Introduction
A large General Electric facility in Shanghai discontinued the manufacture of a water-soluble iodine contrast Omnipaque (iohexol) in April 2022. This has resulted in a significant supply chain disruption of one of the most widely used low-osmolality contrast agents in diagnostic and interventional radiology [1]. Although production has now resumed, iodinated contrast is likely to remain deficient for several months, and due to this shortage, many non-emergency tests are being postponed [2]. Recently, the FDA has further announced that two additional contrast agents, Omnipaque (iohexol, from GE Healthcare) and Visipaque (iodixanol, also from GE Healthcare), are also low in supply [3].

Computed tomography (CT) scans and Magnetic resonance imaging (MRI) are valuable diagnostic tools that help radiologists and physicians diagnose various medical conditions. The first commercial CT scanner was created in the 1970s, MRI in the 1980s [4], and since then, several advanced technologies have taken place in both imaging sectors. In the United States, approximately 70 million CT scans and 35 million MRI scans are conducted annually [5]. CT angiography (CTA) is a non-invasive method that uses an intravenous contrast agent to analyze vascular anatomy and pathology. CT scan is best for assessing endo and perivascular abnormalities as it has a more excellent spatial resolution than magnetic resonance imaging (MRI) [6,7]. Standard angiography may not be appropriate for certain patients, such as those with an allergy to iodinated contrast material or receiving radioactive iodine treatment for thyroid disorders. Similarly, patients with implantable devices, postoperative clips, uncontrolled movements, claustrophobia, or surgical changes that might compromise the magnetic resonance (MR) signal may be unsuitable for MR angiography. Thus, gadolinium usage in CTA has been studied as an alternative option; however, despite multiple studies demonstrating the feasibility of gadolinium catheter arteriography, the use of gadolinium for CTA has not generally been accepted as a viable substitute [8].

Here, the need for gadolinium-based contrast agents (GBCA) is emphasized again due to the shortage of iodinated contrast in the COVID-19 pandemic and other indications mentioned above. This study aims to provide data on using GBCA instead of iodinated difference for CTA during this crisis.

According to the articles mentioned above, patients with adequate renal function are not at a higher risk of developing post-contrast AKI; however, it is uncertain if individuals with an eGFR of less than 30 have a higher risk of post-contrast AKI [8]. Elevation of serum creatinine might be due to confounding variables rather than the iodinated contrast administration [4]. The American College of Radiology (ACR) Committee on Drugs and Contrast Media believes that CI-AKI is a genuine phenomenon, although it is an uncommon entity [8].

Prevention of CI-AKI includes

Avoiding all forms of contrast.

Using a low osmolarity contrast medium.

Expansion of the pre-exposure volume (with isotonic crystalloid preferred over half-isotonic crystalloid).

It is not recommended that all patients require a standard diagnostic examination of their renal function before receiving contrast, only those with risk factors for renal dysfunction [8]. Also, the iodinated difference can be used safely in patients with chronic hemodialysis (HD) who are anuric. Thus, regular post-procedural HD is not required in HD patients receiving IV contrast.
One other factor to consider when administering iodinated contrast is that patients with advanced chronic kidney disease (CKD) (stage IV or V; eGFR < 30) or who have AKI should stop taking metformin before or at the time of the procedure. Metformin must be stopped for 48 hours after the process in this group of individuals and should be resumed after rechecking eGFR once it is normalized [8].

Gadolinium:
Gadolinium has been used as an IV contrast medium for MRI since 1988. It is a rare earth metal in the periodic table's lanthanide class. Because it is very paramagnetic, it modifies the relaxation of water so that it allows differentiation between normal and diseased tissues in imaging. Gadopentetate dimeglumine (Magnevist®) is the first commercially available MRI contrast medium used in clinical studies. GBCAs have also been used in CT imaging since 1989; however, it was not frequently used due to limitations of the single-detector row CT technique. Helical or spiral CT elevated the effectiveness of gadolinium use with CT imaging [4,16,17].

Gadolinium-based contrast agents, renal complication, and prevention:
Initially, GBCAs were considered very safe and a reliable alternative to iodinated contrast with no significant side effects. However, in the early 2000s, a series of studies linked gadolinium contrast to NSF [19]. NSF is an uncommon disease affecting the skin and subcutaneous tissues, which has been described among patients with chronic kidney disease (CKD) but rarely among patients with normal kidney function [18]. Initially, fibrosis was thought to be localized only to the skin and subcutaneous tissues. Thus, it was named nephrogenic fibrosing dermopathy. However, postmortem examinations indicated that the fibrosis could spread to other organ systems such as the heart, skeletal muscles, lungs, and esophagus [20,21].

Decreased renal function is the most significant risk factor for developing NSF with gadolinium use. This is explained by the etiology and pathophysiology of this condition: GBCAs are gadolinium cation-containing chelates. When gadolinium chelates are in the body for an extended period, free gadolinium ions are released, which is hazardous due to their poor solubility. The stimulation of circulating fibrocytes by free gadolinium causes a fibrotic response [8]. Gadolinium is mainly eliminated through the kidneys, with a half-life of around 2 hours in individuals with normal kidney function, while it can last up to 120 hours in patients with severe CKD and requires > 3 hemodialysis sessions to be removed from dialysis patients [18,19]. Gadolinium ions are coupled to a chelating agent that is either linear or macrocyclic. With a linear agent, patients with CKD stage 4 or 5 have a 1.7 percent probability of developing nephrogenic systemic fibrosis (NSF), whereas, with a macrocyclic agent, the risk decreases to a minimum as macrocyclic GBCAs are more thermodynamically stable (low ratio of free gadolinium to complexed ligand at steady state) and kinetically neutral (extended half-life for gadolinium separation from its ligand) [4,16]. According to the ACR, GBCAs are divided into groups based on their structure and likelihood of causing NSF [Table-1] [8]

Table 1: ACR classification of Gadolinium relative to structure and NSF risk [8]

According to the most recent data, NSF or renal toxicity risk after administering group II GBCAs is relatively minimal. Thus, regardless of their dialysis status, withholding group II GBCAs from a patient with renal impairment, the possible danger of late diagnosis or misinterpretation from delaying may exceed the risk of NSF. There is limited data on NSF risk in group III agents, but the group I agents have a high risk of developing NSF in CKD patients [16].

Gadolinium use has also been known to cause CIN among CKD patients. However, it is dose dependent. In one trial, 12.1 % of individuals with CKD who were administered 0.2 mmol/kg of gadolinium had developed CIN, while a dosage of 0.1 mmol/kg was not shown to be nephrotoxic in another study [22,23].

As described, both iodinated and gadolinium-based contrast agents have their attendant risks [Table 2], but overall, the chances are low for these agents when used appropriately.

Table 2: Risks of nephrogenic systemic fibrosis (NSF) and contrast-induced nephropathy (CIN) associated with gadolinium and iodine [18,8,21].

Contrast reactions may be categorized as allergic-like or physiologic. “Allergic-like” reactions are believed to result from an immune response that results in symptoms similar to a typical allergic reaction, such as food, whereas physiologic reactions are physiologic responses to the contrast material, as described in Table 3. While corticosteroid premedication is believed to help prevent allergic-like reactions, this is not thought to be the case for physiologic reactions, which occur via a different mechanism [8].

Table 3: Adverse reactions to contrast agents [8]:

Gadolinium usage in CTA:
Despite developments in MR imaging technology, CT continues to outperform MR imaging in evaluating endo and perivascular anomalies, particularly at the level of the pulmonary circulation and lung parenchyma, for which the speed of CT imaging can help avoid significant motion artifacts due to respiration [29]. Bloem and Wondergem were the first to publish regarding the use of gadolinium in computed tomography (CT) in 1989. They included an image of the urinary bladder and renal collecting system obtained using gadolinium, similar to iodine-enhanced CT in 2 patients [30]. Similarly, in 1993, Kinno et al. used gadolinium-chelate for intra- arterial digital subtraction angiography (DSA) in a patient with a severe allergic reaction to iodinated contrast media [31].

Iodinated contrast agents are quantified by the weight of iodine atoms per ml (mg I/ml), whereas gadolinium chelates are quantified by the number of atoms per ml, i.e., mmol/ml. A gadolinium solution with a concentration of 0.5 mmol/ml has the same number of atoms as an iodinated contrast solution with a concentration of 63 mg I/ml, and a gadolinium-chelate at 0.5 mmol/ml would produce the same degree of attenuation as iodinated contrast solution with a concentration 126 mg I/ml. On CTA, gadolinium appears hyperdense, and the usual dosage for CTA is frequently quadrupled, i.e., 0.4 mmol/kg compared to 0.1 mmol/kg for MRI. Doses like 0.3 mmol/kg - 0.4 mmol/kg gadolinium have been utilized in CTA of the aorta, pulmonary or cervical arteries in various case reports/trials [18,6,32,27,7].

The utilization of gadolinium-based contrast in CT angiography for pulmonary circulation was initially reported in a single case report by Coche et al. [17]. They successfully detected an acute pulmonary embolism in their patient (who had an allergy to iodinated contrast and renal failure) by performing a spiral (dual-detector) CT with a gadolinium-based difference. Later, Remy-Jardin et al. reported in their study of 39 patients that CT pulmonary angiograms using gadolinium-based contrast agents were diagnostic but that CTs with 16 detectors (rather than 4) were required for high-quality examinations. The frequency of diagnostic CT angiograms was significantly greater with 16–detector row CT technology (94 % vs. 68 %) (P = .007), and the scanning time was also shorter in this group [33]. Even patients with pre-existing renal insufficiency could tolerate the gadolinium-based contrast agent at doses of 0.3 and 0.4 mmol/kg, and only one of the patients had a transient reduction of renal function. Otherwise, there were no reported adverse events.

Remy-Jardin et al. also performed similar research on 60 patients to compare the effects of 0.3 mmol/kg (group A) vs. 0.4 mmol/kg (group B) doses. 83 % of CT angiograms in group A and 100 % in group B were evaluated as diagnostic tests, and the researchers concluded that GBCAs are an adequate alternate contrast material for CT pulmonary angiography. In that study, only 1 patient had developed a temporary reduction in creatinine clearance, which was restored within 2 days to baseline kidney function [6].

Similarly, dilution or mixing of gadolinium with iodine or saline and bolus tracking methods would decrease the total volume of contrast necessary without compromising the study. The recent developments in multi-detector row CT scan developments in DSCT and spectral for cardio-thoracic scanning will also provide better temporal resolution using contrast.

Figure 1: Explaining the difference between NSF and CI-AKI along with conclusion

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