We found that the intra-arterial use of IOCM (iodixanol) compared with individual LOCM agents or LOCM as a group was associated with reduced frequency and severity of pain, warmth, and discomfort reported by patients in prospective, head-to-head, RCTs. Older age was associated with greater effect sizes with respect to pain but lesser effects with warmth. The opposite trends were noted as the proportion of women increased in the trials, suggesting both age and gender modify patient-reported outcomes according to the osmolality of CM. There was a moderate degree of heterogeneity among the trials because of differences in trial design, reporting methods of patient symptoms, and external consistency between the trials. There was no evidence of publication bias, and we do not expect additional trials to overturn the results of this analysis.
Our data are consistent with what is known about the vascular biologic effects of iodinated CM. All forms of iodinated CM position iodine on a single benzene ring or a dimer of such rings. The presence or absence of charged side chains, particle concentration in solution (osmolality), viscosity, and iodine concentrations are the main physiochemical characteristics that make each formulation unique. Iodixanol is an iso-osmolar, nonionic, dimer that is isotonic with blood. It is believed that this formulation results in less deformation of cell membranes in blood and the vascular endothelium. As a result, there is an attenuated immediate release of histamine from basophils and nitric oxide from vascular endothelial cells. Thus, there is a blunted initial wave of vasodilation throughout the body as CM travels through the vasculature. In addition, with iso-osmolality, a less pronounced vasoconstriction is anticipated following the initial phase of endothelium-dependent vasodilation. As a result, there is greater vascular stability in arterioles that serve the skeletal muscles and skin in the extremities. This attenuates the activation of nociceptors in nerves supplying both the neurovascular bundles as well as the end-organs. Because the greatest physiochemical difference between IOCM (iodixanol) and LOCM is osmolality as opposed to iodine content or viscosity, we believe, our data support osmolality being the main determinant of symptoms after intravascular injection.
The clinical importance of our findings is highlighted in the ever increasing use of iodinated contrast for intravascular imaging procedures. Our results extend the observations of Justesen and coworkers whose trial included in our meta-analysis . In this trial alone, 1225 patients were randomized to iodixanol and 1227 to iopromide in conventional/digital subtraction angiography of the femoral arterial system. The iodixanol group reported statistically significantly less injection-associated pain (0.9%) than the iopromide group (9.5%) (p < 0.001). In addition, 4.1% in the iodixanol group experienced pain and/or severe heat sensation vs 19. 8% in the iopromide group (p < 0.001). Our analysis suggests these findings can be generalized to other peripheral arterial beds and left ventriculography.
Reduction in pain and discomfort is an important goal for improving the overall tolerability of any procedure. If symptoms related to CM cause tachycardia or body motion, the procedure may be prolonged and the quality of a variety of imaging tests could be affected. This threatens the diagnostic accuracy and subsequent clinical decision making. In addition, poor image quality because of motion artifact may influence the outcomes of an interventional procedure such as a vascular stent placement planned from digital subtraction angiography. Moreover, non-diagnostic studies often lead to repeated examinations, exposing patients to additional injections of contrast and higher doses of radiation. Thus, for all of these reasons, the choice of IOCM over LOCM would be supported in peripheral arteriography procedures where higher degrees of discomfort or body motion would be expected with injection.
Our analysis has all the limitations of any tabular meta-analysis: the response variables measured, stratifications reported, and the individual trial sample sizes. We did not have information on the rates of injection, bolus size, or the use of power injectors, or the use of conscious sedation and analgesic medications which could have influenced the overall size and concentration of CM moving en bloc through the vasculature and its triggering of nociceptors. Importantly, none of the studies had physiologic correlates such as skin temperature, bioimpedance, or plethysmography to investigate the neurovascular origins of discomfort reported. We had insufficient information on the injection site to draw conclusions on outcomes in typically very sensitive vascular territories (distal upper limb and pudendal artery) as well as on injection rates and CM concentration. We included coronary angiography, which for the most part elicits few symptoms, and thus, biased our findings to the null hypothesis. This being considered, the large effect size, internal and external consistency, and absence of publication bias all suggest the differential findings among the CM are valid and likely to be reproduced in everyday clinical practice. Finally, we did not have data on patient motion and image quality, but we suspect in cases where the discomfort was greater, there was more patient motion and the possibility of reduction in image quality.