (plannable) examinations with ICM or GBCA

In all patients with a (documented) history of a hypersensitivity reaction to an iodine-based or gadolinium-based CM, consider an alternative imaging modality. When this is not possible, consider performing an unenhanced exam, but only if this has an acceptable reduction in diagnostic quality.

If the previous hypersensitivity reaction was mild:

Choose a different ICM or GBCA*.
Observe the patient ≥ 30 min with IV in place.

If the previous hypersensitivity reaction was moderate:

Choose a different ICM or GBCA*.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was severe:

If clinically reasonable, defer the imaging study until the results of allergologic skin testing are available.
Refer the patient to a drug allergy specialist for allegologic skin testing with a panel of different iodine-based or gadolinium-based CM.
Apply the advice of the drug allergy specialist for future CM administration.
Premedicate with 2 x 25 mg prednisolone PO/IV** 12h and 2h before CM administration and 2mg clemastine IV within 1h before CM administration.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

B Acute (within hours) or emergency (direct) examinations with ICM or GBCA

In all patients with a (documented) history of a hypersensitivity reaction to an iodine-based CM, consider an alternative imaging modality. When this is not possible, consider performing unenhanced exam, if this has an acceptable reduction in diagnostic quality.

If the previous hypersensitivity reaction was mild:

Choose a different ICM or GBCA*.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was moderate:

Premedicate with 50 mg prednisolone IV** and 2mg clemastine IV within 30min before CM administration.
Choose a different ICM or GBCA*.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was severe:

Premedicate with 50 mg prednisolone IV** and 2mg clemastine IV within 30min before CM administration.
Choose a different ICM or GBCA*.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

II Patients with a previous (acute) hypersensitivity reaction to an unknown ICM or GBCA

A Elective (plannable) examinations with ICM or GBCA

If the previous hypersensitivity reaction was mild:

Proceed with the radiologic examination normally.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was moderate:

Proceed with the radiologic examination normally.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

In cases of doubtful severity consider referring the patient to a drug allergy specialist for allergologic skin testing with a panel of different iodine-based or gadolinium-based CM.

If the previous hypersensitivity reaction was severe:

If clinically reasonable, defer the imaging study until results of allergologic skin testing are available.
Refer the patient to a drug allergy specialist for allergologic skin testing with a panel of different iodine-based or gadolinium-based CM.
Apply the advice of the drug allergy specialist for future CM administration.
Premedicate with 2 x 25 mg prednisolone PO/IV** 12h and 2h before CM administration and 2mg clemastine IV within 1h before CM administration.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

B Acute (within hours) or emergency (direct) examinations with ICM or GBCA

In all patients with a (documented) history of a hypersensitivity reaction to an iodine-based or gadolinium-based CM, consider an alternative imaging modality. When this is not possible, consider performing unenhanced exam, if this has an acceptable reduction in diagnostic quality.

If the previous hypersensitivity reaction was mild:

Proceed with the radiologic examination normally.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was moderate:

Premedicate with 50 mg prednisolone IV** and 2mg clemastine IV within 30min before CM administration
Proceed with the radiologic examination normally.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

If the previous hypersensitivity reaction was severe:

Premedicate with 50 mg prednisolone IV** and 2mg clemastine IV within 30min before CM administration
Proceed with the radiologic examination normally.
Observe the patient ≥ 30 min with IV in place.
Be vigilant to react to a possible new hypersensitivity reaction.

III Patients with a previous breakthrough reaction to CM

In patients with breakthrough hypersensitivity reactions to iodine-based or gadolinium-based CM apply the same as above, but always refer the patient to a drug allergy specialist for allergologic skin testing with a panel of different ICM or GBCA.

IV Patients with previous (acute) hypersensitivity reactions to multiple CM

In patients with hypersensitivity reactions to multiple iodine-based or gadolinium-based CM (either 2 or more different iodine-based CM or gadolinium-based CA or to an iodine-based CM and a gadolinium-based CA) apply the same as above, but always refer the patient to a drug allergy specialist for allergologic skin testing with a panel of different ICM and GBCA.

V Patients with previous non-severe late hypersensitivity reactions to CM

In patients with previous mild or moderate late hypersensitivity reactions to iodine-based CM or gadolinium-based CA premedication is not recommended, even in acute or emergency examinations.

Notes

* Consider cross-reactivity of iodine-based CM (see Introduction to this section, table 2).

**Or equivalent dose of another glucocorticosteroid

25 or 50 mg prednisolone is equivalent to:

20 or 40 mg methylprednisolone.
4 or 8mg dexamethasone.
100 or 200mg hydrocortisone.

Also see the flowcharts.

Considerations

First and foremost, in patients with a (documented) history of a hypersensitivity reaction to a contrast medium, consider an alternative imaging modality first. In many cases, CT with iodinated contrast media can be replaced by ultrasound, with or without contrast media, or MRI, with or without contrast media. When this is not possible, consider performing the examination without a contrast medium, but only if this has an acceptable degree of diagnostic quality. For this, close communication with the referring specialist is mandatory.

When evaluating hypersensitivity reactions, it is difficult to compare literature. In the literature, adverse effects or adverse reactions are often reported which also include (severe) physiologic effects to contrast medium administration and chemotoxic effects. Anxiety may play a role in hypersensitivity reactions (Lalli, 1974).

Based on the available literature it is not possible to conclusively identify a group of patients that is at increased risk for hypersensitivity and should routinely receive premedication prior to contrast administration. In the ACR Manual on Contrast Media v.10.3 (ACR, 2017) and the ESUR v10 guidelines (Clement, 2014; ESUR 2017), the most significant risk factor for increased risk of hypersensitivity reactions remains a documented history of a previous hypersensitivity reaction to a contrast medium. Patients with atopy/ bronchial asthma or multiple allergies could not be established as a consistent risk factor (Chen, 2015; Jung, 2016).

The evidence regarding the effectivity of corticosteroids and antihistamines for pharmacological prevention is very heterogeneous and of low quality (Tramer, 2006; Dawson, 2006; Davenport, 2015). It seems that prophylactic premedication can prevent the number of hypersensitivity reactions after contrast administration, but premedication mainly reduces the number of mild reactions and therefore the total number of reactions (Lasser, 1994). There is little data that premedication reduces the number of moderate and severe hypersensitivity reactions, and its use should therefore be limited.

It was believed that premedication with corticosteroids and H1-antihistamines do not have serious side effects and is not costly. However, recently it has been shown that premedication was associated with brief hyperglycaemia (Davenport, 2010), but also with longer hospital stay, increased costs, and worse clinical outcomes (Davenport, 2016).

The old protocols for premedication (Greenberger, 1984; Greenberger, 1986; Lasser, 1994) are still in widespread use (often slightly modified), but there is no literature to establish an optimal indication or protocol. Recently the Greenberger protocol has been challenged by newer, shorter options for inpatients (Mervak, 2017).

Greenberger protocol (elective examinations 1984):

Prednisolone 50 mg IV - 13h, 7h and 1h before the procedure.
Diphenhydramine 50 mg IV - 1h before the procedure.

Greenberger protocol (emergency examinations 1986):

Hydrocortisone 200 mg IV - immediately and every 4h until procedure is finished
Diphenhydramine 50 mg IV - 1h before the procedure

Lasser protocol (elective examinations 1994):

Methylprednisolone 32 mg IV - 12h and 2h before the procedure.

In addition, premedication is not perfect. In 2 to 17% of premedicated patients so-called “breakthrough” hypersensitivity reactions can occur despite premedication. These are usually of similar severity as the original culprit reaction for which premedication was prescribed and seldom severe (Davenport, 2009; Mervak, 2015; Lee, 2017).

Another main problem is the registration of contrast media in radiology information systems. For a long time, contrast media have not been treated as drugs. Therefore, in many hospitals iodine-based and other contrast media are “doomed” as a group when a single hypersensitivity reaction to one specific agent occurs, without much testing of the specific culprit agent. Like all drugs, hypersensitivity should nowadays be approached at agent level and not at group level. There is growing evidence that suggests that switching to another agent may be an effective strategy (Abe, 2016; Lee, 2017; Park, 2017).

Premedication of late hypersensitivity reactions

There is a paucity of data on the benefits of premedication for non-severe late hypersensitivity reactions. Most of these reactions are self-limiting or can be treated symptomatically. Major international guidelines suggest to perform allergologic skin testing, but do not recommend the use of premedication for non-severe late reactions (ESUR 2018, ACR 2018).

Introduction

Patients report hypersensitivity reactions to contrast media, and often these have occurred in the past. This can involve objective signs or symptoms that fit well with a hypersensitivity reaction. However, in many cases other complaints are reported, such as hyperventilation, vasovagal reactions or panic attacks. These may not fit accurately with a hypersensitivity reaction to CM. In addition, patient’s history can include diseases like severe asthma, mastocytosis or the use of medication that may be associated with an increased risk to hypersensitivity reactions.

For the physician administering the CM it is often not clear how to deal with this kind of situations and whether prophylactic medication is indicated. In addition, the literature on the effectiveness of premedication prior to CM administration remains unclear.

All types of contrast media can give hypersensitivity reactions. See further the Introduction to this section.

All types of contrast media will be evaluated: iodine-based, gadolinium-based, microbubble, CM. Also, all types of administration routes will be covered, intravascular (intravenous or intra-arterial), oral and rectal, intracavitary (joints or bladder), and intraductal (bile or pancreatic ducts). See the submodule ' Hypersensitivity Reactions after Nonvascular CM Administration'.

Conclusions

Factors related to the risk of hypersensitivity reactions after contrast administration.

Low

GRADE

The following factors were associated with an increased risk of adverse drug reaction in patients undergoing coronary angiography or percutaneous coronary intervention and receiving iopromide contrast:

- age < 50 years;
- no premedication with corticosteroids;
- contrast dose < 100mL;
- no pre-procedural hydration;
- left main coronary disease;
- previous ADR to contrast.

Allergic constitution, asthma and sex were not independently associated with the risk of developing an adverse reaction.

Source: (Chen, 2015)

Low

GRADE

The following factors were associated with an increased risk for developing this second acute allergic-like adverse reaction in patients with a history of a hypersensitivity reaction after low-osmolality contrast administration, who were undergoing another enhanced computed tomography with low-osmolality contrast medium and receiving premedication:

- younger age;
- previous severe reaction;
- no corticosteroid premedication.

The following factors were not independently associated with the risk of acute allergic-like adverse reactions: sex, bronchial asthma, allergic rhinitis, chronic urticaria, food allergy, other drug allergy, H2-antihistamines premedication.

Source: (Jung, 2016)

Low

GRADE

The following factors were associated with an increased risk for developing this second hypersensitivity reaction in patients with a history of a moderate or severe hypersensitivity reaction after low-osmolality contrast administration, who were undergoing another enhanced computed tomography with low-osmolality contrast medium and receiving premedication:

- younger age;
- diabetes mellitus;
- chronic urticaria;
- drug allergy;
- not changing the iodinated contrast medium;
- Initial hypersensitivity reaction was severe.

The following factors were not independently associated with the risk of developing a recurrent hypersensitivity reaction: sex, use of premedication.

Source: (Park, 2017)

Prophylactic measures to prevent hypersensitivity reactions after contrast administration

Very low GRADE

It is unclear whether the use of premedication decreases the risk of life-threatening anaphylactic reactions.

The administration of H1-antihistamines immediately prior to the administration of contrast may decrease the risk of developing hypersensitivity reactions due to iodinated contrast.

The administration of corticosteroids given in two doses, 6 hours prior and 2 hours prior to the administration of contrast, both iodinated and non-iodinated, may decrease the risk of developing hypersensitivity reactions due to contrast administration.

Source: (Tramer, 2006)

Literature summary

1. Factors related to the risk of hypersensitivity reactions after contrast administration.

Description of studies

A total of 3 studies described factors independently related to the risk of hypersensitivity reactions after contrast administration. All studies presented multivariate models, but no internal or external validation of these models, or the results of application of these models in clinical practice.

Chen (2015) described the risk factors associated with adverse reactions (occurring within 1 hour after contrast administration) in 17,513 patients who were administered iopromide (300 or 370 mgI/mL) contrast during coronary angiography or Pecutaneous Coronary Intervention (PCI). All patients (not high-risk patients only) were included in this multicentre (63 centres in China) study.

Jung (2016) described risk factors for developing a hypersensitivity reaction after re-administration of low-osmolality iodinated contrast medium for enhanced computed tomography in 322 patients with a history of hypersensitivity reactions after low-osmolality contrast administration. A total of 219 (68%) of the patients had a mild reaction, while 82 (26%) had a moderate reaction, and 21 (7%) a severe reaction in their history. Premedication was decided on an individual basis by clinicians and could consist of oral and/or intravenous H1-antihistamines, H2-antihistamins and corticosteroids.

Park (2017) described risk factors for developing a hypersensitivity reaction after administration of low-osmolar iodinated contrast medium for enhanced computed tomography in 150 patients with a history of moderate 130 (87%) to severe 20 (13%) hypersensitivity reactions after contrast administration in 328 instances of re-exposure. Patients received antihistamines and/or corticosteroids as pre-medication, the exact premedication was decided on an individual basis.

Results

Chen (2015) reported that acute adverse drug reactions (ADRs) occurred in 66/17,513 (0.38%) patients undergoing iopromide (300 or 370 mgI/mL) administration during coronary angiography or Percutaneous Coronary Intervention (PCI), out of which 2 ADRs (0.01%) were severe. Most ADRs manifested as nausea vomiting (0.22%) and rash (0.09%).

The following factors were associated with risk of ADR:

age 50 to 69 versus age < 50 (OR: 0.48, 95% CI: 0.27 to 0.85);
premedication with corticosteroids (OR: 0.41, 95% CI: 0.18 to 0.97);
contrast dose ≥ 100mL (OR 0.50, 95% CI 0.30 to 0.82);
pre-procedural hydration (OR: 0.11, 95% CI: 0.04 to 0.33);
left main coronary disease (OR: 2.27, 95% CI: 1.15 to 4.48);
previous ADR to contrast (OR: 9.30, 95% CI: 1.10 to78.84).

Allergic constitution, asthma and sex were not independently associated with the risk of developing an adverse reaction.

Jung (2016) described that 47/322 (15%) of the patients experienced a recurrence of an allergic reaction after low-osmolality iodinated contrast medium administration for computed tomography, despite premedication.

The following factors were associated with an increased risk for developing this second acute allergic-like adverse reaction:

age (OR: 0.97, 95% CI: 0.94 to 0.99);
previous severe reaction (OR: 8.88, 95% CI: 2.11 to 37.42);
not using corticosteroid premedication (OR: 0.28, 95% CI: 0.10 to 0.78) - people that used corticosteroid medications had a lower risk to experience an allergic reaction.

Park (2017) reported that a recurrence of hypersensitivity reactions after contrast exposure occurred in 64/328 (20%) of the instances of re-exposure to low-osmolar iodinated contrast in patients with a history of moderate or severe reactions.

The following factors were associated with an increased risk for developing this second hypersensitivity reaction:

age (OR: 0.97, 95% CI 0.94 to 0.99);
diabetes mellitus (OR: 6.49, 95% CI: 2.38 to 17.71);
chronic urticaria (OR: 7.61, 95% CI: 1.63 to 35.59);
drug allergy (OR: 3.69, 95% CI: 1.18 to 11.56);
Changing the iodinated contrast medium (OR: 0.33, 95% CI: 0.17 to 0.64);
initial hypersensitivity reaction was severe (OR: 2.67, 95% CI: 1.05 to 6.79).

The following factors were not independently associated with the risk of developing a recurrent hypersensitivity reaction: sex, use of premedication.

Level of evidence

For all the included patient populations the quality of certainty of evidence for the prognostic factors was downgraded from high to low by two points, due to risk of bias and indirectness: the prognostic factors were identified, but the prognostics model was not validated internally and externally. The value of the applicability of the multivariate models in a clinical decision-making process was not evaluated.

2. Prophylactic measures to prevent hypersensitivity reactions after contrast administration

Description of studies

One systematic review (Tramer, 2006) that included 9 RCTs was included in this analysis. The goal of this review was to review the efficacy of pharmacological prevention of serious reactions to iodinated contrast media. A systematic search was performed up to October 2005. The pre-specified inclusion criteria were random allocation of patients, use of premedication alone or in combination, presence of a placebo or a no treatment control group, and reporting of presence or absence of allergic reactions. A total of 9 trials with 10,011 adult patients were included in the review analysis. No RCTs that answered the search question were found that were published after Tramer, 2006.

Results

Tramer (2006) reported 9 trials (including 10,011 adults) tested H1 antihistamines, corticosteroids, and an H1 to H2 combination. No trial included exclusively patients with a history of allergic reactions. Many outcomes were not allergy related, and only a few were potentially life threatening. No reports on death, cardiopulmonary resuscitation, irreversible neurological deficit, or prolonged hospital stays were found. In two trials, 3/778 (0.4%) patients who received oral methylprednisolone 2×32 mg or intravenous prednisolone 250 mg had laryngeal oedema compared with 11/769 (1.4%) controls (odds ratio 0.31, 95% confidence interval 0.11 to 0.88). In two trials, 7/3093 (0.2%) patients who received oral methylprednisolone 2×32 mg had a composite outcome (including shock, bronchospasm, and laryngospasm) compared with 20/2178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60). In one trial, 1/196 (0.5%) patient who received intravenous clemastine 0.03 mg/kg and cimetidine 2 to 5 mg/kg had angio-oedema compared with 8/194 (4.1%) controls (odds ratio 0.20, 0.05 to 0.76).

Level of evidence

The quality of certainty of evidence for the outcome hypersensitivity reaction was downgraded from high to very low due to risk of bias (as described below), heterogeneity of included studies, inconsistency of results and imprecision of outcome measures (low numbers of events).

The risk of bias of the included studies was deemed high: in no report was an adequate randomisation method described, and only in one was treatment allocation concealed. In four reports, evidence existed of adequate blinding of patients, caregivers, and observers. No report described a complete patient follow-up that enabled an intention to treat analysis.

Search and select

To answer our clinical question a systematic literature analysis was performed for the following research questions:

1) What factors are related to an increased risk of developing hypersensitivity reactions after contrast administration?

P (patient category): patients undergoing radiological examinations with contrast media;

I (intervention): presence of prognostic factors;

C (comparison): absence of prognostic factors;

O (outcome) allergic reactions to contrast, hypersensitivity reaction, type I / type IV, severe allergic reaction.

2) What are the effects of a prophylactic measure to prevent hypersensitivity reactions after contrast administration compared to a different measure to prevent hypersensitivity reactions after contrast administration or no prophylactic measure, in patients undergoing radiological examinations with contrast media?

P (patients): patients undergoing radiological examinations with contrast media;

I (intervention): prophylactic measure to prevent hypersensitivity reactions after contrast administration;

C (comparison): no prophylactic measure or a different prophylactic measure to prevent hypersensitivity reactions after contrast administration;

O (outcome): allergic reactions to contrast, hypersensitivity reaction, type I/ type IV, severe allergic reaction.

Relevant outcome measures

The working group considered allergic reactions to contrast/ hypersensitivity reactions critical outcome measures for the decision-making process.

Search and select (method)

The databases Medline (OVID), Embase and the Cochrane Library were searched from 1^st of December 1980 to 4^th of December 2017 using relevant search terms for systematic reviews (SRs), randomized controlled trials (RCTs) and observational studies (OBS). The literature search resulted in 478 hits: 42 SRs, 129 RCTs and 307 OBS.

Studies were selected based on the following criteria:

adult patients undergoing radiological examinations with contrast media;
evaluation of effectiveness of prophylactic measures to prevent hypersensitivity reactions after contrast administration;
or: Evaluation or identification of factors associated with an increased risk of hypersensitivity reactions after contrast administration. These factors could be treatment related, or patient related. Studies were only included when the identified risk factors were corrected for confounders (multivariate models);
reports predefined outcome measure: hypersensitivity reactions;
no reports of case series or exploratory findings (n ≥ 10).

Based on title and abstract a total of 123 studies were selected. After examination of full text, a total of 119 studies were excluded and 4 studies were definitely included in the literature summary. Reason for exclusion is reported in the exclusion table.

Three studies were included for the research question regarding the identification of factors related to associated with an increased risk of hypersensitivity reactions after contrast administration. One systematic review (Tramer, 2006) was included for the research question regarding the comparison of the different prophylactic measures to prevent hypersensitivity reactions after contrast administration. The most important study characteristics and results were included in the evidence tables. The evidence tables and assessment of individual study quality are included.

References

Abe S, Fukuda H, Tobe K, Ibukuro K. Protective effect against repeat adverse reactions to iodinated contrast medium: Premedication versus. changing the contrast medium. Eur Radiol 2016; 26: 2148-2154.
<p align="left">American College of Radiology. ACR Manual on contrast media, v10.3. Available at: www.acr.org/Clinical-Resources/Contrast-Manual. Accessed: 11 July 2019.
Chen JY, Liu Y, Zhou YL, et al. Safety and tolerability of iopromide in patients undergoing cardiac catherization: real-world multicenter experience with 17,513 patients from the TRUST trial. Int J Cardiovasc Imaging 2015; 31: 1281-1291
Clement O, Webb JAW. Acute Adverse Reactions to Contrast Media: Mechanisms and Prevention. In: Thomsen HS, Webb JAW (eds). Contrast media: safety issues and ESUR guidelines, 3rd edition. Heidelberg: Springer Nature, 2014, 51-60.
Davenport MS, Cohan RH, Caoili EM, Ellis JH. Repeat contrast medium reactions in premedicated patients: frequency and severity. Radiology 2009; 253:372-379.
Davenport MS, Cohan RH, Caoili EM, Ellis JH. Hyperglycemic consequences of corticosteroid premedication in an outpatient population. AJR Am J Roentgenol 2010; 194 (6):W483-488,
Davenport MS, Mervak BM, Ellis JH, Dillman JR, Dunnick NR, Cohan RH. Indirect Cost and Harm Attributable to Oral 13-Hour Inpatient Corticosteroid Prophylaxis before Contrast-enhanced CT. Radiology 2016; 279: 492-501
Davenport MS, Cohan RH, Ellis JM. Contrast media controversies in 2015: Imaging patients with renal impairment or risk of contrast reaction. AJR Am J Roentgenol 2015; 204: 1-8
Dawson P. Adverse reactions to intravascular contrast agents: routine prophylaxis is not supported by evidence. BMJ 2006; 333: 663-664
European Society of Urogenital Radiology Contrast Media Safety Committee. ESUR Guidelines on contrast safety, v10. Available at: www.esur-cm.org. Accessed: 11 July 2019
Greenberger PA, Patterson R, Radin RC. Two pretreatment regimens for high-risk patients receiving radiographic contrast media. J Allergy Clin Immunol 1984; 74 (4 Pt 1):540-543.
Greenberger PA, Halwig JM, Patterson R, Wallemark CB. Emergency administration of radiocontrast media in high risk patients. J Allergy Clin Immunol 1986; 77: 630-634
Jingu A, Fukuda J, Taketomi-Takahashi A, et al. Breakthrough reactions of iodinated and gadolinium contrast media after oral steroid premedication protocol. BMC Med Imaging. 2014;14:34.
Jung JW, Choi YH, Park CM, Park HW, Cho SH, Kang HR. Outcomes of corticosteroid prophylaxis for hypersensitivity reactions to low osmolar contrast media in high-risk patients. Ann Allergy Asthma Immunol 2016; 117: 304-309
Katayama H, Yamguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic and nonionic contrast media. A report from the Japanese committee on the safety of contrast media. Radiology 1990; 175: 621-628.
Lalli AF. Urographic contrast media reactions and anxiety. Radiology 1974; 112:267-271
Lasser EC, Berry CC, Mishkin MM, Williamson B, Zheutlin N, Silverman JM. Pretreatment with corticosteroids to prevent adverse reactions to nonionic contrast media. AJR Am J Roentgenol 1994; 162: 523-526.
Lee SY, Yang MS, Choi YH, et al. Stratified premedication strategy for the prevention of contrast media hypersensitivity in high risk patients. Ann Allergy Asthma Immunol 2017; 118: 339-344.e1.
Mervak BM, Davenport MS, Ellis JH, et al. Rates of breakthrough reactions in inpatients at high risk receiving premedication before contrast-enhanced CT. AJR Am J Roentgenol. 2015; 205: 77-84.
Mervak BM, Cohan RH, Ellis JH, Khalatbari S, Davenport MS. 5-hour intravenous corticosteroid premedication has a breakthrough reaction rate that is non-inferior to that of a traditional 13-hour oral regimen. Radiology 2017; 285: 425-433
Park HJ, Park JW, Yang MS, Kim MY, Kim SH, Jang GC, Nam YH, Kim GW, Kim S, Park HK, Jung JW, Park JS, Kang HR. Re-exposure to low osmolar iodinated contrast media in patients with prior moderate-to-severe hypersensitivity reactions: A multicentre retrospective cohort study. Eur Radiol 2017; 27: 2886-2893
Tramer MR, von Elm E, Loubeyre P, Hauser C. Pharmacological prevention of serious anaphylactic reactions due to iodinated contrast media: systematic review. BMJ 2006; 333: 675-682.

Evidence tables

Table of quality assessment for systematic reviews of RCTs and observational studies

Based on AMSTAR checklist (Shea, 2007; BMC Methodol 7: 10; doi:10.1186/1471-2288-7-10) and PRISMA checklist (Moher, 2009; PLoS Med 6: e1000097; doi:10.1371/journal.pmed1000097)

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/not applicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Tramer, 2006

Yes

Included studies: yes. Excluded studies: no

Yes

Unclear

Yes

Research question (PICO) and inclusion criteria should be appropriate and predefined.
Search period and strategy should be described; at least Medline searched; for pharmacological questions at least Medline + EMBASE searched.
Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons.
Characteristics of individual studies relevant to research question (PICO), including potential confounders, should be reported.
Results should be adequately controlled for potential confounders by multivariate analysis (not applicable for RCTs).
Quality of individual studies should be assessed using a quality scoring tool or checklist (Jadad score, Newcastle-Ottawa scale, risk of bias table et cetera).
Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, intervention and definition of outcome measure to allow pooling? For pooled data: assessment of statistical heterogeneity using appropriate statistical tests (for exampl Chi-square, I²)?
An assessment of publication bias should include a combination of graphical aids (for exampl funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies.
Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.

Evidence table for systematic review of RCTs and observational studies (intervention studies)

Research question:

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Tramer, 2006

[individual study characteristics deduced from [1st author,

year of publication

]]

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to October, 2005

A: Bertrand, 1992

B: Chevrot, 1988

C: Ginsberg, 1996

D: Lasser, 1987

E: Lasser, 1994

F: Ring, 1985

G: Small, 1982

H: Smith, 1995

I: Wicke, 1975

Study design: RCT

Setting and Country: Switzerland

Source of funding and conflicts of interest:

Not reported

Inclusion criteria SR:

1) trials (without language restrictions)

that tested premedication in patients who received iodinated

contrast media.

2) random allocation of patients, use of premedication alone or in combination, presence of a placebo or a no treatment control group, and reporting of presence or absence of allergic reactions

Exclusion criteria SR: Not reported

9 studies included

Important patient characteristics at baseline:

Number of patients; characteristics important to the research question and/or for statistical adjustment (confounding in cohort studies); for example, age, sex, bmi, ...

N, mean age

A: 400 patients, age NR

B: 121 patients, age NR

C: 86 patients, age NR

D: 6763 patients, age NR

E: 1155 patients, age NR

F: 779 patients, age NR

G: 220 patients, age NR

H: 299 patients, age NR

I: 208 patients, age NR

Sex:

Groups comparable at baseline? Unclear

Describe intervention:

A: Hydroxyzine 100 mg PO 12 h before (200)

B: Betamethasone 8 mg IV with CM

C: Dexamethasone 4 mg PO 4×/d for 24 h (42);

D: methylprednisolone 2×32 mg PO evening and 2 h before

(2513, group 1); methylprednisolone 32 mg PO 2 h before

(1759, group 2);

E: methylprednisolone 2×32 mg PO 6-24 h and 2 h before

(580);

F: Prednisolone 250 mg IV (198); clemastine 0.03 mg/kg IV

(191); clemastine 0.03 mg/kg + cimetidine 2-5 mg/kg (according to renal function) IV (196);

G: Chlorpheniramine 10 mg SC 15 min before (78); placebo (saline) SC (71);

H: Dimenhydrinate 25 mg IV 15 to 45 min before (150);

I: Clemastine 2 mg IV with CM (92);

Describe control:

A: placebo

B: no treatment

C: placebo

D: placebo PO as for group 1 (1603); placebo

PO as for group 2 (888)

E: placebo PO (575)

F: placebo (saline) IV

(194); timing not specified

G: no treatment (71)

H: placebo

(saline) IV (149)

I: placebo (saline) IV (116)

End-point of follow-up:

Not reported

For how many participants were no complete outcome data available?

Not reported

Outcome measure-1

No reports on death, cardiopulmonary resuscitation, irreversible neurological deficit, or prolonged hospital stays were found. In two trials, 3/778 (0.4%) patients who received oral methylprednisolone 2×32 mg or intravenous prednisolone 250 mg had laryngeal oedema compared with 11/769 (1.4%) controls (odds ratio 0.31, 95% confidence interval 0.11 to 0.88). In two trials, 7/3093 (0.2%) patients who received oral methylprednisolone 2×32 mg had a composite outcome (including shock, bronchospasm, and laryngospasm) compared with 20/2178 (0.9%) controls (odds ratio 0.28, 0.13 to 0.60). In one trial, 1/196 (0.5%) patients who received intravenous clemastine 0.03 mg/kg and cimetidine 2-5 mg/kg had angio-oedema compared with 8/194 (4.1%) controls (odds ratio 0.20, 0.05 to 0.76).

Facultative:

Brief description of author’s conclusion: Life threatening anaphylactic reactions due to iodinated contrast media are rare. In unselected patients, the usefulness of premedication is doubtful, as a large number of patients need to receive premedication to prevent one potentially serious reaction. Data supporting the use of premedication in patients with a history of allergic reactions are lacking. Physicians who are dealing with these patients should not rely on the efficacy of premedication.

Level of evidence: GRADE Very Low due to high risk of bias (problems with allocation and blinding) and imprecision (small amount of events, very rare serious adverse events)

Table of quality assessment - prognostic factor (PF) studies

Based on: QUIPS^A (Haydn, 2006; Haydn 2013)

Research question:

Study reference (first author, year of publication)	Study participation¹ Study sample represents the population of interest on key characteristics? (high/moderate/low risk of selection bias)	Study Attrition² Loss to follow-up not associated with key characteristics (i.e., the study data adequately represent the sample)? (high/moderate/low risk of attrition bias)	Prognostic factor measurement³ Was the PF of interest defined and adequately measured? (high/moderate/low risk of measurement bias related to PF)	Outcome measurement³ Was the outcome of interest defined and adequately measured? (high/moderate/low risk of measurement bias related to outcome)	Study confounding⁴ Important potential confounders are appropriately accounted for? (high/moderate/low risk of bias due to confounding)	Statistical Analysis and Reporting⁵ Statistical analysis appropriate for the design of the study? (high/moderate/low risk of bias due to statistical analysis)
Chen, 2015	Low	Low	Low	Low	Low	Low
Jung, 2016	Low	Low	Low	Low	Low	Low
Park, 2017	Low	Low	Low	Low	Low	Low

^Ahttps://methods.cochrane.org/sites/methods.cochrane.org.prognosis/files/public/uploads/QUIPS%20tool.pdf

¹Adequate description of: source population or population of interest, sampling and recruitment, period and place of recruitment, in- and exclusion criteria, study participation, and baseline characteristics.

² Adequate response rate, information on dropouts and loss to follow-up, no differences between participants who completed the study and those lost to follow-up.

³ Method of measurement is valid, reliable, setting of measurement is the same for all participants.

⁴ Important confounders are listed, method of measurement is valid, reliable, setting of measurement is the same for all participants, important confounders are accounted for in the design (matching, stratification, initial assembly of comparable groups), or analysis (appropriate adjustment)

⁵ Enough data are presented to assess adequacy of the analysis, strategy of model building is appropriate and based on conceptual framework, no selective reporting

Evidence table for prognostic factor studies

Research question:

Study reference

Study characteristics

Patient characteristics

Prognostic factor(s)

Follow-up

Estimates of prognostic effect

Comments

Chen, 2015

Type of study: observational

Setting and country: China

Funding and conflicts of interest: first author is an employee of Bayer

HealthCare. The other authors have no conflicts of interest to disclose.

Inclusion criteria: Patients undergoing cardiac catheterization were enrolled.

Exclusion criteria:

Pregnant and lactating women, and patients who had contraindications towards iopromide or towards cardiac catheterization, were excluded.

N=17513

Mean age ± SD: 60 ± 11 years

Sex: 66% M / 34% F

Describe prognostic factor(s) and method of measurement:

Not described explicitly, but described in results section (see column Outcomes).

Duration or endpoint of follow-up: Unclear

For how many participants were no complete outcome data available?

Not reported

Reasons for incomplete outcome data described?

Not reported

that acute adverse drug reactions (ADRs) occurred in 66/17,513 (0.38%) patients undergoing iopromide (300 or 370 mgI/mL) administration during coronary angiography or Percutaneous Coronary Intervention (PCI), out of which 2 ADRs (0.01%) were severe. Most ADRs manifested as nausea vomiting (0.22%) and rash (0.09%).

The following factors were associated with risk of ADR:

age 50-69 versus age < 50 (OR: 0.48, 95% CI: 0.27 to 0.85);

premedication with corticosteroids (OR: 0.41, 95% CI: 0.18 to 0.97);

contrast dose ≥100mL (OR 0.50, 95% CI 0.30 to 0.82);

pre-procedural hydration (OR: 0.11, 95% CI: 0.04 to 0.33);

left main coronary disease (OR: 2.27, 95% CI: 1.15 to 4.48);

previous ADR to contrast (OR: 9.30, 95% CI: 1.10 to78.84).

Allergic constitution, asthma and sex were not independently associated with the risk of developing an adverse reaction.

Adverse events (AEs) were recorded by the investigator in a case report form (CRF). The incidence, seriousness, duration, relationship to study drug, action taken and outcome were recorded. AEs were judged to be ADRs (i.e. related to study drug) by either the investigator and by the

study sponsor, Bayer HealthCare Company Ltd.

Jung, 2016

Type of study: retrospective observational

Setting and country: Korea, hospital

Funding and conflicts of interest: not reported

Inclusion criteria: high-risk patients, defined as those who had a previous history of acute allergic-like reactions to LOCM, underwent

CT enhanced with LOCM after premedication at Seoul National

University Hospital between June 2010 and May 2012.

Exclusion criteria: not reported

N= 322

Mean age ± SD: 55 ± 13

Sex: 47% M / 53% F

Describe prognostic factor(s) and method of measurement:

Patient demographics, comorbid diseases, and prescription medications taken at the time the patients underwent CT were extracted from electronic medical records. A retrospective review of the following information was performed: nature and severity of previous reactions, recurrence of hypersensitivity after premedication, interval between ICM exposures, and the details of the premedication regimen.

Duration or endpoint of follow-up:

For how many participants were no complete outcome data available?

Not reported

Reasons for incomplete outcome data described? Not reported

47/322 (15%) of the patients experienced a recurrence of an allergic reaction after low-osmolality iodinated contrast medium administration for computed tomography, despite premedication.

The following factors were associated with an increased risk for developing this second acute allergic-like adverse reaction:

age (OR: 0.97, 95% CI: 0.94 to 0.99);previous severe reaction (OR: 8.88, 95% CI: 2.11 to 37.42);

corticosteroid premedication (OR: 0.28, 95% CI: 0.10 to 0.78).

Park, 2017

Type of study: retrospective observational

Setting and country: Korea, hospital

Funding and conflicts of interest: not reported

Inclusion criteria: all patients who had previously experienced a moderate or severe initial HSR to LOCM and in whom the subsequent exposure occurred between 1 January 2014 and 31

December 2014.

Exclusion criteria: not reported

N=150

Mean age ± SD: 62 ± 12

Sex: 50 % M / 50 % F

Describe prognostic factor(s) and method of measurement:

Not described explicitly, but described in results section (see column Outcomes).

Duration or endpoint of follow-up:

For how many participants were no complete outcome data available?

N (%): not reported

Reasons for incomplete outcome data described? Not reported

recurrence of hypersensitivity reactions after contrast exposure occurred in 64/328 (20%) of the instances of re-exposure to low-osmolar iodinated contrast in patients with a history of moderate or severe reactions.

The following factors were associated with an increased risk for developing this second hypersensitivity reaction:

age (OR: 0.97, 95% CI 0.94 to 0.99);

diabetes mellitus (OR: 6.49, 95% CI: 2.38 to 17.71);

chronic urticaria (OR: 7.61, 95% CI: 1.63 to 35.59);

drug allergy (OR: 3.69, 95% CI: 1.18 to 11.56);

changing the iodinated contrast medium (OR: 0.33, 95% CI: 0.17 to 0.64);

initial hypersensitivity reaction was severe (OR: 2.67, 95% CI: 1.05 to 6.79).

The following factors were not independently associated with the risk of developing a recurrent hypersensitivity reaction: sex, use of premedication.

¹ Incremental predictive value is the predictive value beyond standard demographic factors and the established risk factors (e.g. smoking, blood pressure, lipid levels, diabetes, cancer stage, et cetera), for example change in c-statistic.

Table: exclusion after examination of the full text

Author and Year	Reason for exclusion
Agardth, 1983	Does not fulfil inclusion criteria: no control group.
Aggarwal, 2015	Does not fulfil inclusion criteria: the effect of prophylactic measures is not examined (this is a sefty study on the risks of beta-blockers).
Ahn, 2015	Does not fulfil inclusion criteria: the diagnostic criteria of cutaneous test for hypersensitivity reactions after contrast administration are studied.
Al-Ahmad, 2015	Two case-reports.
Ansell, 1980	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Aurnol, 2013	Conference abstract
Barrett, 1992	Does not fulfil inclusion criteria: hypersensitivity reactions are not reported as an outcome
Beaty, 2008	Does not fulfil inclusion criteria: examines physician’s beliefs about the relation between contrast hypersensitivity and seafood allergy.
Bellin, 2011	Narrative review
Ben-Noun, 1998	Does not fulfil inclusion criteria: descirbes relation between drug-induced asthma and contrast medium
Benson, 2017	Does not fulfil inclusion criteria: describes result of hospital alert system, no control group.
Berti, 2016	Does not fulfil inclusion criteria: describes diagnostic properties of cutaneous tests for contrast medium for hypersensitivity reactions
Bertrand, 1992	Already included in systematic review of Tramer, 2006
Boehm, 2016	Narrative review
Bohm, 2006	Narrative review
Bohm, 2012	Does not fulfil inclusion criteria: proposes a classification system for hypersensitivity reaction, no original patient data presented
Bohm, 2017	Does not fulfil inclusion criteria: article is in German
Bonadonna, 2014	Narrative review
Bottinor, 2013	Narrative review
Boulos, 2017	Does not fulfil inclusion criteria: validation of a sepsis prediction score
Boyd, 2017	Narrative review
Brockow, 2005	Narrative review
Brockow, 2014	Narrative review
Bumbacea, 2013	Narrative review
Chevrot, 1988	Already included in systematic review of Tramer, 2006
Choi, 2008	Case-report
Christiansen, 2002	Narrative review
Chuang, 2009	Does not fulfil inclusion criteria: contrast hypersensitivity is not an outcome measure
Cohan, 1997	Narrative review
Courvoisier, 1998	Case report
Davenport, 2009	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Davenport, 2010	Does not fulfil inclusion criteria: studies saftey of a corticosteroid regimen
Davenport, 2011	Does not fulfil inclusion criteria: studies saftey of a corticosteroid regimen
Davenport, 2016	Does not fulfil inclusion criteria: studies saftey of a corticosteroid regimen
Davenport, 2017	Narrative review
Davis, 2015	Narrative review
Della-Torre, 2015	Does not fulfil inclusion criteria: no control group
Dewachter, 2011	Does not fulfil inclusion criteria: effect of preventive measures not examined
Dillman, 2007	Does not fulfil inclusion criteria: effect of preventive measures not examined
Dillman, 2008	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Engl, 1988	Letter tot he Editor
Esplugas, 2002	Narrative review
Farnam, 2012	Narrative review
Fineman, 2014	Narrative review
Freed, 2001	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Ginsberg, 1996	Already included in systematic review of Tramer, 2006
Gomes, 2005	Narrative review
Hermans, 2017	Narrative review
Heshmatzadeh, 2016	Narrative review
Hsieh, 2014	Does not fulfil inclusion criteria: studies the effects of ignoring drug allergy alerts in electronic patient database
Hsu Blatman, 2017	Narrative review
Inbaraj, 1970	Narrative review or book chapter
Inbaraj, 2017	Does not fulfil inclusion criteria: no univariate or multivariate analysis of risk factor of hypersensitivity reactions after contrast administration.
Jingu, 2014	Does not fulfil inclusion criteria: no univariate or multivariate analysis of risk factor of hypersensitivity reactions after contrast administration.
Kalaiselvan, 2014	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Kaufman, 2013	Does not fulfil inclusion criteria: adresses medical myths in narrative review.
Ketkar, 2003	Case report
Kim, 2011	Does not fulfil inclusion criteria: no control group
Kopp, 2008	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Kwan, 2006	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Kyung, 2013	Does not fulfil inclusion criteria: analysis of classification systems for hypersensitivity reactions after contrast administration only.
Ioh, 2010	Does not fulfil inclusion criteria: no univariate or multivariate analysis of risk factor of hypersensitivity reactions after contrast administration.
Lasser, 1987	Already included in systematic review of Tramer, 2006
Lasser, 1988	Same population and results as Lasser, 1987 (which is included in the literature analysis).
Lasser, 1994	Already included in systematic review of Tramer, 2006
Lasser, 1995	Letter to the editor
Lasser, 2004	Narrative review
Lee, 2017	Does not fulfil inclusion criteria: no control group
Leone, 2008	Does not fulfil inclusion criteria: describes causes of adverse drug reactions overall
Liccardi, 2008	Narrative review
Liccardi, 2009	Narrative review
Mammarappallil, 2016	Does not fulfil inclusion criteria: report show often adverse reactions after contrast administration are not documenten adrquately
Marcelino, 2016	Conference abstract
Maurer, 2013	Conference abstract
Mervak, 2015	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Mervak, 2016	Conference abstract
Mishra, 2013	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Montandon, 2016	Two case-reports
Morcos, 1998	Letter to the editor
Morcos, 2005	Narrative review
Morzycki, 2017	Narrative review
Muller, 2014	Does not fulfil inclusion criteria: no univariate or multivariate analysis of risk factor of hypersensitivity reactions after contrast administration.
Nazer, 2011	Conference abstract
Newman, 2001	Case report
Nguyen, 2008	Does not fulfil inclusion criteria: contrast hypersensitivity is not an outcome measure
Niell, 2014	Does not fulfil inclusion criteria: studies the educational value of an online didactic model about contrast hypersensitivity reactions
Nilsson, 2001	Does not fulfil inclusion criteria: no control group of patients with a history of hypersensitivity to contrast medium, who do not receive prophylactic measures
Petscavge, 2014	Does not fulfil inclusion criteria: studies the educational value of an didactic tool about contrast hypersensitivity reactions
Plagova, 2017	Narrative review
Power, 2016	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Pradubpongsa, 2013	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Prieto-Garcia, 2013	Does not fulfil inclusion criteria: examines diagnostic properties of cutaneous tests for diagnosing hypersensitivity reactions after contrast administration.
Rajesh, 2016	Conference abstract
Rerkpattanapipat, 2011	Narrative review
Ring, 1985	Already included in systematic review of Tramer, 2006
Rosada Ingelmo, 2016	Narrative review
Ryu, 2015	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Schopp, 2013	Narrative review
Seymour, 1994	Does not fulfil inclusion criteria: descirbes practice variation in administration of prophylaxis for hypersensitivity reactions after contrast administration.
Seymour, 1995	Letter to the Editor
Sheikh, 2013	Narrative review
Siegrist, 2016	Case report
Sikka, 2016	Narrative review
Simons, 2010	Narrative review
Small, 1982	Already included in systematic review of Tramer, 2006
Smithe, 1995	Already included in systematic review of Tramer, 2006
Soffer, 2017	Case report
Soyyigit, 2016	Does not fulfil inclusion criteria: examines diagnostic properties of cutaneous tests for diagnosing hypersensitivity reactions after contrast administration.
Szebeni, 2001	Narrative review
Szebeni, 2005	Narrative review
Tepetam, 2016	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Trcka, 2008	Does not fulfil inclusion criteria: examines diagnostic properties of cutaneous tests for diagnosing hypersensitivity reactions after contrast administration.
Trout, 2011	Does not fulfil inclusion criteria: physician survey on use of gadolinium containing contrast medium in children.
Tsushima, 2016	Does not fulfil inclusion criteria: physician survey on knowledge of risk factors of complications of contrast medium administration.
Wang, 2008	Does not fulfil inclusion criteria: univariate analysis of risk factor of hypersensitivity reactions after contrast administration only.
Wang, 2017	Does not fulfil inclusion criteria: describes the use of epinephrine for all drug hypersensitivity reactions
Wu, 2016	Commenatry, not an original article.
Yang, 2015	Does not fulfil inclusion criteria: describes the before and after effects of an electrocin consultation system on the risk of of hypersensitivity reactions after contrast administration.
Zukiwski, 1990	Does not fulfil inclusion criteria: describes risk factors in a very specific population, univariate analysis only.

Authorization date and validity

Last review : 24-06-2020

Last authorization : 24-06-2020

The board of the Radiological Society of the Netherlands will determine at the latest in 2024 if this guideline (per module) is still valid and applicable. If necessary, a new working group will be formed to revise the guideline. The validity of a guideline can be shorter than 5 years, if new scientific or healthcare structure developments arise, that could be seen as a reason to commence revisions. The Radiological Society of the Netherlands is considered the keeper of this guideline and thus primarily responsible for the actuality of the guideline. The other scientific societies that have participated in the guideline development share the responsibility to inform the primarily responsible scientific society about relevant developments in their field.

Module[1]	Control holder(s)[2]	Year of authorisation	Next assessment actuality guideline[3]	Frequency of assessing actuality[4]	Who monitors actuality[5]	Relevant factors for changes in recommendations[6]
Prophylaxis of hypersensitivity reactions	NVvR	2019	2024	5 years	NVvR	New tests or new information on diagnostic parameters of tests available

[1] Name of module

2 Responsible authors (per module)

3 Year in which the guideline should be assessed for updating

4 Time frame: Once every 6 months, one year, two years, five years, or longer

5 Responsible scientific society

6 Variety of reasons: new drugs, new therapies, et cetera

Initiative and authorization

Initiative:

Nederlandse Vereniging voor Radiologie

Authorized by:

Nederlandse Internisten Vereniging
Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
Nederlandse Vereniging van Spoedeisende Hulp Artsen
Nederlandse Vereniging voor Cardiologie
Nederlandse Vereniging voor Dermatologie en Venereologie
Nederlandse Vereniging voor Heelkunde
Nederlandse Vereniging voor Radiologie
Nederlandse Vereniging van Ziekenhuisapothekers
Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
Nederlandse Vereniging voor Intensive Care
Patiëntenfederatie Nederland
Nederlandse Vereniging voor Allergologie en Klinische Immunologie

General details

The guideline development was assisted by the Knowledge Institute of the Federation Medical Specialists and was financed by the Quality Funds for Medical Specialists (Stichting Kwaliteitsgelden Medisch Specialisten: SKMS).

Scope and target group

Goal

The aim of the Part 2 of Safe Use of Contrast Media guidelines is to critically review the present recent evidence with the above trend in mind and tries to formulate new practical guidelines for all hospital physicians to provide the safe use of contrast media in diagnostic and interventional studies. The ultimate goal of this guideline is to increase the quality of care, by providing efficient and expedient healthcare to the specific patient populations that may benefit from this healthcare and simultaneously guard patients from ineffective care. Furthermore, such a guideline should ideally be able to save money and reduce day-hospital waiting lists.

Users

This guideline is intended for all hospital physicians that request or perform diagnostic or interventional radiologic or cardiologic studies for their patients in which CM are involved.

Samenstelling werkgroep

A multidisciplinary working group was formed for the development of the guideline in 2016. The working group consisted of representatives from all relevant medical specialization fields that are involved with intravascular contrast administration.

All working group members have been officially delegated for participation in the working group by their scientific societies. The working group has developed a guideline in the period from May 2016 until July 2019.

The working group is responsible for the complete text of this guideline.

Working group

A.J. van der Molen, radiologist, Leiden University Medical Centre, Leiden (chairman)
R.W.F. Geenen, radiologist, Noordwest Ziekenhuisgroep (NWZ), Alkmaar
T. Leiner, radiologist, University Medical Centre Utrecht, Utrecht (until November 2018)
H.M. Dekker, radiologist, Radboud University Medical Centre, Nijmegen
I.A. Dekkers, clinical epidemiologist and radiologist in training, Leiden University Medical Centre, Leiden
K. van der Putten, nephrologist, Tergooi, Hilversum
J.G.R. de Monchy, allergologist, DC-Klinieken, Amsterdam
H.R.H. de Geus, internist-intensivist, Erasmus Medical Centre, Rotterdam
S.W. Zielhuis, hospital pharmacist, Medical Centre Leeuwarden, Leeuwarden
O.R.M. Wikkeling, vascular surgeon, Heelkunde Friesland Groep, location: Nij Smellinghe Hospital, Drachten
I. Brummer, emergency physician, Treant Healthcare Group, Emmen
M. van der Vlugt, cardiologist, Radboud University Medical Centre, Nijmegen (until April 2018)
M. Gotte, cardiologist, Free University Medical Centre, Amsterdam (from July 2018)
S.H. Kardaun, dermatologist, University Medical Centre Groningen, Groningen (until March, 2018)

Methodological support

I.M. Mostovaya, senior advisor, Knowledge Institute of the Federation Medical Specialists
J. Buddeke, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)
W. Harmsen, advisor, Knowledge Institute of the Federation Medical Specialists (from April 2018)

Declaration of interest

The working group members have provided written statements about (financially supported) relations with commercial companies, organisations or institutions that are related to the subject matter of the guideline. Furthermore, inquiries have been made regarding personal financial interests, interests due to personal relationships, interests related to reputation management, interest related to externally financed research and interests related to knowledge valorisation. The statements on conflict of interest can be requested at the administrative office of the Knowledge Institute of Medical Specialists and are summarised below.

*Last name*	*Function*	*Other positions*	*Personal financial interests*	*Personal relations*	*Reputation management*	*Externally financed research*	*Knowledge valorisation*	*Other interests*	*Signed*
*Van der Putten*	Internist nephrologist	None	None	None	None	None	None	None	14-10-2015
*Van der Vlugt*	Cardiologist	None	None	None	Chairman of the working group Cardiac MRI & CT and Nuclear imaging of the Netherlands Society of Cardiology	None	None	None	03-01-206
*Roodheuvel*	Emergency physician	Instructor OSG/VvAA for courses on echography – paid position Member of department for burn treatment – unpaid.	None	None	None	None	None	None	21-12-2015
*Geenen*	Radiologist	Member of commission prevention of PC-AKI	None	None	None	None	None	Has held several presentation about contrast media on invitation (GE, BAYER)	25-3-2016
*Zielhuis*	Hospital pharmacist	None	In the past (2013-2015) has participated in an advisory panel on expensive medication for the companies AbbVie and Novartis. Has received an expense allowance for this. Both forms do not produce contrast media that this guideline is about. Currently not active in an advisory panel.	None	None	None	None	None	8-1-2016
*De Geus*	Internist-Intensivist Erasmus MC Rotterdam	None	None	None	None	None	None	None	Ja, 31-03-2016
*Dekkers*	Radiologist in training and PhD-candidate	None	None	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable	Ja, 8-7-2016
*Wikkeling*	Vascular surgeon	None	None	None	None	None	None	Not applicable	19-7-2016
*Dekker*	Radiologist	None	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable	Not applicable	10-7-2016
*Van der Molen*	Chairman Radiologist at LUMC	None	None	None	None	None	Not applicable	One-off royalties Springer Verlag (2014) Reference work Safety of contrast medicine One-off payment by Guerbet for (2014) reference card management of CM reactions (educative material) Incidental payments for presentations or being day chairman at contrast safety congress (2016 Netherlands + Europe all firms: GE, Guerbet, Bracco, Bayer	6-9-2016
*Kardaun*	Dermatologist - researcherUniversitair Medisch Centrum Groningen: unpaid	Replacing dermatologist in clinical practice - unpaid Member of scientific advisory board of Lareb (Dutch center for pharmacovigilance): unpaid	None	None	None	None	None	None	24-2-2016
*Brummer*	Emergency physician Treant zorggroep location Emmen and Stadskanaal	None	None	None	None	None	None	None	23-2-2018

Patient involvement

It was challenging to find representation for the patient’s perspective, since the guideline does not discuss a specific group of patients with a disease. The Dutch Kidney Patients Association was invited to participate in an advisory board to the working group, but declined since this subject was not specific enough for them to give adequate input; The Dutch Kidney Patients Association did provide written feedback for specific modules during the commentary phase. The Dutch Kidney Patients Association and the Patient Federation of the Netherlands was invited to participate in the invitational conference in which the framework of the guideline was discussed. Furthermore, the concept guideline has been submitted for feedback during the comment process to the Patient Federation of the Netherlands and the Dutch Kidney Patient Association.

Method of development

Evidence based

Implementation

In the different phases of guideline development, the implementation of the guideline, and the practical enforceability of the guideline were taken into account. The factors that could facilitate or hinder the introduction of the guideline in clinical practice have been explicitly considered. The implementation plan can be found with the Related Products. Furthermore, quality indicators were developed to enhance the implementation of the guideline. The indicators can also be found with the Related Products.

Methods and proces

AGREE

This guideline has been developed conforming to the requirements of the report of Guidelines for Medical Specialists 2.0 by the advisory committee of the Quality Counsel. This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (www.agreetrust.org), a broadly accepted instrument in the international community and on the national quality standards for guidelines: “Guidelines for guidelines” (www.zorginstituutnederland.nl).

Identification of subject matter

During the initial phase of the guideline development, the chairman, working group and the advisor inventory the relevant subject matter for the guideline. Furthermore, an Invitational Conference was organized, where additional relevant subjects were discussed. A report of this meeting can be found in Related Products.

Clinical questions and outcomes

During the initial phase of guideline development, the chairman, working group and advisor identified relevant subject matter for the guideline. Furthermore, input was acquired for the outline of the guideline during an Invitational Conference. The working group then formulated definitive clinical questions and defined relevant outcome measures (both beneficial land harmful effects). The working group rated the outcome measures as critical, important and not important. Furthermore, where applicable, the working group defined relevant clinical differences.

Strategy for search and selection of literature

For the separate clinical questions, specific search terms were formulated and published scientific articles were sought after in (several) electronic databases. Furthermore, studies were scrutinized by cross-referencing for other included studies. The studies with potentially the highest quality of research were looked for first. The working group members selected literature in pairs (independently of each other) based on title and abstract. A second selection was performed based on full text. The databases, search terms and selection criteria are described in the modules containing the clinical questions.

Quality assessment of individual studies

Individual studies were systematically assessed, based on methodological quality criteria that were determined prior to the search, so that risk of bias could be estimated. This is described in the “risk of bias” tables.

Summary of literature

The relevant research findings of all selected articles are shown in evidence tables. The most important findings in literature are described in literature summaries. When there were enough similarities between studies, the study data were pooled.

Grading quality of evidence and strength of recommendations

The strength of the conclusions of the scientific publications was determined using the GRADE-method. GRADE stands for Grading Recommendations Assessment, Development and Evaluation (see http://www.gradeworkinggroup.org/) (Atkins, 2004).

GRADE defines four gradations for the quality of scientific evidence: high, moderate, low or very low. These gradations provide information about the amount of certainty about the literature conclusions. (http://www.guidelinedevelopment.org/handbook/).

Formulating conclusions

For diagnostic, etiological, prognostic or adverse effect questions, the evidence was summarized in one or more conclusions, and the level of the most relevant evidence was reported. For intervention questions, the conclusion was drawn based on the body of evidence (not one or several articles). The working groups weighed the beneficial and harmful effects of the intervention.

Considerations

Aspects such as expertise of working group members, patient preferences, costs, availability of facilities and organisation of healthcare aspects are important to consider when formulating a recommendation. These aspects were discussed in the paragraph Considerations.

Formulating recommendations

The recommendation answers the clinical question and was based on the available scientific evidence and the most relevant considerations.

Constraints (Organisation of healthcare)

During the development of the outline of the guideline and the rest of the guideline development process, the Organisation of healthcare was explicitly taken into account. Constraints that were relevant for certain clinical questions were discussed in the Consideration paragraphs of those clinical questions. The comprehensive and additional aspects of the Organisation of healthcare were discussed in a separate chapter.

Development of quality indicators

Internal (meant for use by scientific society or its members) quality indicators are developed simultaneously with the guideline. Furthermore, existing indicators on this subject were critically appraised; and the working group produces an advice about such indicators. Additional information on the development of quality indicators is available by contacting the Knowledge Institute for the Federation Medical Specialists. (secretariaat@kennisinstituut.nl).

Knowledge Gaps

During the development of the guideline, a systematic literature search was performed the results of which help to answer the clinical questions. For each clinical question the working group determined if additional scientific research on this subject was desirable. An overview of recommendations for further research is available in the appendix Knowledge Gaps.

Comment- and authorisation phase

The concept guideline was subjected to commentaries by the involved scientific societies. The commentaries were collected and discussed with the working group. The feedback was used to improve the guideline; afterwards the working group made the guideline definitive. The final version of the guideline was offered for authorization to the involved scientific societies and was authorized.

References

Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-E842.

Medisch Specialistische Richtlijnen 2.0. Adviescommissie Richtlijnen van de Raad Kwalitieit, 2012. Available at: https://richtlijnendatabase.nl/over_deze_site/richtlijnontwikkeling.html.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available at: http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. Erratum published in: BMJ 2008;336(7654).

Ontwikkeling van Medisch Specialistische Richtlijnen: stappenplan. Kennisinstituut van Medisch Specialisten.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.