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Short-, Mid-, and Long-Term Strategies to Manage the Shortage of Iohexol - RSNA Publications Online

Summary

Due to a severe U.S. shortage of contrast media (iohexol) widely used for CT scanning, affected radiology departments will need to institute emergency changes in imaging protocols and patient triage.

Essentials

  • ■ Short-term strategies to mitigate the iohexol shortage include establishing an incident command center to direct and monitor iodinated contrast usage, delaying elective contrast-enhanced CT exams, contrast dose reduction, and alternative diagnostic modalities.

  • ■ Mid-term strategies include contrast repackaging, multi-use, and multi-access strategies, communication and negotiation with payers on billing and reimbursement, and communication with ordering providers to ensure compliance.

  • ■ Long-term strategies include advocating for legislation to facilitate expansion of contrast manufacturing plants including in the United States and institutional stockpiling of contrast supplies.

Introduction

The spike in COVID-19 cases in Shanghai, China led to the Chinese government's lockdown of more than 26 million people on March 31, 2022. The lockdown impacted GE Healthcare's primary pharmaceutical manufacturing facility for iohexol (Omipaque, GE Healthcare, Waukesha, WI, USA) iodinated contrast media (ICM). The facility is currently operating at partial capacity, with approximately 1/3 of the workforce quarantined within the compound, resulting in approximately 25% production capacity. In addition, supply chain issues associated with the lockdown have created delays in transport and distribution of iohexol. Therefore the expectation is that only 20% of the demand for iohexol will be available for the near term (1). The only other pharmaceutical facility capable of producing iohexol, (located in Ireland) is already operating at maximum capacity. GE Healthcare expects the shortage to be most severe over the next two weeks, with persistent supply issues through the end of June 2022, assuming return to normal production capacity within that period.

Four companies supply ICM to the US market, including Bayer Corporation (Whippany, NJ, USA), Bracco Diagnostics Inc. (Monroe Township, New Jersey, USA), GE Healthcare and Guerbet LLC (Princeton, NJ, USA). However, two agents dominate the US ICM market, iohexol and iopamidol (Isovue, Bracco Diagnostics) which together comprise >90% of ICM infusions in the US. Iohexol constitutes 50% of the market for ICM in the US, while iopamidol comprises the other 40-50% of ICM use. Collectively Bracco, Bayer, and Guerbet are unable to rapidly scale up production to meet the demand for ICM created by the reduction in iohexol production. In this statement, we present short-, medium- and long-term responses to managing the ICM shortage. In the opinions below, providers are cautioned that these strategies constitute emergency responses to what may be otherwise considered standard of care diagnostic imaging.

Immediate response to ICM shortage (weeks)

Radiology departments and healthcare institutions need to immediately assess their daily utilization of ICM, the total ICM supply available, predicted deliveries arriving in the near future, and the estimate of days of ICM on-hand. These metrics allow comparison of current use rates those associated with mitigation efforts. Many radiology departments are reported to have less than a few weeks of ICM supply on hand, without a known next ICM delivery, or a planned delivery schedule. Efforts to reduce ICM utilization may be most effective if focused to CT scanning, since ICM use for CT constitutes more than 70% of overall ICM use in most hospitals.

Incident command center: An institution-wide committee comprised of radiology, operational and institutional leadership should be established, to create plans for contrast mitigation and conservation, engage stakeholders, and implement new workflows and processes. The committee should hold daily huddles and periodically provide communication to the radiology team members and the institution as a whole. An important first step is an institution-wide inventory of ICM, as contrast media is typically stored throughout diagnostic and procedural areas in both in-patient and ambulatory settings, including but not limited to Radiology, Cardiology, endoscopy, and perioperative areas. Daily updates on the remaining supply and the utilization rate from prior days should also be shared, in addition to operational updates. Although ICM is used throughout health care systems including in many areas outside of Radiology departments, leaders in Radiology are well positioned to provide appropriate direction and oversight in this crisis.

Scheduling: For institutions facing a shortage of ICM, radiology departments should consider delaying elective contrast-enhanced imaging studies when safe for patient care. Contrast-enhanced CT exams can be categorized as either a) emergent or cannot be delayed versus b) can be delayed by 3 months.

Individual specialty CT and other sections using ICM should categorize their imaging and treatment studies accordingly

Departments should identify and communicate those studies classified as emergent /cannot be delayed as priority studies to the hospital community. Such studies may include certain interventional radiology, cardiology procedures and emergent CT examinations (Table 1 and 2). Examples of imaging studies that can be delayed by 3 months may include routine contrast-enhanced CT examinations for follow-up of diseases such as cancer, stable aneurysm, post-treatment aneurysm (when the patient is asymptomatic and without clinical evidence for disease progression). Delaying imaging should be a consideration both for exams being scheduled and those already scheduled. Designation to delay the exams can be done in tandem with protocol changes, specifically categorizing scheduled contrast-enhanced CT exams as “CT with contrast”, “non-contrast CT”, “delay exam by 3 months”, or “reschedule for MRI or ultrasound”. Protocol changes and exam rescheduling discussions must include the radiologist and the ordering provider, as appropriate timing of imaging may not be readily apparent to the radiologist or scheduler. Timely communication with the patient, both directly from radiology and through the ordering provider, is also needed to avoid confusion and miscommunication. Sample scripts for communication with the patient, provider, and public have been drafted by Vanderbilt University Medical Center(2).

Table 1: CT Studies Requiring Iodinated Contrast Media
Table 1:

Table 2: Triage of Vascular and Interventional Procedures Requiring Use of Iodinated Contrast Media*
Table 2:

Contrast media substitution: Many institutions have reached out to alternate vendors for other sources of ICM. However, in the short-term, most vendors are unlikely to accept new customer orders if they are already at full capacity. In the longer term, institutions may seek to diversify their ICM vendors to avoid future crises.

Table 3: Potential Imaging Alternatives to Be Considered Due to Shortage of CT with Iodinated Contrast Media
Table 3:

Barium can be considered as an alternative oral ICM for CT abdomen and pelvis exam. However, oral barium contrast should be avoided if there is concern for gastrointestinal perforation or leak. Sorbitol- mannitol-xanthan gum (Breeza, Beekley Medical; Bristol, CT, USA) or diatrizoate meglumine (Gastrografin, Bracco Diagnostics) can also be considerations for oral ICM administration. Diatrizoate meglumine can also be used for fluoroscopy exams and for rectal administration. For certain fluoroscopic imaging, including catheter angiography and intraoperative arthrography, some studies have suggested use of gadolinium contrast, with consideration and adjustment for differences in the k-edge of iodine (33 keV) compared to gadolinium (50 keV)(3). Gadolinium contrast use with x-ray imaging constitutes off-label use and should only be pursued if absolutely necessary given the FDA's recommendation against this practice. CO2 angiography has been used for patients with contraindications to ICM, including in renal disease or severe allergies, and can be a consideration during the current crisis(4). Alternative agents can be considered for genitourinary imaging, including cystography, retrograde ureterography, and for percutaneous renal access and nephrostomy procedures. Iothalamate meglumine, Cystoconray, Guerbet LLC) or diatrizoate meglumine are considerations, and for percutaneous nephrostomy procedures, gadolinium contrast or CO2 injection can be considered.

Evaluate expanded use of non-contrast CT protocols: Shortage of ICM may be severe enough to be considered a patient care emergency. In that setting, the radiology department and hospital may need to institute emergency measures for ICM conservation. During such a crisis, reconsideration of CT examinations that may be performed without ICM should be considered. Non-contrast CT could be considered for some initial screening examinations, such as CT of the head and neck to evaluate for infection. If there is a positive finding potentially indicating infected fluid collection, follow-up MRI can be performed, or if contraindicated, CT with contrast. Patients undergoing CT of the abdomen and pelvis for abdominal pain or distension with concern for hernia, diverticulitis, appendicitis, abscess, or bowel obstruction can be performed without ICM. Similarly, oncology patients undergoing follow-up CT of the chest, abdomen, and pelvis for testicular or prostate cancer, lymphoma, leukemia or myeloma, or CT neck in the setting of lymph node follow-up, can be performed without ICM. Follow-up CT imaging post abscess drainage or immediate post-surgical CT scans can also be performed without ICM. Imaging for patients with minor trauma can also be done without contrast.

Alternative imaging examinations: In some circumstances, alternatives to contrast-enhanced CT examinations may be useful (Table 2). MR angiography (MRA) can be performed in place of CT angiography (CTA) in a number of settings, including abdominal aortic aneurysm or descending thoracic aorta dissection in patients with stable vital signs, extremity run-offs, follow-up of or post-treated cerebral aneurysms or high-flow vascular malformations, and follow-up of traumatic vascular injuries. Cancer follow-up for fluorodeoxyglucose F18 (FDG)-avid tumors may be shifted to PET-CT, including non-contrast CT. For the evaluation of liver lesions and cirrhosis, MRI liver can substitute for multi-phase liver CT. MRI can also be considered for appendicitis and adrenal nodule evaluation. Ultrasound can be considered for patients with epigastric or pelvic pain, or for evaluation of subcutaneous soft tissue masses as a first-line imaging modality. Workflows can be optimized to facilitate for stroke codes to undergo abbreviated brain MRI/MRA protocols.

As MRI volumes increase during the ICM shortage, challenges with access need to be considered. This can be alleviated through shortened protocol times, by prioritizing necessary sequences, utilization of advanced imaging acceleration algorithms, including compressed sensing and deep learning image reconstruction for de-noising and image sharpening, and scheduling template modifications to allow for shorter block times to facilitate increased scanning. Gaps in the MRI schedule also need to be implemented to facilitate scanning of emergent indications from the emergency room, such as stroke codes, which would otherwise go to CT.

Immediate changes to the administered dose of ICM may be considered. For departments that use weight-based dosing protocols(5), dose reduction by 20-30% may be successfully implemented. Online weight-based calculators are available for dose calculation(6). For radiology departments not using weight-based dosing for CT, we suggest an across-the-board reduction in dose by 20-30 mL for all indications when using multi dose vials and injectors. For single use vials, radiology departments may consider rounding down to the dose available in the nearest lower single-use vial if within 10-20 ml. For example, if 110 ml is needed based on weight-based dosing, round down to use the 100 ml vial (rather than 125 ml vial). For the smallest adults, consider adjusting the lowest administered dose to 60 ml.

Finally, radiology departments are encouraged to review CT protocol parameters to maximize image contrast for any given dose of ICM, including implementing a) lower kV image acquisition and b) dual energy CT for dose reduction. In all cases an attempt should be made to minimize repeat administration of ICM by reviewing and reinforcing image acquisition timing strategies and breath- holding instructions.

Mid-term response to ICM shortage (next two months)

Considerations for repackaging of ICM centrally within the pharmacy of single or multiple use vials can be made. This will require International Organization for Standardization (ISO) class 5 clean rooms, with high efficiency penetration air filtration of 99.9% efficiency at 0.3 micron-sized particles and 240-480 air changes per hour(7). Repackaging may be considered for smaller ICM aliquots, e.g., applications requiring 10 mL ICM, or for conversion of multi-use 500 mL bottles for smaller single-use doses.

Considerations when converting single use vials to multi-use. Current guidelines only allow for single puncture of ICM vials. This step, therefore, must be planned, coordinated and implemented in conjunction with pharmacy and hospital infection control staff to ensure patient safety. If multi-use is considered, contrast transfer sets are used with tubing and one-way valves to prevent microbial introduction into the ICM. Single-use vials are preservative-free (no anti-microbial preservatives), so precautions need to be taken. At two of our institutions (TMG, MMB), the pharmacy leadership may allow vials to be drawn from more than once, with expiration of the vial after 4 hours from initial spike if drawn outside of a cleanroom. ICM drawn and held inside of a cleanroom will maintain USP 797 designation with expiration after 30 hours at room temperature or 9 days under refrigeration. One study showed zero failed sterility samples from single dose vials accessed in cleanrooms over a 24-hour period(8). If ICM shortages persist into and beyond the summer, consideration for radiology leaders to engage with the Centers for Disease Control and the Food and Drug Administration to consider pathways and mechanisms to permit or create multi-puncture ICM bottles, that will improve contrast access, reduce waste, while also preventing contamination.

Billing issues. Practice and ordering modifications will have downstream effects on reimbursement and billing. Early engagement with payers outlining what to expect and discussing correct approaches to billing can help prevent rejections of payment or delays in authorization. Making the payers aware of likely increases in downstream MRI orders and pre-authorizations and the collective justification may help prevent delays and facilitate a more streamlined process. Considering most contrast-enhanced CT examinations administer and bill for single-use vials as part of the exam, with new workflows that may use a single-use vial for two examinations, structuring ICM billing on a per mL basis in place of per vial billing would avert billing confusion and the potential for rejections or risk of billing fraud.

Hospital communication. Radiology departments involved in ICM shortage planning need to actively communicate the nature, extent, and new ICM policies to ordering providers. Electronic medical record and ordering systems may be available to facilitate ICM conservation practices. Clinical decision support mechanisms have been mandated by the Centers for Medicare and Medicaid Services for healthcare institutions that will be tied to reimbursements(9). Most institutions have or are in the process of implementing this software. Review and modification of the algorithms for imaging recommendations and standardization of appropriate alternative examinations to contrast-enhanced CT during the ICM shortage crisis would improve compliance from ordering providers. Additionally, electronic medical record system alerts (reminding staff of the ICM shortage and of new ICM guidelines) should improve compliance. Some ordering systems have the ability to flag ICM examinations and provide feedback or alternative imaging to better direct hospital staff regarding new ICM policies.

Longer term response to ICM shortage (next two years)

Globalization of the supply chain and just-in-time delivery have been upended by the COVID-19 pandemic and the recent war Ukraine. The challenges of the past few years have affected the longstanding plans of the world's largest companies and are forcing them to reconsider the basic tenets of the supply chain. Not surprisingly, the general public may be more aware of extraordinary headlines regarding supply chain problems affecting non-medical compared to medical supplies. For example, Tim Cook, the CEO of Apple, revealed that supply constraints cost the company $6 billion in each of the last two quarters, with ongoing impact for several additional quarters. At Ford Motor Company, supply disruptions for computer chips led Chief Financial Officer John Lawler to report that Ford currently has “about 53,000 vehicles on wheels” completed but awaiting installation of components affected by semiconductor supply shortages. Perhaps because of these and more widely understood headlines (e.g., the shortage of baby formula), the supply chain problems of the healthcare industry have been under reported in the media.

While similar in origin, hospital supply shortages are far more critical to patient survival than the supply of iPhones or an F-150 truck. We are painfully learning that the hospital supply chains are vulnerable to the vicissitudes of politics/ country of origin and the pandemic. Supply chain problems impact the ability of healthcare provides to care for patients. Few might have imagined that China would quarantine the entire population of cities as large as quarantines of Shanghai (26 million people) and Beijing (22 million people) as a response to COVID-19. Early in the COVID-19 pandemic in 2020, hospitals were faced with shortages of basic items like sterile gloves, hospital masks, and gowns. Despite that experience, no large institutions or companies expressed clear concern about the supply of intravenous ICM only a few months ago. Perhaps we should have been aware of the impossible becoming possible.

The radiology and hospital community should take this lesson as a wake-up call to adapt our supply chain to prevent similar emergencies in the future. We need to endeavor that companies with majority market share have more plant capacity with consideration for facilities located in the United States. Increasing the number of sites for chemical manufacturing and pharmaceutical preparation can be accomplished, with several cities and states likely embracing such new production facilities by providing tax advantages to companies to achieve it. In addition, a brief survey of bottles of Omnipaque 350 (iohexol, 350 mg iodine per ml) in our facilities revealed expiration dates in 2025, which is almost 3 years into the future. Perhaps hospitals and imaging centers will need to keep a 6-month supply of ICM on hand rather than simply a week's supply. This will result in additional storage costs, but longer term will provide a safety net for supply disruption. We should also look at the ancillary components for ICM administration (e.g., IV needles, tubing for the injectors) and make certain we have adequate supplies in stock. Any and all supplies we use may be the next subject of shortages over the next few months or years.

The current limited distribution channels for ICM (e.g., McKesson and Cardinal Health) coupled with consolidation of buyers into group purchasing organizations have placed significant downward pressure on the profitability of the ICM manufacturers, limiting their ability to expand manufacturing capabilities with a reasonable rate of return. We need to make certain that the additional cost for the manufacturers is met to encourage additional expenditures and capacity.

Summary

The iohexol shortage has forced healthcare institutions to implement innovative strategies to adapt their protocols for patient management. These strategies include immediate short-term contrast conservation, in addition to mid-term and long-term strategies to mitigate the current and future supply chain disruptions.

References

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