Advances in Contrast Agents for Contrast-Enhanced Magnetic Resonance Imaging.

INTRODUCTION: Magnetic resonance imaging (MRI) is a well-established medical invention in modern medical technology diagnosis. It is a nondestructive, versatile, and sensitive technique with a high spatial resolution for medical diagnosis. However, MRI has some limitations in differentiating certain tissues, particularly tiny blood vessels, pathological to healthy tissues, specific tumors, and inflammatory conditions such as arthritis, atherosclerosis, and multiple sclerosis. The contrast agent (CA) assisted imaging is the best possible solution to resolve the limitations of MRI. METHOD: The literature review was carried out using the keywords, "MRI, T1&T2 relaxation, MRI CAs, delivery and adverse effects, classification of CAs." The tools used for the literature search were PubMed, Scopus, and Google Scholar. RESULT AND DISCUSSION: The literature findings focus on MRI technique, limitations, and possible solutions. Primarily, the review focuses on the mechanism of CAs in image formation with detailed explanations of T1 and T2 relaxations, the mechanism of the MRI-CA image formations. This review presents the adverse effects of CA as well as available marketed formulations and recent patents to extent complete information about the MRI-CA. CONCLUSION: MRI generates detailed visual information of various tissues with high resolution and contrast. The proton present in the biological fluid plays a crucial role in MR image formation, and it is unable to distinguish pathological conditions in many cases. The CAs are the best solution to resolve the limitation by interacting with native protons. The present review discusses the mechanism of CAs in contrast enhancement and its broad classification with the latest literature. Furthermore, the article presents information about CA biodistribution and adverse effects. The review concludes with an appropriate solution for adverse effects and presents the future prospective for researchers to develop advanced formulations.

Quercetin, a Promising Clinical Candidate for The Prevention of Contrast-Induced Nephropathy.

Iodinated contrast media (CM) are the leading cause of acute renal failure of toxic origin. Between 21% and 50% of patients that receive them develop contrast-induced nephropathy (CIN). All prophylactic measures used so far have failed to provide effective prevention. Since oxidative stress is involved in the damage, a possible preventive strategy could be the administration of antioxidant substances, such as quercetin. This compound has shown renoprotective effects in experimental studies. The aim of this study was to evaluate whether quercetin may be helpful in preventing CIN in patients undergoing coronary catheterization. A clinical phase II study was conducted. Patients were distributed in two groups, namely, CM (patients who only received contrast media) and CM+Q (patients who were pretreated with quercetin orally for 3-5 days). Results showed less incidence of CIN in the CM+Q group, possibly due to glomerular protection, evidenced by a lower increase in serum creatinine and albuminuria; and a lower decrease in the glomerular filtration rate (GFR). Furthermore, in this group, the relative risk of developing CIN observed in patients that received a high dose of contrast media was inferior. In conclusion, this is the first study that demonstrates that quercetin is a promising safe candidate in preventing CIN.

Molecular Photoacoustic Contrast Agents: Design Principles & Applications.

Photoacoustic imaging (PAI) is a rapidly growing field which offers high spatial resolution and high contrast for deep-tissue imaging in vivo. PAI is nonionizing and noninvasive and combines the optical resolution of fluorescence imaging with the spatial resolution of ultrasound imaging. In particular, the development of exogenous PA contrast agents has gained significant momentum of late with a vastly expanding complexity of dye materials under investigation ranging from small molecules to macromolecular proteins, polymeric and inorganic nanoparticles. The goal of this review is to survey the current state of the art in molecular photoacoustic contrast agents (MPACs) for applications in biomedical imaging. The fundamental design principles of MPACs are presented and a review of prior reports spanning from early-to-current literature is put forth.

The effect of major adverse renal cardiovascular event (MARCE) incidence, procedure volume, and unit cost on the hospital savings resulting from contrast media use in inpatient angioplasty.

OBJECTIVE: To determine the net economic impact of switching from low-osmolar contrast media (LOCM) to iso-osmolar contrast media (IOCM; iodixanol) in patients undergoing inpatient coronary or peripheral angioplasty in the United States (US). METHODS: A budget impact model (BIM) was developed from a hospital perspective. Nationally representative procedural and contrast media prevalence rates, along with MARCE (major adverse renal cardiovascular event) incidence and episode-related cost data were derived from Premier Hospital Data (October 2014 to September 2015). A previously estimated relative risk reduction in MARCE associated with IOCM usage (9.3%) was applied. The higher cost of IOCM was included when calculating the net impact estimates at the aggregate, hospital type, and per hospital levels. One-way (±25%) and probabilistic sensitivity analyses identified the model's most important inputs. RESULTS: Based on weighted analysis, 513,882 US inpatient angioplasties and 35,610 MARCE cases were estimated annually. Switching to an "IOCM only" strategy from a "LOCM only" strategy increases contrast media cost, but prevents 2,900 MARCE events. The annual budget impact was an estimated saving of $30.71 million, aggregated across all US hospitals, $6,316 per hospital, or $60 per procedure. Net savings were maintained across all univariate sensitivity analyses. While MARCE/event-free cost differential was the most important factor driving total net savings for hospitals in the Northeast and West, procedural volume was important in the Midwest and rural locations. CONCLUSIONS: Switching to an "IOCM only" strategy from a "LOCM only" approach yields substantial net global savings to hospitals, both at the national level and within hospital sub-groups. Hospital administrators should maintain awareness of the factors that are likely to be more influential for their hospital and recognize that purchasing on the basis of lower contrast media cost may result in higher overall costs for patients undergoing inpatient angioplasty.

Large abnormal peak on capillary zone electrophoresis due to contrast agent.

Background Some iodinated radio-contrast media absorb ultraviolet light and can therefore be detected by capillary zone electrophoresis. If seen, these peaks are typically small with 'quantifications' of below 5 g/L. Here, we describe the detection of a large peak on capillary zone electrophoresis that was due to the radio-contrast agent, Omnipaque™. Methods Serum from a patient was analysed by capillary zone electrophoresis, and the IgG, IgA, IgM and total protein concentrations were measured. The serum sample was further analysed by gel electrophoresis and immunofixation. Results Capillary zone electrophoresis results for the serum sample showed a large peak with a concentration high enough to warrant urgent investigation. However, careful interpretation alongside the serum immunoglobulin concentrations and total protein concentration showed that the abnormal peak was a pseudoparaprotein rather than a monoclonal immunoglobulin. This was confirmed by analysis with gel electrophoresis and also serum immunofixation. The patient had had a CT angiogram with the radio-contrast agent Omnipaque™; addition of Omnipaque™ to a normal serum sample gave a peak with comparable mobility to the pseudoparaprotein in the patient's serum. Conclusions Pseudoparaproteins can appear as a large band on capillary zone electrophoresis. This case highlights the importance of a laboratory process that detects significant electrophoretic abnormalities promptly and interprets them in the context of the immunoglobulin concentrations. This should avoid incorrect reporting of pseudoparaproteins which could result in the patient having unnecessary investigations.

Iodinated Contrast Media and the Alleged "Iodine Allergy": An Inexact Diagnosis Leading to Inferior Radiologic Management and Adverse Drug Reactions.

Purpose To test the hypothesis that the incomplete diagnosis "iodine allergy" is a possibly dangerous concept for patients under routine radiologic conditions. Materials and Methods 300 patients with a history of an "iodine allergy" were retrospectively screened and compared with two age-, sex-, and procedure-matched groups of patients either diagnosed with a nonspecific "iodine contrast medium (ICM) allergy" or an allergy to a specific ICM agent. For all groups, the clinical symptoms of the most recent past adverse drug reaction (ADR), prophylactic actions taken for subsequent imaging, and ultimate outcome were recorded and analyzed. Results The diagnosis "iodine allergy" was not otherwise specified in 84.3 % patients. For this group, in most cases, the symptoms of the previous ADRs were not documented. In contrast, the type of ADR was undocumented in only a minority of patients in the comparison groups. In the group of patients with an "iodine allergy" the percentage of unenhanced CT scans was greater than within the other two groups (36.7 % vs. 28.7 %/18.6 %). ADRs following prophylactic measures were only observed in the "iodine allergy" group (OR of 9.24 95 % CI 1.16 - 73.45; p < 0.04). Conclusion This data confirms the hypothesis that the diagnosis "iodine allergy" is potentially dangerous and results in uncertainty in clinical management and sometimes even ineffective prophylactic measures. Key points · The term "iodine allergy" is imprecise, because it designates allergies against different substance classes, such as disinfectants with complexed iodine and contrast media containing covalently bound iodine.. · There is a clear correlation between the exactness of the diagnosis - from the alleged "iodine allergy" to "contrast media allergy" to naming the exact culprit CM - and the quality of documentation of the symptoms.. · Management of patients diagnosed with "iodine allergy" was associated with uncertainty leading to unenhanced scans and sometimes unnecessary prophylactic actions.. · The term "iodine allergy" should be omitted, because it is potentially dangerous and can decrease the quality of radiology exams.. Citation Format · Böhm Ingrid, Nairz Knud, Morelli John N et al. Iodinated Contrast Media and the Alleged "Iodine Allergy": An Inexact Diagnosis Leading to Inferior Radiologic Management and Adverse Drug Reactions. Fortschr Röntgenstr 2017; 189: 326 - 332.

Stratified premedication strategy for the prevention of contrast media hypersensitivity in high-risk patients.

BACKGROUND: Although the severity of hypersensitivity reactions to iodinated contrast media varies, it is well correlated with the severity of recurrent reactions; however, prophylaxis protocols are not severity-stratified. OBJECTIVE: To assess the outcomes of tailored prophylaxis according to the severity of hypersensitivity reactions to iodinated contrast media. METHODS: Our premedication protocols were stratified based on the severity of previous reactions: (1) 4 mg of chlorpheniramine for mild reactions, (2) adding 40 mg of methylprednisolone for moderate reactions, and (3) adding multiple doses of 40 mg of methylprednisolone for severe index reactions. Cases of reexposure in patients with a history of hypersensitivity reactions were routinely monitored and mandatorily recorded. RESULTS: Among a total of 850 patients who underwent enhanced computed tomography after severity-tailored prophylaxis, breakthrough reactions occurred in 17.1%, but most breakthrough reactions (89.0%) were mild and did not require medical treatment. Additional corticosteroid use did not reduce the breakthrough reaction rate in cases with a mild index reaction (16.8% vs 17.2%, P = .70). However, underpremedication with a single dose of corticosteroid revealed significantly higher rates of breakthrough reaction than did double doses of corticosteroid in cases with a severe index reaction (55.6% vs 17.4%, P = .02). Changing the iodinated contrast media resulted in an additional reduction of the breakthrough reaction rate overall (14.9% vs 32.1%, P = .001). CONCLUSION: In a total severity-based stratified prophylaxis regimens and changing iodinated contrast media can be considered in patients with a history of previous hypersensitivity reaction to iodinated contrast media to reduce the risk of breakthrough reactions.

Contrast media use in patients with chronic kidney disease undergoing coronary angiography: A systematic review and meta-analysis of randomized trials.

BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CA), adequate hydration and minimizing volume of contrast media (CM) are class 1b recommendations for preventing contrast induced nephropathy (CIN). Current data are insufficient to justify specific recommendations about isoosmolar vs. low-osmolar contrast media by the ACCF/AHA/SCAI guidelines. METHODS: Randomized trials comparing IOCM to LOCM in CKD stage 3 and above patients undergoing CA, and reporting incidence of CIN (defined by a rise in creatinine of 25% from baseline) were included in the analysis. The secondary outcome of the study was the incidence of serum creatinine increase by >1mg/dl. RESULTS: A total of 2839 patients were included in 10 trials, in which 1430 patients received IOCM and 1393 received LOCM. When compared to LOCM, IOCM was not associated with significant benefit in preventing CIN (OR=0.72, [CI: 0.50-1.04], P=0.08, I2=59%). Subgroup analysis revealed non-significant difference in incidence of CIN based on baseline use of N-acetylcystine (NAC), diabetes status, ejection fraction, and whether percutaneous coronary intervention vs coronary angiography alone was performed. The difference between IOCM and LOCM was further attenuated when restricted to studies with larger sample size (>250 patients) (OR=0.93; [CI: 0.66-1.30]) or when compared with non-ionic LOCM (OR=0.79, [CI: 0.52-1.21]). CONCLUSION: In patients with CKD stage 3 and above undergoing coronary angiography, use of IOCM showed overall non-significant difference in incidence of CIN compared to LOCM. The difference was further attenuated when IOCM was compared with non-ionic LOCM.

MRI contrast agents: Classification and application (Review).

Magnetic resonance imaging (MRI) contrast agents are categorised according to the following specific features: chemical composition including the presence or absence of metal atoms, route of administration, magnetic properties, effect on the magnetic resonance image, biodistribution and imaging applications. The majority of these agents are either paramagnetic ion complexes or superparamagnetic magnetite particles and contain lanthanide elements such as gadolinium (Gd3+) or transition metal manganese (Mn2+). These elements shorten the T1 or T2 relaxation time, thereby causing increased signal intensity on T1-weighted images or reduced signal intensity on T2-weighted images. Most paramagnetic contrast agents are positive agents. These agents shorten the T1, so the enhanced parts appear bright on T1-weighted images. Dysprosium, superparamagnetic agents and ferromagnetic agents are negative contrast agents. The enhanced parts appear darker on T2-weighted images. MRI contrast agents incorporating chelating agents reduces storage in the human body, enhances excretion and reduces toxicity. MRI contrast agents may be administered orally or intravenously. According to biodistribution and applications, MRI contrast agents may be categorised into three types: extracellular fluid, blood pool and target/organ-specific agents. A number of contrast agents have been developed to selectively distinguish liver pathologies. Some agents are also capable of targeting other organs, inflammation as well as specific tumors.

[General adverse reactions to contrast agents. Classification and general concepts]. / Reacciones adversas generales a los contrastes. Clasificación y conceptos generales.

General adverse reactions to intravenous contrast agents are uncommon, although relevant due to the growing number of radiologic tests that use iodinated or gadolinium-based contrast agents. Although most of these reactions are mild, some patients can experience significant reactions that radiologists should know how to prevent and treat.

[Iodinated contrast agents used in Radiology]. / Contrastes yodados de utilización en Radiología.

Iodinated contrast media are widely used in Radiology practices with a very low rate of adverse effects, being contrast-induced nephropathy the most serious one. In the majority of cases it is temporary and reversible, even though it can increase the inhospital morbidity and mortality in patients with risk factors. We will describe the various measures of prevention, being hydration and use of non-ionic contrast low osmolality those which have demonstrated greater effectiveness. Precautions to be taken in some risk situations, as patients treated with metformin or with impaired renal function, are also discussed.

Hypersensitivity to contrast media and dyes.

This article updates current knowledge on hypersensitivity reactions to diagnostic contrast media and dyes. After application of a single iodinated radiocontrast medium (RCM), gadolinium-based contrast medium, fluorescein, or a blue dye, a hypersensitivity reaction is not a common finding; however, because of the high and still increasing frequency of those procedures, patients who have experienced severe reactions are nevertheless frequently encountered in allergy departments. Evidence on allergologic testing and management is best for iodinated RCM, limited for blue dyes, and insufficient for fluorescein. Skin tests can be helpful in the diagnosis of patients with hypersensitivity reactions to these compounds.

Magnetic resonance imaging using gadolinium-based contrast agents.

The purpose of this article was to review the basic properties of available gadolinium-based magnetic resonance contrast agents, discuss their fundamental differences, and explore common and evolving applications of gadolinium-based magnetic resonance contrast throughout the body excluding the central nervous system. A more specific aim of this article was to explore novel uses of these gadolinium-based contrast agents and applications where a particular agent has been demonstrated to behave differently or be better suited for certain applications than the other contrast agents in this class.

Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms.

In forensic pathology routine, fatal cases of contrast agent exposure can be occasionally encountered. In such situations, beyond the difficulties inherent in establishing the cause of death due to nonspecific or absent autopsy and histology findings as well as limited laboratory investigations, pathologists may face other problems in formulating exhaustive, complete reports, and conclusions that are scientifically accurate. Indeed, terminology concerning adverse drug reactions and allergy nomenclature is confusing. Some terms, still utilized in forensic and radiological reports, are outdated and should be avoided. Additionally, not all forensic pathologists master contrast material classification and pathogenesis of contrast agent reactions. We present a review of the literature covering allergic reactions to contrast material exposure in order to update used terminology, explain the pathophysiology, and list currently available laboratory investigations for diagnosis in the forensic setting.

Classification of structurally related commercial contrast media by near infrared spectroscopy.

Near infrared spectroscopy (NIRS) is a non-destructive measurement technique with broad application in pharmaceutical industry. Correct identification of pharmaceutical ingredients is an important task for quality control. Failure in this step can result in several adverse consequences, varied from economic loss to negative impact on patient safety. We have compared different methods in classification of a set of commercially available structurally related contrast media, Iodixanol (Visipaque(®)), Iohexol (Omnipaque(®)), Caldiamide Sodium and Gadodiamide (Omniscan(®)), by using NIR spectroscopy. The performance of classification models developed by soft independent modelling of class analogy (SIMCA), partial least squares discriminant analysis (PLS-DA) and Main and Interactions of Individual Principal Components Regression (MIPCR) were compared. Different variable selection methods were applied to optimize the classification models. Models developed by backward variable elimination partial least squares regression (BVE-PLS) and MIPCR were found to be most effective for classification of the set of contrast media. Below 1.5% of samples from the independent test set were not recognized by the BVE-PLS and MIPCR models, compared to up to 15% when models developed by other techniques were applied.

Au-Cu(2-x)Se heterodimer nanoparticles with broad localized surface plasmon resonance as contrast agents for deep tissue imaging.

We report a new type of heterogeneous nanoparticles (NPs) composed of a heavily doped semiconductor domain (Cu2-xSe) and a metal domain (Au), which exhibit a broad localized surface plasmon resonance (LSPR) across visible and near-infrared (NIR) wavelengths, arising from interactions between the two nanocrystal domains. We demonstrate both in vivo photoacoustic imaging and in vitro dark field imaging, using the broad LSPR in Cu2-xSe-Au hybrid NPs to achieve contrast at different wavelengths. The high photoacoustic imaging depth achieved, up to 17 mm, shows that these novel contrast agents could be clinically relevant. More broadly, this work demonstrates a new strategy for tuning LSPR absorbance by engineering the density of free charge carriers in two interacting domains.

[Prevention of contrast-induced nephropathy in the context of evidence-based medicine].

The paper considers the mechanisms of development of contrast-induced nephropathy in the use of iodinated radiopaque contrast agents (RCAs), as well as the criteria of their assessment. It gives different existing recommendations for prevention of the nephrotoxic effects of RCAs.

Nephrogenic systemic fibrosis.

OBJECTIVE: The purpose of this article is to discuss nephrogenic systemic fibrosis (NSF) in detail regarding its history, possible pathophysiology, clinical and pathologic presentations, diagnosis, and implications for the radiology community. CONCLUSION: NSF is a potentially lethal disorder that occurs in patients with reduced kidney function. Current evidence suggests a strong association with gadolinium-based contrast agents--mostly used in MRI--in this patient group. This has urged the radiology community to emphasize careful screening for the presence of renal dysfunction among patients for whom gadolinium-enhanced MRI is contemplated. Appropriate selection of gadolinium-based contrast agent type, avoidance of nonstandard dosage, patient education, and informed consent have been recommended by authorities.

Assessment of neovascular permeability in a pancreatic tumor model using dynamic contrast-enhanced (DCE) MRI with contrast agents of different molecular weights.

OBJECT: We evaluated the relationship of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters and contrast agents with different molecular weights (MW) in a pancreatic tumor mouse model. MATERIALS AND METHODS: Panc02 tumors were induced in mice at the hind leg. DCE-MRI was performed using Gadolinium (Gd)-based contrast agents with different MW: Gd-DOTA (0.5 kDa), P846 (3.5 kDa), and P792 (6.47 kDa). Quantitative vascular parameters (AUC, K(trans), V(e), and V(p)) were calculated according to a modified Tofts two-compartment model. Values for all contrast groups were compared for tumor and control (muscle) tissues. RESULTS: Values for K(trans) and V(e) were significantly higher in tumor tissue than in muscle tissue. When comparing contrast agents, lowest absolute K(trans) values were observed using P792. The relative increase in K(trans) in tumor tissue compared with normal tissue was highest after the use of P792. In both tumor and normal tissues, K(trans) decreased with increasing molecular weight of the contrast agent used. CONCLUSION: It was demonstrated that values for the different DCE-MRI vascular (permeability) parameters are highly dependent on the contrast agent used. Due to their potential to better differentiate tumor from muscle tissue, higher molecular weight contrast agents show promise when evaluating tumors using DCE-MRI.

T2 exchange agents: a new class of paramagnetic MRI contrast agent that shortens water T2 by chemical exchange rather than relaxation.

Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T(2) of bulk water protons. The magnitude of the line-broadening T(2) exchange (T(2exch)) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T(2exch) contribution to the water linewidth was initially observed in experiments involving Eu(3+)-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu(3+) complexes having water exchange rates ranging from zero (no exchange) to 5 × 10(6) s(-1) (fast exchange) were performed. The results showed that the exchange relaxivity (r(2exch)) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T(2exch) agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes.