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One of the most used drugs in the world is not really a drug, at least not in the usual sense.
It's more like a dye.
Doctors call this drug "contrast," the abbreviation for contrast agent.
Contrast agents are chemical compounds that help physicians improve the quality of an imaging test. In the emergency department where I work, the contrast is usually given intravenously during a CT scan.
About 80 million CT scans are performed each year in the US, while the majority is done with contrast media.
Most of the contrast agents I use contain iodine, which can block X-rays. This effect illuminates parts of an image, greatly improving the ability of doctors to detect tumors, certain infections, and blood clots.
What sets contrast media apart from the typical drugs is the fact that they have no direct therapeutic effect. You will not feel better or treat what makes you ill. However, you can help your doctor make the right diagnosis.
Because these medicines are used in some patients who may not be in some way wrong with them, and in others who may be seriously ill, contrast media must be used relatively safe.
And by and large they are. Some patients may experience severe allergic reactions or cardiovascular complications, but these are rare. Others may experience nausea or headache.
However, there is a generally dreaded adverse effect of contrast – kidney damage. As a result, patients who are considered by their physicians to be at risk for kidney problems are often denied contrast media. The downside is that these patients may not get the diagnostic information that is most useful to them.
In recent years, however, several new physicians have questioned whether this effect has been overstated.
Is it time to reconsider the risk?
The first report of kidney damage after intravenous contrast, known as contrast-induced nephropathy (CIN), appeared in a Scandinavian medical journal in 1954. The patient was given an early form of contrast agent for a diagnostic test. The patient quickly developed kidney failure and died. The authors suggested that the contrast may have been responsible because they could not find another clear cause during an autopsy.
Similar reports appeared with other doctors now prepared for the opportunity. In the 1970s, renal injury was a "known complication" in patients with risk factors for kidney disease such as diabetes. Until 1987, intravenous contrast was the third leading cause of hospital-acquired renal failure.
The assumption that contrast agents were risky had a significant impact on how often doctors used them. In a survey conducted by European radiologists in 1999, 100 percent of respondents believed that CIN was present in at least 10-20 percent of high-risk patients, and nearly 20 percent believed that it occurred in over 30 percent of those patients. A 2006 survey found that 94 percent of radiologists believed that contrast was contraindicated beyond a certain limit of kidney function – a threshold that could exceed nearly one in ten middle-aged American men.
Jeffrey Newhouse, a professor of radiology at Columbia University, had the impression that something was wrong with conventional wisdom. He has administered contrast thousands of times and it rarely seemed to him that contrast could be considered directly toxic. There were often too many variables in the game.
Newhouse chose the primary literature. In 2006, he and a colleague reviewed more than 3,000 contrast-induced nephropathy studies and came to an astounding conclusion: Only two had control groups and neither had found the contrast to be dangerous.
"Anyone assumed that kidney damage after contrast was a result of contrast," Newhouse said, "but these studies had no control groups!"
In other words, there was no group of patients who did not receive comparative data for comparison.
Newhouse discovered that almost every study that supported CIN had fallen victim to this deficiency. The importance of controls in each experiment is basic research. Without them you can not say anything about the causation.
What came next was brilliant. "After criticizing those who did the experiment without the control, we decided to take control without the experiment," Newhouse said. He reviewed data from 32,000 inpatients for ten years, but none of them contrasted. He found that in more than half of the patients there were fluctuations in kidney function that would have met the criteria for CIN if they had received contrast.
This implies the possibility that other causes of kidney injury – and not contrast – may have explained the association found in previous studies.
Other researchers entered after Newhouse published its findings in 2008. Doctors in Wisconsin performed the first large CIN study with a control group in 2009. In more than 11,500 patients, renal injury rates were similar between those who received contrast media and those who did not.
However, there was a major flaw in the study – it was retrospective, meaning it relied on medical records and previously collected data. When conducting a study in this way, randomization to different treatments can not be used to avoid bias that could falsify the results.
For example, if treating physicians in the Wisconsin study were concerned, as opposed to high-risk patients, they might have turned them into a group that was treated without CT scans. These sicker patients may have had kidney injury for other reasons, which could mask a real difference between the groups.
The next generation of retrospective studies attempted to use a special statistical technique to control these prejudices.
The first two appeared in 2013. Researchers in Michigan found that the contrast was associated with kidney damage only in the highest risk patients, while colleagues from the Mayo Clinic found no relationship between contrast and kidney damage with more sophisticated methods.
A third study by Johns Hopkins appeared in 2017. Even in nearly 18,000 patients, she found no relationship between contrast and kidney damage. A meta-analysis of more than 100,000 patients also found no connection in 2018.
What did Newhouse do with these results?
"Almost harmless and totally harmless – we are somewhere between these two," he says. "But how much damage is done by holding back the stuff, we just do not know."
Nevertheless, Dr. Michael Rudnick, a kidney specialist at the University of Pennsylvania, is not so sure it's time to completely remove contrast media. He believes there may still be danger to the most at-risk patients, the Michigan researchers found. And he pointed out that even sophisticated statistical analysis can not influence all possible distortions. That can only be a randomized study.
However, Rudnick says that it is unlikely that we will receive a randomized, controlled trial because of the possibility that the contrast could be harmful and ethics committees are unlikely to approve such an assessment.
It is a mystery that existing beliefs about contrast agents could limit our ability to conduct appropriate investigations to investigate this belief.
Matthew Davenport, lead author of the 2013 Michigan study and chairman of the American College of Radiology's Committee on Drugs and Contrast Media, says that "the vast majority of things that we thought CIN probably does not apply to".
However, he agrees with Rudnick that there could still be a real danger for the most at-risk patients. He reiterated current recommendations from the American College of Radiology that the decision to use contrast media in patients with pre-existing kidney disease should remain an individualized clinical decision.
If you need a scan that may require contrast, talk to you about the risks and benefits of the medicine and make the decision with your doctor.
Clayton Dalton is a resident physician at the Massachusetts General Hospital in Boston.