When the dye starts, it might feel like you are peeing your pants. Don’t worry, you won’t actually pee. It’s just a side effect of the dye.”
During my time in New Zealand, I have heard that speech far too many times. (The consequence of a strange rule that requires a doctor to be present any time a patient receives a contrast CT.) I have had a lot of time to contemplate that statement during the small hours of the morning in the quiet of the radiographer’s office. As I repeatedly turned the statement over in my head, it slowly dawned on me that it might be really important.
Why do patients suddenly feel warm? Are they experiencing significant vasodilation? Could that vasodilation explain why patients always seem to crash in CT?
Those ruminations led down a medical literature rabbit hole. I still don’t have a definitive answer. However, the physiologic effects of contrast are far more complex than I had previously considered. We spend way too much time talking about the (potentially mythical) effect of contrast on kidneys, and not nearly enough talking about its other possible side effects.
Do patients die more often in CT?
First, we should probably consider the premise that patients are more likely to die while at CT. That fact was drilled into me from multiple sources throughout my training. We all can remember patients who arrested in the CT scanner. We are almost as superstitious about the CT scanner as we are about the word “quiet”, but do we have reason to be?
I would really like to know if this is a true relationship, but I haven’t found any solid data. There is a mountain of anecdote, but anecdote is the realm of cognitive biases. We may just remember the arrests in the CT scanner better, because they occur outside of our usual environment and are therefore the most chaotic arrests we run. This availability bias could be compounded by confirmation bias, as once the “patients go to CT to die” meme is born, we are more likely to notice (and talk about) the arrests in CT than we are arrests that occur in the resuscitation room.
In order to really answer this question, you need more than a simple tabulation of the total number of arrests that occur in different areas of the hospital. You would need to know exactly how long patients spend in different departments (far fewer minutes are spent in radiology than in the ED or ICU), to determine whether the incidence of arrest was higher than expected by chance alone. You would also have to account for the fact that only the sickest patients get CTs.
I find this question fascinating, but I cannot answer it in this post. Instead, I will assume the meme is true; that the CT scanner is a dangerous place. This post is focused on whether the physiologic changes caused by contrast dye might explain this phenomenon.
Side effects are relatively common
Contrast, like all medical interventions, is associated with a wide range of adverse events, from only mildly annoying (feeling like you are peeing when you aren’t) to severe (cardiac arrest). Mild adverse events probably occur in as many as 15% of patients, but severe events (generally cardiovascular and neurologic) only impact about 1-2%. (Namasivayam 2006) The rate of morality is uncertain, but is reported to be between 0.5 and 1 in 100,000. (Namasivayam 2006; ACR 2017)
Known cardiovascular side effects of contrast include hypotension, angina, arrhythmias, and cardiovascular collapse. (Widmark 2007; ACR 2017; Morzycki 2017) Vasovagal responses, with hypotension and bradycardia, are also common. (ACR 2017) In the past, extremely high osmole loads could also cause decompensation in patients with heart failure, but we don’t use those dyes anymore. (Widmark 2007) Just to add some confusion, although hypotension is a definite possibility, hypertension is also listed as a possible adverse event. (Widmark 2007; Morzycki 2017)
Why might they die? Some physiology
There doesn’t seem to be much doubt that contrast causes some degree of vasodilation. The sensation of warmth I mentioned at the outset is well described with intravascular iodinated contrast dyes, and generally considered to be the result of vasodilation. (Hirshfeld 1990; Widmark 2007)
Vasodilation has been confirmed in multiple animal models. Although higher osmolar agents cause more vasodilation, there seems to be a direct chemotoxic effect of all contrast agents that isn’t seen from similar concentrations of sodium chloride. (Almen 1994) However, the physiology is rather complex, and probably incompletely understood. Through a combination of ionic effects and direct effects on blood cells and the endothelium, the administration of contrast results in activation of the complement and coagulation cascades, as well as the release of a large number of vasoactive compounds, including histamine, bradykinin, serotonin, leukotrienes, and prostaglandins. (Almen 1994; Morzycki 2017)
Although I have not found direct trial evidence, multiple sources indicate that these reactions to contrast are more likely in sicker or unstable patients. (Bush 1991; ACR 2017)
Calcium may also play a role
The contrast binds calcium, resulting in functional hypocalcemia, which has been associated with adverse cardiovascular events. (Widmark 2007; ACR 2017) The drop in calcium level seems to be very short lived. However, in physiologic studies during angiography, acute drops of about 0.3 mmol/L were seen over just a few seconds, which I suppose could be important for some patients. (Hayakawa 1993)
Other factors to consider
Contrast agents seem to be directly cardiotoxic, resulting in decreased contractility. (Hirshfeld 1990; Almen 1994) However, the impacts of contrast on the myocardium have generally been tested during angiography, which involves much larger doses of contrast injected intra-arterially, so may not be significant with intravenous CT contrast. Furthermore, despite decreased cardiac contractility, cardiac output generally increases because of decreased vascular resistance and increased heart rate. (Hirshfeld 1990)
High doses of these agents injected directly into the coronary artery in a pig model resulted in ventricular fibrillation in 92% of cases, but it isn’t clear that data is relevant to normal doses given intravenously. (Almen 1994)
Although there won’t be any immediate effect, all contrast agents result in a degree of osmotic diuresis, which may be important in critically ill patients.
The anaphylactoid component
Anaphylactoid reactions are a well known complication of CT contrast, and may also play an important role in the sudden deterioration of patients after a contrast CT. (Widmark 2007) These are events that look like allergic reactions, but aren’t the result an antigen-antibody interaction. The exact mechanism is unclear, and is likely multifactorial, including direct interactions with cells resulting in the release histamine, leukotrienes, bradykinin, prostaglandins, and other immune mediators, as well as the direct activation of the complement, coagulation, and kinin cascades. (Bush 1991; Almen 1994) Pre-existing activation of the complement pathway may increase the chance of an anaphylactoid reaction, meaning it is more likely to occur in sicker patients. (Bush 1991) The underlying pathophysiology probably shares multiple mechanisms with the non-anaphylactoid vasodilation discussed above. The potential for anaphylactoid reactions is an important consideration when treating, and perhaps attempting to prevent, deterioration in patients receiving contrast.
How much hypotension?
Although patients do occasionally deteriorate after a CT scan, I have not personally noticed a strong association with the administration of contrast and changes in vital signs. However, I came across one study that provides some really interesting information. Widmann and colleagues (2018) performed a double blind RCT of 2 different contrast agents (low and iso-osmolar) in patients who were anesthetized for CT guided radiofrequency ablation of liver tumours. (These patients were on propofol and fentanyl, which is a reasonable surrogate for the pharmaceutical cocktail my ED patients might be on, but unlike ED patients, none of these patients were in shock prior to the scan.) What makes the study interesting for our purposes is that all patients had arterial lines in place. In the group receiving the low-osmolar contrast, blood pressure dropped by a mean of 31/16, with 60% of the group dropping to a systolic BP below 80 and a MAP below 55. More interesting, in my mind, is that while this drop occurred 60 seconds after contrast was given, the blood pressure had completely returned to normal by 105 seconds. In other words, even if I had set my blood pressure cuff to cycle every 2 minutes, I probably would have missed this drop.
Of course, this is an extremely transient drop in blood pressure. It is a disease (or monitor) oriented outcome, not a patient oriented outcome. But it lends some credence to the idea that, in the right patient, especially with pre-existing shock, the contrast could result in sudden deterioration.
Personally, being an emergency doctor, the vast majority of patients I bring to CT are still having their blood pressure measured with a cuff. It is extremely likely that I would miss many of these transient hypotensive episodes (especially if, as so frequently happens, the machine thinks there was an error and simply cycles again). Perhaps our critical care colleagues, with their fancy arterial lines, can comment on these results.
Impact on clinical practice
First, I think it is important to be clear: although serious adverse events do occur after contrast, they are rare. I could find no evidence to support the concept that “CT is where patients go to die”. If a patient requires a contrast CT to make an important diagnosis, these physiologic musings should not interfere with that scan.
I had never really considered the variety of adverse events and physiologic changes associated with CT contrast. Obviously, we are all exposed (ad nauseum) to the (probably false) idea that contrast kills kidneys, but the real pathophysiology is a lot more complicated. It is fascinating that the warning given hundreds of times a week by the radiographer – you might feel like you peed your pants – could hint at an important physiologic fact completely unknown to the emergency doctor.
We all need to prepare for the possibility that our patients will deteriorate in radiology (or anywhere we transfer them). Honestly though, because of the prevalent concept that patients are more likely to arrest in CT, many of us may already be hypervigilant about the patients we sent to CT.
However, it has changed the way I think about the CT scanner. I spend a lot of time talking about the potential physiological dangers of intubation; about the need to resuscitate before we intubate. In critical care, we have grown wary propofol induced hypotension.
But CT contrast is like propofol. It is vasodilatory and may be a direct cardiac suppressant. It can cause further cardiovascular issues through hypocalcemia and anaphylactoid reactions. Ultimately, I think CT contrast deserves the same respect we give propofol. We need to “resuscitate before we radiate”.
Practically speaking, there may not be a lot to change. Most patients are already getting stabilized before transport to CT. I already accompany my sickest patients to radiology, and I bring push dose epinephrine (among other supplies) with me.
However, a strategy relying on push dose pressors is probably not ideal. You are in another room while the CT scan is done, so there will always be a delay to treatment. Furthermore, as we saw in study by Widmann, the drop in blood pressure can be quite rapid, so unless you have an arterial line in place, you may not notice.
The one major change I will make after reviewing this literature is to lower my threshold for a vasopressor drip in patients going to CT. It doesn’t have to be running at a high rate, but I think it should be running. (Similarly, I like to have a norepinephrine drip ready or running in all sick patients I am intubating.) Although norepinephrine is probably fine (and is my vasopressor of choice in almost all scenarios), the risk of anaphylactoid reactions means epinephrine is probably the ideal choice.
CT contrast is not inert. We spend way too much time talking about its (minimal to non existent) effects on the kidneys. Instead, I think the critical care community (and our patients) might benefit from paying more attention to its cardiovascular effects.
- Other side effects of contrast that are worth knowing
- Vasovagal events
- Exacerbations of myasthenia gravis
- Extravasation injuries
ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. Version 10.3, 2017. http://www.acr.org/quality-safety/resources/contrast-manual.
Almén T. The etiology of contrast medium reactions. Investigative radiology. 1994; 29 Suppl 1:S37-45. [pubmed]
Beckett KR, Moriarity AK, Langer JM. Safe Use of Contrast Media: What the Radiologist Needs to Know RadioGraphics. 2015; 35(6):1738-1750.
Bush WH, Swanson DP. Acute reactions to intravascular contrast media: types, risk factors, recognition, and specific treatment. AJR. American journal of roentgenology. 1991; 157(6):1153-61. [pubmed]
Hirshfeld JW. Cardiovascular effects of iodinated contrast agents. The American journal of cardiology. 1990; 66(14):9F-17F. [pubmed]
Hayakawa K, Mitsumori M, Uwatoko H, et al. Acute electrolyte disturbances in coronary sinus during left coronary arteriography in man. Acta radiologica. 1993; 34(3):230-6. [pubmed]
Morzycki A, Bhatia A, Murphy KJ. Adverse Reactions to Contrast Material: A Canadian Update. Canadian Association of Radiologists journal = Journal l’Association canadienne des radiologistes. 2017; 68(2):187-193. [pubmed] [free full text]
Namasivayam S, Kalra MK, Torres WE, Small WC. Adverse reactions to intravenous iodinated contrast media: a primer for radiologists. Emergency radiology. 2006; 12(5):210-5. [pubmed]
Widmark JM. Imaging-related medications: a class overview. Proceedings (Baylor University. Medical Center). 2007; 20(4):408-17. [pubmed]