Contrast-enhanced voiding urosonography in the assessment of vesical-ureteral reflux: the time has come.

Vesicoureteral reflux (VUR) is a pathological condition contradistinguished by monolateral or bilateral retrograde flow of urine from the bladder to the ureter and to the kidney. If not properly recognized and treated, VUR can potentially be associated to several complications such as recurrent infections and possible secondary scars with Chronic Kidney Disease (CKD). Furthermore, it represents an important risk factor for nephrovascular hypertension. During the last 20 years, the diagnostic approach to this entity has passed through several, drastic changes: indeed, since its introduction in 1994 contrast-enhanced voiding urosonography (ceVUS) has gradually accompanied the voiding cystourethrography (VCUG) as alternative imaging technique for the diagnosis and staging of VUR. Despite a large number of papers has strongly encouraged its use in clinical practice, due to the lack of ionizing radiations and its high sensitivity rate, to date almost all the guidelines only include the VCUG for VUR diagnosis. The introduction of technologically advanced US software and the approval of the intravesical administration of ultrasound contrast agents by the Food and Drug Administration (FDA) and by the European Medicine Agency (EMA) have to induce the Scientific Community to a deep revaluation of the role of ceVUS in the diagnosis and follow-up of VUR: urosonography might extensively replace VCUG as the reference method, reserving to cystourethrography a role in the most complex anatomic settings for pre-surgical evaluation.

Emergency and critical care applications for contrast-enhanced ultrasound.

INTRODUCTION: Contrast-enhanced ultrasound (CEUS) using intravascular microbubbles has potential to revolutionize point-of-care ultrasonography by expanding the use of ultrasonography into clinical scenarios previously reserved for computed tomography (CT), magnetic resonance imaging, or angiography. METHODS: We performed a literature search and report clinical experience to provide an introduction to CEUS and describe its current applications for point-of-care indications. RESULTS: The uses of CEUS include several applications highly relevant for emergency medicine, such as solid-organ injuries, actively bleeding hematomas, or abdominal aortic aneurysms. Compared with CT as the preeminent advanced imaging modality in the emergency department, CEUS is low cost, radiation sparing, repeatable, and readily available. It does not require sedation, preprocedural laboratory assessment, or transportation to the radiology suite. CONCLUSIONS: CEUS is a promising imaging technique for point-of-care applications in pediatric and adult patients and can be applied for patients with allergy to CT contrast medium or with impaired renal function. More high-quality CEUS research focusing on accuracy, patient safety, health care costs, and throughput times is needed to validate its use in emergency and critical care settings.

The effect of aspirated barium sulfate, iodixanol, and diatrizoic acid on survival and lung injury in a lagomorph model.

OBJECTIVES/HYPOTHESIS: Contrast agents are an integral component of the video fluoroscopic swallow study. Agents commonly used include barium sulfate (E-Z Paque), iodixanol (Visipaque), and diatrizoic acid (Gastrografin). Barium is water insoluble, whereas iodixanol and diatrizoic acid are water-soluble iodine-based agents. The detrimental effect of these agents on the lungs has not been systematically evaluated. Our aim was to evaluate and compare the effects of aspirated barium, iodixanol, and diatrizoic acid on pulmonary injury in a lagomorph model. STUDY DESIGN: Animal model. METHODS: Twenty adult male New Zealand White rabbits were divided into four groups (n = 5). Group 1 received 3 mL of barium sulfate injected into the trachea for 3 consecutive days. Group 2 received 3 mL of iodixanol injected into the trachea for 3 consecutive days. Group 3 received 3 mL of diatrizoic acid injected into the trachea for 3 consecutive days. A control group received 3 mL of air injected into the trachea under an identical protocol. All animals were euthanized on day 4, and the lung and trachea were harvested for blinded histopathologic analysis. The primary outcome measure was survival. The secondary endpoint was a blinded, histologic grading system of lung injury. RESULTS: Two animals in the barium group, one in the diatrizoic acid group, and 0 animals in the iodixanol and control groups died. The overall lung injury score for the barium (60.60 ± 6.34) and iodixanol groups (52.30 ± 3.11) were significantly higher (worse) than the diatrizoic acid (49.60 ± 7.64) and control groups (37.80 ± 3.56) (P < .05). Diatrizoic acid produced the least amount of lung injury. CONCLUSIONS: The data suggest that 3 mL of aspirated barium sulfate (E-Z Paque) over 3 consecutive days causes more severe lung injury in a lagomorph model than 3 mL of aspirated iodixanol (Visipaque) and diatrizoic acid (Gastrografin). Diatrizoic acid caused the least histologic evidence of lung injury. LEVEL OF EVIDENCE: NA Laryngoscope, 127:E148-E152, 2017.

Presumed Gadolinium Toxicity in Subjects With Normal Renal Function: A Report of 4 Cases.

OBJECTIVE: The aim of this study was to examine and report 4 patients who developed symptomatology shortly after gadolinium-based contrast agent (GBCA) administration. MATERIALS AND METHODS: History taking and targeted physical examination were performed on 4 subjects who reported development of new disease features within hours to 4 weeks of having received an intravenous administration of GBCA. RESULTS: Two subjects were assessed at 2 months (patient P2mo) and at 3 months (patient P3mo) after GBCA administration (early stage), and 2 subjects were assessed at 7 years (patient P7yr) and 8 years (patient P8yr) after having received GBCA administration (late stage). Clinical features were similar between subjects, and included central torso pain (all), peripheral arm and leg pain (all), clouded mentation (n = 2), and distal arm and leg skin thickening and rubbery subcutaneous tissue (one early and both late subjects). Gadolinium was detected as follows: in a 24-hour urine specimen, 1 month after disease development (18 µg/24 hours and 82 µg/24 hours in patients P2mo and P3mo, respectively); hair (0.0007 µg/g) and urine (0.0644 µg/g) samples, 7 years after disease development (late stage, patient P7yr); and saphenous vein sample, 8 years after disease development (0.27 ± 0.007 ng/62 mg sample) (late stage, patient P8yr). CONCLUSIONS: Gadolinium toxicity may occur in subjects with normal renal function. Central torso and peripheral arm and leg distribution pain were common features. Distal arm and leg skin thickening and rubbery subcutaneous tissue were seen in late stages. Clouded mentation is also common. Vigilance to identify additional cases and investigate strategies for prevention and treatment is warranted to increase even further the safety of a very safe diagnostic procedure, GBCA-enhanced magnetic resonance imaging.

Self-reported gadolinium toxicity: A survey of patients with chronic symptoms.

PURPOSE: This study aims to describe the self-reporting symptoms experienced by individuals with self-reported normal renal function after gadolinium based contrast agent (GBCA) administration. MATERIALS AND METHODS: This HIPAA-compliant, IRB-approved study consisted of an anonymous online survey of patients who believe that they suffer from gadolinium toxicity. 50 respondents completed the nine-question survey. RESULTS: Fifty (100%) of the subjects ascribed their complaints to gadolinium exposure. Thirty-three (66%) described the onset immediately following GBCA administration and 16 (32%) within 6weeks. The most common symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change (77.6% each). Other symptoms occurred with lesser incidence. CONCLUSIONS: This survey represents an initial description of patients with normal renal function who self-described toxicity related to GBCA administration. Bone and joint complaints and skin changes are two of the most common complaints.

A low incidence of iodine-induced hyperthyroidism following administration of iodinated contrast in an iodine-deficient region.

OBJECTIVE: There are limited data on the incidence of iodinated contrast-induced thyrotoxicosis, particularly in iodine-deficient regions. The aim of this study was to determine the incidence of iodinated contrast-induced thyrotoxicosis and to determine whether thyrotoxicosis was more common in patients ≥70 years compared to those <70 years of age. DESIGN: A prospective study of adult patients undergoing an outpatient CT with iodinated contrast was performed. MEASUREMENTS: Thyroid function tests (TFTs) and urine iodine measurements were performed prior to the scan. TFTs were repeated at 4- and 8-weeks postscan. Changes in TFTs from baseline were analysed. RESULTS: A total of 102 patients were included in the final analysis. Overall, TSH levels dropped (P = 0·0002), and free T3 (FT3 ) levels increased (P = 0·04) between baseline and week 4 with normalization by week 8; however, these changes were not considered clinically significant. No significant differences in free T4 (FT4 ) occurred in the overall group (P = 0·82). There were no differences in TFTs between baseline and 4 or 8 weeks for those patients aged <70 compared to ≥70 years. Two patients developed new subnormal TSH values. Of these, one had a 90-mm follicular variant papillary thyroid carcinoma diagnosed while the other had a normal thyroid assessment and TSH spontaneously normalized by 12 weeks. CONCLUSIONS: Only 2% of patients developed subclinical hyperthyroidism following a standard dose of iodinated contrast for CT investigations. Given the low incidence of iodine-induced thyrotoxicosis, there is no indication for routine pre- and post-CT thyroid function testing in our region.

alpha2-Adrenergic agonists protect against radiocontrast-induced nephropathy in mice.

Radiocontrast nephropathy (RCN) is a common clinical problem for which there is no effective therapy. Utilizing a murine model, we tested the hypothesis that alpha(2)-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective alpha(2)-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. alpha(2)-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid ( approximately 90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular alpha(2)-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but alpha(2)-agonists failed to preserve the viability of both cell types. We conclude that alpha(2)-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As alpha(2)-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.

Barium toxicity after exposure to contaminated contrast solution--Goias State, Brazil, 2003.

Barium-containing contrast solutions are commonly used in radiologic studies. On May 22, 2003, three patients at radiology clinics in Goias State, Brazil, were hospitalized after ingesting such solutions; two persons died within 24 hours of hospitalization. Exposure occurred during radiologic examination of the upper or lower gastrointestinal tract. An investigation was conducted by municipal and state public health authorities with assistance from the Ministry of Health's National Agency for Sanitary Surveillance (ANVISA) and Brazil's Field Epidemiology Training Program (FETP), known locally as EPISUS. This report summarizes the results of that investigation, which found that 44 persons had suspected barium toxicity, nine of whom died. Eight of the nine deaths were linked to a single lot of brand A contrast solution. A national recall was announced on May 23, and the manufacturing facility was inspected and closed. Clinicians should be alert for signs of barium toxicity in patients in the hours after administration of contrast solutions during radiologic studies.

Diagnostic use of physicians' detection of urine fluorescence in a simulated ingestion of sodium fluorescein-containing antifreeze.

STUDY OBJECTIVE: We sought to assess physicians' ability to accurately determine the presence or absence of sodium fluorescein (SF) in urine at a concentration corresponding to that present after ingestion of a toxic amount of commercial automotive antifreeze. METHODS: We studied 2 different urine specimen evaluation formats--one presenting isolated specimens, and the other presenting specimens grouped for comparison--to determine whether the visual clues afforded by grouped comparison aided the accuracy of the evaluation. On each study day, 3 urine specimens (1 control specimen obtained before SF administration and 2 specimens obtained after SF administration) were obtained from each of 9 or 10 volunteers. Each of these 27 or 30 urine specimens were presented sequentially and in random order to 2 emergency physicians during separate evaluation time periods. Each physician was asked to classify each specimen as fluorescent or nonfluorescent (sequential format). After a rest period, each physician, again separately, was asked to look at the same 27 or 30 urine specimens, this time all together in a test tube rack so that grouped comparisons were possible. The physicians again classified each sample as either fluorescent or nonfluorescent (grouped format). We assessed sensitivity, specificity, and accuracy of the evaluation by each presentation format (sequential or grouped). RESULTS: Mean examiner sensitivity, specificity, and accuracy for detecting the presence of SF in urine using the sequential presentation format were 35%, 75%, and 48%, respectively, whereas the same test performance indices were 42%, 66%, and 50%, respectively, when the grouped format was used. CONCLUSION: Wood's lamp determination of urine fluorescence is of limited diagnostic utility in the detection of SF ingestion in an amount equivalent to toxic ingestion of some ethylene glycol--containing automotive antifreeze products.

Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism.

BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.

Comparative cytotoxicity of ionic and non-ionic radiocontrast agents on MDCK cell monolayers in vitro.

BACKGROUND: Intravascular radiocontrast agents may cause acute renal failure, particularly in patients with pre-existing renal insufficiency. Direct cytotoxic effects of radiocontrast agents on renal tubular cells may contribute to the pathogenesis of radiocontrast-induced nephropathy. METHODS: We analysed the cytotoxicity of the ionic radiocontrast agents diatrizoate (monomeric) and ioxaglate (dimeric), as well as of the non-ionic radiocontrast agents iohexol (monomeric) and iodixanol (dimeric) on the renal epithelial Madin Darby Canine Kidney (MDCK) cell line grown on permeable supports. The toxicity assays assessed cell viability, transmonolayer resistance and inulin permeability between the apical and basal cell culture compartment. In addition, the distribution of the tight-junction-associated membrane proteins ZO-1 and occludin was analysed using immunofluorescence microscopy. RESULTS: In all assays the high osmolal ionic compound diatrizoate had significant cytotoxic effects that included the partial redistribution of the tight-junction-associated membrane proteins into a cytoplasmic compartment. To a lesser extent this redistribution also occurred with the dimeric ionic compound ioxaglate, but not with the non-ionic radiocontrast agents. With regards to cell viability, transmonolayer resistance and inulin permeability the radiocontrast agents with reduced osmolality were significantly less toxic than diatrizoate, independent of their ionic strength. CONCLUSIONS: Physicochemical factors contribute to the cytotoxicity of radiocontrast agents in vitro. The redistribution of tight-junction-associated membrane proteins by the ionic radiocontrast agents corresponds with the loss of the barrier function of the epithelial cell monolayer, which is a major pathophysiological mechanism in acute renal failure. The radiocontrast agents with reduced osmolality are less cytotoxic than diatrizoate, independent of their ionicity. Hyperosmolality appears to be a more important determinant of the cytotoxicity of diatrizoate than ionic strength.

Fatal poisoning due to intravasation after oral administration of barium sulfate for contrast radiography.

A fatal poisoning after oral administration of barium sulfate for contrast radiography is reported. Barium sulfate is an insoluble salt and therefore is almost nontoxic. The case described here involves a 61-year-old woman who underwent two CT scans of the digestive tract with oral administration of barium sulfate during a surgical procedure. Within several hours after the first barium swallow examination the patient presented nonspecific neurologic and cardiovascular manifestations that rapidly progressed and led to death a few days later. Laboratory findings demonstrated elevated levels of barium in the blood and cerebrospinal fluid. The most likely mechanism of poisoning was progressive intravasation of barium due to stasis of contrast material related to intestinal obstruction.

Fatal ascending tonic-clonic seizure syndrome.

A fatal case of ascending tonic-clonic seizure (ATCS) syndrome resulted from the inadvertent, unrecognized use of a hyperosmolar ionic contrast agent during myelography. The patient presented with lower-extremity myoclonic jerking, agitation, hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation. Emergency physicians must be cognizant of this unique toxidrome to initiate early, aggressive care.