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ACEP Now: Vol 36 – No 04 – April 2017

ILLUSTRATION: Chris Whissen PHOTOS: shutterstock.com

In the last few decades, as advanced imaging has become pervasive, a few adverse effects relating to its use have been accepted: There are small age-dependent harms suspected from radiation exposure, the underappreciated harms of overdiagnosis and false-positive results, and the deleterious effect on renal function from contrast-induced nephropathy (CIN). It is not unusual for radiology departments to have a renal function cutoff for the use of intravenous contrast or even a protocol requiring hydration or other preventive therapy for those “at risk.”

However, physicians have been wringing their hands over CIN unnecessarily. It may not even be a relevant clinical entity in the context of the emergency department. While many observational studies have documented the substantial incidence of acute kidney injury (AKI) following intravenous (IV) contrast exposure, per the common general definition of CIN, it has been challenging to find a proper control group. Are patients developing subsequent AKI because of the IV contrast or due to the morbidity of the acute illness indicating the need for the CT?

This viewpoint is not new but has been gaining steam over the last few years, particularly in the radiology literature. In 2013, a group from the Mayo Clinic performed a systematic review and meta-analysis of the evidence published prior to 2011 regarding the association with IV contrast exposure and subsequent AKI.¹ These authors identified 13 nonrandomized studies comprising 25,950 patients, most of which were published after 2008. There was no statistically significant difference in incidence of AKI, need for dialysis, or death in their comparison, and any trend, if present, actually favored the IV contrast cohort.

Subsequently, these same authors and a group from the University of Michigan published several competing retrospective cohort studies showing differing conclusions.^2,3 Each group, with slightly different methodology, presented retrospective single-center analyses of tens of thousands of patients. Again, these were not randomized trials with proper control groups, but rather they used statistical propensity-matching techniques attempting to minimize confounding effects. In the data presented by the University of Michigan, a small increase in the likelihood of AKI was observed in relation to contrast exposure, and the likelihood increased as the glomerular filtration rate decreased. In the data presented by the Mayo Clinic, no association of AKI with contrast exposure was observed.

Finally, most recently, a group from Johns Hopkins University weighed in; call it a tiebreaker. It performed its own slightly different propensity-matching analysis.⁴ The authors included not only emergency department patients undergoing CT with and without IV contrast but also ED patients not undergoing any advanced imaging. These authors controlled for factors such as critical illness, vital signs, potentially nephrotoxic medication exposures, and comorbid baseline features. In their analysis, again, no association was found between IV contrast exposure and AKI across all their comparison groups.

These dogma-challenging findings seem a little less revelatory when considered in the context of the literature regarding treatments to prevent CIN. Recently, yet another study tested sodium bicarbonate against sodium chloride as periprocedural hydration to prevent CIN.⁵ In an intensive care unit (ICU) cohort, the frequency of AKI was similar as was the need for renal replacement therapy, ICU length of stay, and mortality. These data were consistent with multiple previous studies, which were unable to reliably demonstrate a renal protective effect from sodium bicarbonate.

Furthermore, these data were also consistent with previous studies unable to reliably find any specific protective benefit from theophylline or N-acetylcysteine, with statins having shown the most promise but no consistent positive result. This has left the cornerstone of preventive therapy as isotonic volume expansion or, simply, intravenous hydration with sodium chloride. However, even this commonly prescribed treatment has been called into question by a recent trial published in The Lancet.⁶ These authors randomized patients at risk for CIN to either protocolized sodium chloride hydration prior and following IV contrast exposure or to usual care. In their cohort of approximately 600 patients, the exact same number of patients, eight in each group, developed AKI.

The sum of this evidence leads to a very reasonable question, “Is our commonly held concern regarding CIN valid?” The retrospective data hardly answers the question, but it reasonably suggests at least equipoise for future research. Then, in the context of the repeated failures to find a preventive treatment, it is similarly reasonable to suggest the disease in question may be something of a mirage.

Are patients developing subsequent AKI because of the IV contrast or due to the morbidity of the acute illness indicating the need for the CT?

To start chipping away at the definitive answer, a truly randomized prospective sample will be needed. Patients for whom a contrast study is indicated but whose renal function would otherwise exclude the use of contrast could be randomized at the point of imaging acquisition. Other than the brief interruption to enroll patients with informed consent, the most significant resource outlay would be to follow up changes in renal function and other outcomes at appropriate intervals. Many other trials test far less for larger investments, and hopefully, the data in question can be forthcoming in the not-so-distant future.

In the meantime, these data probably allow for a loosening of adherence to strict protocols and cutoffs regarding the use of IV contrast. The baseline risk for developing CIN is still low regardless of renal function, and decisions regarding its use should be weighed individually against the potential for missed serious diagnoses if IV contrast is not used.

References

1. McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013;267(1):119-128.
2. Davenport MS, Khalatbari S, Dillman JR, et al. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105.
3. McDonald JS, McDonald RJ, Carter RE, et al. Risk of intravenous contrast material-mediated acute kidney injury: a propensity score-matched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014;271(1):65-73.
4. Hinson JS, Ehmann MR, Fine DM, et al. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med. 2017; [Epub ahead of print]
5. Valette X, Desmeulles I, Savary B, et al. Sodium bicarbonate versus sodium chloride for preventing contrast-associated acute kidney injury in critically ill patients: a randomized controlled trial. Crit Care Med. 2017;45(4):637-644.
6. Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial (published online ahead of print Feb. 20, 2017). Lancet.