One of the most widely used drugs in the world is not a drug, at least not in the usual sense.
It's more like a dye.
Doctors call this drug "contrast", shorthand for contrast agents.
Contrast agents are chemical compounds that doctors use to improve the quality of an imaging test. In the emergency room, where I work, the contrast is usually given intravenously during a CT scan.
About 80 million CT scans are performed annually in the United States, and the majority are made in contrast.
Most contrast agents I use contain iodine, which can block X-rays. This effect causes parts of an image, which significantly improves the physicians' ability to detect things such as tumors, certain types of infections and blood clots.
One thing about contrast agents that make them different from typical drugs is that they have no direct therapeutic effect. They don't make you feel better or treat what makes you worried. But they can be crucial to help your doctor make the right diagnosis.
Because these drugs are used in some people who may not prove to be wrong with them, and in others who can be seriously ill, contrast agents must be quite safe.
And basically they are. Some patients may develop severe allergic reactions or cardiovascular complications, but these are rare. Others may experience nausea or headaches.
But there is a generally scared negative effect of contrast ̵
In recent years, however, new studies have led some doctors to question whether this effect has been overestimated.
Is it time to reconsider the risk?
The first report on renal damage after intravenous contrast, known as contrast-induced nephropathy or CIN, appeared in a Scandinavian medical journal 1954. An early form of contrast had been given to a patient for a diagnostic test. The patient quickly developed kidney failure and died. The authors suggested that the contrast may have been responsible, as they could not find any other clear cause during an autopsy.
With other doctors now primed for the opportunity, similar reports began. By the 1970s, kidney damage had become a "well-known complication" of contrast in patients with risk factors for kidney disease, such as diabetes. In 1987, intravenous contrast was proclaimed as the third leading cause of hospital-acquired renal failure.
The belief that contrast agents were risky had a significant effect on how often doctors used them. In a 1999 study by European radiologists, 100 percent of respondents believed that CIN occurred in at least 10-20 percent of risk patients, and nearly 20 percent believed it occurred in over 30 percent of such patients. A 2006 study showed that 94 percent of radiologists considered contrast to be contraindicated beyond a certain threshold of renal function – a threshold that nearly 1 in 10 middle-aged American men could exceed.
Men Dr. Jeffrey Newhouse, a radiology professor at Columbia University, had a hunch that something was not quite right with conventional wisdom. He has administered contrast thousands of times, and rarely did it seem to him that contrast can be said to have been directly toxic. There were often too many variables that were played.
Newhouse decided to go back to primary literature. In 2006, he and a colleague reviewed more than 3,000 studies on contrast-induced nephropathy and came to an astounding conclusion. Only two had used control groups, and none of them had found that contrast was dangerous.
"Everyone assumed that kidney damage after contrast was a result of the contrast," Newhouse said, "but these studies had no control groups!"
In other words, there was no group of patients who had not received contrast for use for comparison.
Newhouse discovered that almost every study supporting CIN had fallen prey to this shortcoming. The importance of controls in any experiment is basic science; without them, you cannot say anything about causation.
What came next was brilliant. "We have criticized those who did the experiment without the control, we decided to do the control without the experiment," Newhouse said. He reviewed 10 years of data from 32,000 hospitalized patients, none of whom received contrast. He found that more than half of the patients had fluctuations in their kidney function that would have met CIN criteria if they were in contrast.
This increased the possibility that other causes of kidney damage – and not the contrast – could have explained the compound found in previous studies.
Other researchers increased after Newhouse published their results in 2008. Doctors in Wisconsin conducted the first major study of CIN with a control group in 2009. In more than 11,500 patients, total kidney damage was similar in subjects who received contrast and those who did not. .
However, there was a great weakness with the study – it was retrospective, which meant that it concerned medical records and previously collected data. When a study is performed in this way, randomization to different treatments cannot be used to protect against prejudices that can distort the results.
So, for example, if doctors who treated patients in the Wisconsin study were concerned about contrasting with high-risk patients, they might have steered them to the group who received CT scans without it. These diseased patients may have been more likely to get kidney damage from other causes, which can mask a true difference between the groups.
The next generation of retrospective studies attempted to use a particular statistical technique to control these bias voltages.
The first two appeared in 2013. Researchers in Michigan found that contrast was associated with kidney damage in only high-risk patients, while counterparts at the Mayo Clinic, using some more sophisticated methods, did not find any relationship between contrast and kidney damage.
A third study, from Johns Hopkins, emerged in 2017. It also found no relationship between contrast and kidney damage in nearly 18,000 patients. And in 2018, a meta-analysis of more than 100,000 patients also found no association.
What did Newhouse do from these results?
"Almost harmless and completely harmless – we are somewhere between the two," he says. "But how much damage is there to keeping things together? We just don't know."
Still Dr. Michael Rudnick, a kidney specialist at the University of Pennsylvania, is not so sure that it is time to completely clear contrast agents. He believes there may still be a danger to the highly risked patients found by the Michigan researchers. And he pointed out that even sophisticated statistical analyzes cannot control all possible phenomena. Only one randomized test can do that.
Here is the ruben. Rudnick says we are unlikely to receive a randomized controlled trial because there is still a possibility that contrast may be harmful and ethics committees are unlikely to approve such a trial.
It is a belief that existing belief in contrast media can actually limit our ability to conduct appropriate trials to investigate that belief.
Matthew Davenport, senior author of the 2013 Michigan study and president of the American College of Radiology Committee on Drugs and Contrast Media, says "most of the things we used to think were probably not CIN."
But he agrees with Rudnick that there can still be real danger for the high-risk patients. He echoed the current American College of Radiology recommendations that the decision to use contrast in patients with existing kidney disease should remain an individualized clinical decision.
Currently, if you need a scan that may require contrast, talk about the risks and benefits of the medicine for you and make the decision with your doctor.
Clayton Dalton is a resident physician at Massachusetts General Hospital in Boston.