Miscellaneous adverse effects of low-versus high-osmolality contrast media: a study revised.

The authors analyzed data from two recent articles in Radiology in which the quality and results of randomized control trials (RCTs) comparing the efficacy or safety of the low-osmolality contrast media (LOM) iopamidol, iohexol, and ioxaglate with that of the high-osmolarity contrast media (HOM) diatrizoate, iodamide, iopamide, iothalamate, and metrizoate were assessed. One conclusion in the source articles was that no differences were seen between the two groups of contrast media in frequency of nausea, vomiting, and urticaria. However, the LOM group included both nonionic LOM (NIM) and the ionic contrast medium ioxaglate. The authors found that various complications associated with the use of contrast media were much less common with NIM than with HOM; statistically this lower frequency is highly significant. This difference was obscured in the previous studies by the pooling of RCTs in which the less toxic NIM were used and RCTs in which the more toxic ionic contrast medium ioxaglate was used.     

Quality assessment of randomized controlled trials of contrast media

Numerous randomized controlled trials (RCTs) have been conducted to define the relative benefits of low-osmolality contrast media (LOM) and high-osmolality contrast media (HOM). Because of the clinical and economic significance of the conclusions drawn from these RCTs, the authors used a standardized instrument to evaluate the quality of study design and data analysis of 100 RCTs published between 1982 and 1987 that compared LOM and HOM. The mean quality score (+/- standard deviation) was 39 +/- 12 (maximum possible score, 100). The largest number of patients studied in any RCT was 435; the smallest was five. A majority of the RCTs received high scores on three attributes of quality, intermediate scores on seven, and low scores on nine. These results underscore the difficulty of designing, performing, analyzing, and reporting high-quality RCTs. Nevertheless, limitations in study design and data analysis need to be considered when interpreting results of these RCTs. Future RCTs comparing LOM and HOM should be performed with greater attention to basic elements of good study design and data analysis.     

Contrast medium-induced adverse reactions: economic outcome

Because the cost of managing an expected greater number of adverse reactions when high-osmolality contrast media (HOM) are used could offset the higher material cost of low-osmolality contrast media (LOM), a prospective study was done of 795 inpatients undergoing any of four procedures involving intravascular injection of HOM: cardiac catheterization, peripheral angiography, head computed tomography (CT), or body CT. The resources used in managing HOM-induced adverse reactions were measured, and the costs of these resources were estimated. Four hundred five patients (51%) had adverse reactions. Reactions were grouped into three classes according to their severity. Class 1 (mild) reactions occurred in 358 patients (45%), class 2 (moderate) reactions occurred in 44 patients (6%), and class 3 (severe) reactions occurred in three patients (0.4%). Ninety-nine patients (12%) consumed resources as a result of an adverse reaction. The average cost of these resources per patient undergoing examination was $1.07 to the radiology department, $5.83 to the hospital, and $12.93 to a charge-paying insurer. Mean (+/- standard deviation) cost to the hospital for managing class 1, class 2, and class 3 reactions were $2.52 +/- $5.33, $24 +/- $54, and $910 +/- $749, respectively. By comparison, the difference in material cost of HOM versus LOM ranged from $93 for body CT to $179 for cardiac catheterization. Even if LOM were to induce no adverse reactions, the increased material cost associated with universal substitution of LOM for HOM would be greater than the expected cost of managing adverse reactions when HOM are used.     

Radiocontrast-associated renal dysfunction: a comparison of lower-osmolality and conventional high-osmolality contrast media

Nephropathy is an established untoward event associated with intravascular administration of conventional high-osmolality contrast media (HOM). It has not been shown previously that lower-osmolality contrast media (LOM) are less nephrotoxic in a clinical setting. We evaluate the ability to replace HOM with LOM (in lower-extremity angiography) to reduce the incidence of nephropathy. We use multiple definitions for contrast-induced nephropathy (six different magnitudes of rise of serum levels of creatinine or blood urea nitrogen in various periods). The incidences of nephrotoxic effects with LOM vs HOM in patients with presumed risk factors, including preexisting renal insufficiency and diabetes, are evaluated also. When all patients are considered, the incidence of contrast-induced nephropathy for LOM vs HOM (defined as an increase in serum creatinine level greater than 0.3 mg/dl and greater than 20% on day 1, 2, or 3 and on day 5, 6, or 7, is 7% vs 26% (p = .001). When only patients with preangiography azotemia are considered, the incidence of contrast-induced nephropathy for LOM vs HOM is 10% vs 41% (p = .017); for diabetic patients, regardless of preangiography creatinine level, the incidence is 10% vs 31% (p = .012). Although contrast-induced nephropathy may develop even in a patient with no risk factors who receives LOM, LOM is associated with a decreased incidence of this condition, to various degrees, depending on the presence of risk factors.     

Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.

The comparative frequency of and risk factors for nephrotoxicity with low-osmolality contrast medium (LOM) versus high-osmolality contrast medium (HOM) were investigated. A randomized, double-blind clinical trial was conducted in patients undergoing diagnostic angiocardiography (n = 430) or contrast material-enhanced body computed tomography (CT) (n = 499). Nephrotoxicity was defined as an increase in serum creatinine level that was greater than both 33% and 0.4 mg/dL (40 mumols/L) above the baseline level within 48 hours after the radiologic procedure. The frequency of nephrotoxicity was similar in patients who received LOM versus those who received HOM: 13 of 479 (2.7%) versus 13 of 450 (2.9%), respectively (P = .87), overall; 4.4% versus 4.0% in angiocardiography patients (P = .84); and 1.2% versus 2.0% in body CT patients (P = .35). Factors associated (P less than .05) with increased risk of nephrotoxicity were insulin-dependent diabetes, baseline serum creatinine level greater than 1.5 mg/dL (130 mumols/L), concurrent use of furosemide, and angiocardiographic examination. Patients who have preexisting renal insufficiency may be at higher risk for nephrotoxicity with HOM than with LOM.     

The significance of 'no significant difference'

It is generally accepted that patients experience less discomfort with low osmolality contrast media (LOM) than with high osmolar media (HOM). Hard statistical facts from so called 'high quality' controlled trials, proving that more significant reactions such as vomiting, hives, urticaria or anaphylactic complications also are less common with LOM are, however, not readily available (3). One reason for this may be that most of the well designed controlled studies performed may have been tailored by the drug manufacturer for a specific purpose: to fulfil the format requirements for registration by the licensing governmental authorities. For this the sponsor, to save time, usually engages several medical centres, each only performing 15 to 60 studies (4). Materials of such a size are of course much too small to reveal any change in the frequency of a complication occurring with an incidence of only a few per cent or less. The absence of a statistically significant difference in such low incidences of complications does not justify any conclusion. The question then arises: how big a material would be needed to obtain a fair chance to statistically verify a clinically highly important decrease in the incidence of a complication from, for instance, 10 to 5 per cent? This paper deals with such questions.     

Trends in adverse events after IV administration of contrast media

OBJECTIVE: Data collected from 1985 to 1999 on adverse events after the IV administration of contrast media were evaluated to identify trends. MATERIALS AND METHODS: Data collected on 391 adverse events after 90,473 administrations of iodinated contrast media and 19 events after 28,340 administrations of gadolinium were evaluated. Reactions were graded as mild, moderate, or severe. Data were also collected regarding contrast extravasation. RESULTS: When only ionic iodinated contrast material was used, the adverse reaction rate was 6-8%. With the selective use of contrast material, the adverse reaction rate was 0.6% and 0.7%, respectively, for ionic and nonionic agents. The rate decreased to 0.2% with the universal use of nonionic agents. More than 90% of adverse reactions were allergic-like. Seven severe reactions (0.05%) and no deaths occurred in the ionic group. During the selective use period, one death occurred in the nonionic group. No severe reactions or deaths occurred during the first 5 years of universal nonionic use. Since then, 10 severe reactions (0.02%) and one death have occurred. Seven reactions occurred in patients after helical CT angiography. The extravasation rate for iodinated contrast material has remained constant at 0.3-0.4% annually. The adverse reaction rate to gadolinium contrast material was 0.06%. CONCLUSION: Mild and moderate adverse events are more common with ionic contrast material than with nonionic. Most reactions are allergic-like. Severe reactions are seen equally with ionic and nonionic contrast material but differ in type. The reactions were allergic-like in the ionic group but were predominantly attributable to cardiopulmonary decompensation in the nonionic group. Helical CT angiography may play a role in reactions.     

国产非离子型对比剂碘佛醇安全性的临床研究

目的 研究国产非离子型对比剂碘佛醇的安全性. 资料与方法 对随机抽取的159例腹部增强CT检查资料进行分析,对比剂注射流率3～6 ml/s,剂量为80～100 ml.全部病例增强前2 h内、增强后即时、1 h、48 h分别进行生命体征、12导联心电图及注射部位观察,于增强前2 h内与增强后48 h分别抽血检测肾功能与血液生化指标,并于增强时、增强后即时、5～15 min、1 h与48 h分别观察与记录不良反应. 结果 159例患者注射对比剂后出现热感和潮红者占8.8%(14/159);轻度不良反应发生率为1.26%(2/159).未见中、重度不良反应出现. 结论 国产非离子型对比剂碘佛醇临床应用的安全性较高.     

Long-term results using a nonionic contrast medium--a report of clinical experiences

Between January 1982 and May 1986 more than 50,000 patients were examined radiologically with water-soluble (ionic and nonionic) contrast media at the Department of Radiology Rudolfsstiftung, Vienna. In 1983 only 2.2% of the contrast agents used were nonionic, in 1985 the share had increased to 53.3%. During this period the rate of drug-related side effects (DRSE) decreased from 6.9% (1983) to 3.3% (1985). From 1983 to 1985 DRSE were observed with 1952 patients after administration of ionic agents, whereas after application of nonionic media adverse reactions occurred in only 6 cases, so that DRSE rates of 6.98% respectively 0.07% resulted for ionic respectively nonionic contrast media. These results are discussed with regard to the physicochemical properties und physiological actions of ionic and nonionic contrast agents.     

A comparison of iopamidol and ioxaglate in CT enhancement

We evaluated the adverse reactions (AR) rate produced in patients to see if any difference related to the diferent chemotoxicities of two low-osmolality contrast media (CM), could be detected. We compared the AR rate intravenous administration for brain or body computed tomography (CT) enhancement of either the ionic CM ioxaglate 320 mgI/ml or the non-ionic iopamidol 300 mgI/ml at a dose of 0.8 gI/kg. Three hundred and thirty patients (164 ioxaglate, 166 iopamidol) were studied according to a randomized double-blind design. AR reported by the patients (subjective) and/or observed by the radiologist (objective) were recorded by the radiologist on the patients record card. Laboratory test were performed prior to and 24 h after contrast administration.Fifty-nine mild to moderate AR occurred in 30 patients (18.3%) receiving ioxaglate, 4 mild to moderate AR occurred in 2 patients (1.2%) receiving iopamidol (P < 0.05). No severe AR occurred in either group.The results of our study are comparative to the available evidence from 16 comparative randomized trials of iopamidol versus ioxaglate both after intraarterial and intravenous administration that gave an overall odds ratio of 3.9 [confidence interval (CI) 95% = 3.1–4.9].The diagnostic efficacy of the two CM was comparable. This study showed that the non-ionic CM iopamidol was better tolerated than the ionic ioxaglate after intravenous administration. We conclude that the chemotoxicity of the molecule influences the AR when CM with comparable osmolality are administered. Correspondence to: Carlo Del Favero     

Breakthrough adverse reactions to low-osmolar contrast media after steroid premedication

OBJECTIVE: The purpose of this study was to review the nature of adverse reactions, or "breakthrough reactions," experienced by patients who received steroid premedication and low-osmolar contrast media. We compared the demographics of patients having these breakthrough reactions with those of patients who did not develop these reactions. MATERIALS AND METHODS: We retrospectively reviewed our radiology quality improvement database to identify patients with breakthrough reactions that occurred from January 1, 1994, through October 1, 1999, and we reviewed their medical records. We compared these patients with a control cohort of patients who had a history of prior adverse reaction to contrast media but no breakthrough reaction after administration of low-osmolar contrast media and premedication with corticosteroids. RESULTS: Over the 6-year period, 52 patients experienced 61 breakthrough reactions. The breakthrough reaction was mild in 76% of the patients. The breakthrough reaction was similar to the patient's initial adverse reaction in 85% of the patients. A history of seafood allergy or hay fever was statistically more likely to be identified in the breakthrough group than the control group. CONCLUSION: Breakthrough reactions occur in a substantial number of patients despite premedication with steroids and use of low-osmolar contrast agents. Typically the breakthrough reaction is of similar severity to the patient's initial reaction. Severe or life-threatening reactions are seen in 24% of patients.     

A double-blind,comparative study of gadodiamide injection and gadopentetate dimeglumine in MRI of the central nervous system

Summary Seventy-nine patients with known or suspected central nervous system lesions were studied with MRI in a phase III double-blind study. Forty were given gadopentetate dimeglumine (Gd-DTPA) and 39 gadodiamide injection (Gd-DTPA BMA), a new low-osmolar nonionic contrast enhancing medium. The dosage was 0.1 mmol/kg body weight, corresponding to 0.2 ml/kg. Spin-echo sequences were performed before and immediately after injection. The safety and efficacy of the two contrast media were assessed. No changes were observed in blood pressure, heart rate or neurological status. Five adverse effects (two episodes of headaches, two of nausea and one of dizziness) were reported by 2 patients who received gadodiamide injection and 1 who received gadopentetate dimeglumine. All events were mild and their relationship to the contrast media was uncertain. For both contrast media statistically significant changes in serum iron were observed 24 h after injection. More than 70% of the patients had abnormal findings on MRI, and in 56% of these contrast enhancement of the abnormal structure or lesion was seen. Contrast enhancement provided the diagnosis in about 50%, changed it in 40% and increased diagnostic confidence in 95%.     

Intravenous urography with a new non-ionic contrast media in a clinical phase III study: iopentol vs iohexol

The safety and diagnostic efficacy of iopentol 300 mg I/ml were compared with iohexol 300 mg I/ml in 300 patients submitted for urography. The study was carried out as a double-blind, randomised parallel study where 149 patients received iopentol and 150 patients iohexol. There were no significant differences between the patients receiving the two contrast media with regard to demographic parameters, rate of injection or total dose of injected contrast media. No changes in blood pressure and no clinically important changes in heart rate were detected in the two groups. No serious adverse effects occurred. Seven patients (5%) in the iohexol and 12 patients (8%) in the iopentol group experienced adverse effects other than a sensation of warmth. Fourteen iohexol patients (9%) and 18 iopentol patients (12%) experienced warmth related to the contrast injection. Excellent films were obtained in most patients and no difference in diagnostic quality between iopentol and iohexol was observed.     

Efficacy and safety of digital subtraction angiography with special reference to contrast agents

We evaluated the diagnostic accuracy and complications of digital subtraction angiography (DSA) in a series of clinical trials conducted on patients primarily with cerebral vascular disease and those evaluated before and after surgery or percutaneous transluminal angioplasty. Double-blind studies of the carotid-vertebral arteries of 300 of the 2,200 patients using DSA imaging and a variety of ionic and nonionic contrast agents showed that although subjects tolerated the injection of nonionic contrast better than ionic, nonionic contrast administration did not lead to better image quality. Of 764 patients receiving ionic contrast media, 3.3% had mild-to-serve adverse reactions; of 350 injected with nonionic contrast agents, 1.7% had mild-to-severe adverse reactions. If the sole consideration is safety, use of ionic contrast media is justified.     

Safety and tolerability of iodixanol in healthy volunteers with reference to two monomeric X-ray contrast media.

The low osmolar, non-ionic X-ray contrast media have shown a lower frequency of adverse events than the older ionic ones. In this study changes in routine clinical-chemical parameters in blood and urine, vital signs and adverse events were recorded in six groups of 10 healthy male volunteers receiving either iodixanol, a new non-ionic, dimeric X-ray contrast medium for general vascular use, or one of the two non-ionic, monomeric contrast media iopentol and iopamidol. Minor decreases were observed in the values for haemoglobin, haematocrit and erythrocytes 5 min and 3 days after injection of iodixanol. A minor increase was seen in platelets and total protein after 3 days. A transient increase in serum osmolality was seen 5 min after the injections of iopentol and iopamidol. This was not seen in any iodixanol group. The level of thyrotropin showed an increase in all groups at 3 days. It was back to normal within 21 days. No changes of clinical importance were seen regarding blood pressure, heart rate or ECG in any volunteer. No severe adverse events were reported. All events were of short duration, and of mild or moderate intensity. The results, however, may indicate a lower frequency of adverse events/discomfort after the administration of the dimeric iodixanol than the 2 monomeric contrast media iopentol and iopamidol.     

Iohexol and ioxaglate in peripheral angiography

A double-blind, cross-over trial of the non-ionic, low-osmolar contrast medium iohexol (Omnipaque) and the ionic, low-osmolar medium ioxaglate (Hexabrix) at concentrations of 300 mg I/ml was carried out in 107 consecutive patients with arterial insufficiency of the lower limbs. The purpose of the study was to observe possible 'carry-over' effects from any of the contrast media, and to evaluate patient discomfort such as pain, adverse reactions, or effect on peripheral blood pressure. No carry-over effect was seen. Ioxaglate caused less injection pain and heat sensations than iohexol, and showed less effect on the systemic blood pressure.     

Incidence of ventricular fibrillation during coronary arteriography in the rabbit. A comparative study of isotonic ioxaglate and iohexol

The incidence of major ECG changes, particularly ventricular fibrillation, was evaluated in rabbits during prolonged, selective right coronary injection of sodium/meglumine ioxaglate (Hexabrix 160) and iohexol (Omnipaque 140), two isotonic contrast media. The anesthetized animals (n = 12) per test solution) each received 1.5 ml of contrast material, delivered at a rate of 3 ml/minute. Both contrast media caused major ECG changes, which were reversible within seconds after administration. No fibrillation occurred with ioxaglate, but ventricular fibrillation was seen in seven animals given iohexol. There was a significant difference in the incidence of ventricular fibrillation between the contrast media (P less than .01). Both test solutions induced transient, more or less marked bradycardia, but without significant differences. The intracoronary injections produced similar decreases in blood pressure for both contrast agents. Reactive hypertension was observed only in those animals in which an episode of fibrillation occurred with iohexol. The causes underlying these effects are analyzed for both contrast agents.     

Iohexol, ioxaglate and iopamidol in coronary angiography. A double-blind comparative study of 300 patients

A randomized, double-blind study was carried out in 300 consecutive coronary angiography examinations to investigate the clinical safety of three low osmolar contrast media, iohexol 300, ioxaglate 320 and iopamidol 300, and the electrocardiographic changes that occurred with them. The ECG from electrode V5/V6 or AVF and intra-arterial pressure were monitored continuously, and recorded before and after the first contrast injections into the left and right coronary arteries. Of the variables tested, no statistically significant changes occurred in systolic arterial pressure, PR interval or ventricular extrasystole. The QT interval increased in the ioxaglate group (p = 0.001). Heart rate decreased in all groups, but slightly less in the ioxaglate group than in the iopamidol group (p = 0.02). The ST segment depression (mean 0.67m) was more marked in the ioxaglate group than in the other treatment groups (p = 0.0001) during right coronary angiography. The same characteristics, but less marked, were observed during left coronary angiography, the ioxaglate group (mean 0.251mm) differing from the iopamidol group (mean 0.050mm) (p = 0.04). No significant difference in severe adverse reactions were detected between these groups (ioxaglate 1, iopamidol 1). Ioxaglate produced mild side effects (nausea, vomitus, urticaria) in 16% of the patients, the other two contrast agents producing side effects in 1%.     

Adverse reactions to low osmolar iodine contrast media (second report)]

From January to December 1990, we performed a prospective survey of adverse reactions to contrast media at two different institutes of Juntendo University. We collected a total of 4555 case sheets during the period. The radiological procedures we investigated were computed tomography, intravenous urography, arteriography, venography and myelography. Low osmolar iodine contrast medium was used almost exclusively (except for five cases). The overall incidence of adverse reactions was 7.0%, and there were no severe or fatal reactions. The incidence of adverse reactions was higher in females (8.5%) than in males (6.1%). The incidence of adverse reactions increased according to the dose of contrast medium, especially when more than 101 ml was injected. Intra-arterial injection caused adverse reactions most often, followed by regular intravenous injections, followed by bolus intravenous injections. Adverse reactions occurred most often during injection. The next occurred in 5 minutes after injection, and then, 5-10 minutes after the injection of contrast medium. The incidence of adverse reactions was higher in patients with a history of allergy or previous reactions. Allergic adverse reactions were observed at a higher frequency. Pretesting was performed in 56.7% of the cases.     

Tolerance data of Gd-DTPA: a review

Gd-DTPA is the first paramagnetic contrast agent approved for clinical use in cranial and spinal MRI in the F.R.G., U.S.A., Japan and several other countries. After submission 13,439 patients were enrolled in standardized protocolled clinical trials. The observed adverse drug reactions (ADRs) after i.v. injection of Gd-DTPA were comparable to those after administration of iodinated non-ionic roentgen contrast media (CM). However, the overall incidence of ADRs after intravenous injection of 0.1 or 0.2 mmol/kg body weight Gd-DTPA was found to be even lower. Adverse events were observed in only 1.46% of the patients - or 1.14% if localized warmth is excluded. None of them was critical. There was no correlation between patient age and the incidence of ADRs. In patients with a known history of allergy the incidence of ADRs was increased by a factor 3-4, which is still lower than the incidence reported after intravenous administration of iodinated non-ionic roentgen CM to patients without known allergy. Good renal tolerance was seen in all patients, irrespective of pre-existing renal impairment. Fast bolus injections of Gd-DTPA were tolerated without added risk. The favorable safety profile is also reflected in the post marketing surveillance reports since Gd-DTPA became available as a commercial drug.