The Skeleton for Global Risk Assessment in Radiology

January 14, 2019

 

I have mentioned on several occasions the need for a global information sheet on the risks inherent in all Radiology exams. This is a skeleton outline:

 

Essentially everything in health care have risks, in addition to the benefits, associated with them. The present document provides an overview of the severe risks associated with Radiology procedures, their approximate likelihoods, and who are most at risk.

 

X-ray based procedures (includes CT). 

The risks: The severe risk associated with all x-ray based procedures is the development of cancer from x-ray injury. X-ray procedures include: plain x-rays (such as chest x-ray or bone x-ray), CT scans, fluoroscopy, angiography, and many interventional procedures. Very high x-ray delivery to patients can result in immediate toxic effects, like hair loss, skin burns, and cataract formation, but it is really cancer development that is the major and more likely concern. 

 The likelihood: It is estimated that a radiation exposure of 10 mSv is associated with a 1 in 1,000 risk of developing malignancy/cancer. Using present CT technology, this usually amounts to 2-3 CTs being performed within 1 year to get to this risk level. Angiographic procedures often have this exposure level. It is extremely unlikely to experience significant risk following plain x-rays at the current time, but remember: everything in moderation. Cancer development is delayed after the x-ray exposure. Blood cell cancers such as leukemia have the shortest interval till development, as short as 2 years. Solid organ malignancy development arises after a longer interval, often 20 years, and these include cancers of the breast, thyroid, and gastrointestinal. 

Who are at most risk: children and young adults are at greatest risk, both because their cell replication is occurring at a faster rate (cells replicating are more likely to experience the injury) and because they have a longer life span to develop cancers that may arise 20 years after exposure. The widely published risk that I have written above of: 10 mSv is associated with a 1 in 1,000 risk of developing malignancy/cancer, actually is modeled for a 40 yr old male. The highest risk is a 1 yr old female where the same 10 mSv dose is associated with approximately 1 in 100 chance of developing cancer.

 

Contrast Media Induced Acute Kidney Injury (CI-AKI).

The risks: CI-AKI (also [formerly] known as contrast induced nephropathy- CIN) is most often associated with the use of Iodine based contrast agents (IBCAs), as used in CT and angiography. Rarely it may occur with Gadolinium-based contrast agents (GBCAs). Most likely this is a dose-related effect that accounts for this, the typical volume of contrast used in CT is 75-150 ml, whereas with MRI it is 10-20 ml. Renal failureis the risk, and it is measured in terms of either absolute increase in serum Creatinine (sCr) or % increase in sCr. Traditionally CI-AKI has been expressed in terms of simply the increase in sCr within 24-48 hrs, but the majority of these are transient and actually last for < 48 hours, so essentially are not important. Currently transient CI-AKI is distinguished from persistent CI-AKI, with persistent CI-AKI being the injury that matters.

The likelihood:  Transient CI-AKI can occur in essentially anyone who receives an IBCA. Meaningful, persistent CI-AKI, has the greatest impact in patients who have moderately poor renal function (estimated Glomerular Filtration Rate [eGFR] from 60-90). This is why many centers may avoid giving iv IBCA in individuals with a sCr above 2, and perhaps certainly above 3. The concern is the worsening of kidney function, such that individuals who basically are managing quite well, with no special attention needed to their kidneys, then require dialysis or renal transplant because of CI-AKI. The annual mortality associated with this decline of renal function from CI-AKI from category 3 chronic renal failure to 5 (from being ok [category 3] to requiring dialysis [category 5]) has been estimated to be as high as 40%. The risk of this occurring varies between studies, from up to 20%, but the true number may be 1%.

Who are at most risk: Individuals in stage 3 renal failure (eGFR 60-90). Elderly individuals have a greater likelihood to be in this status, and also unaware that they are. Individuals who have experienced major trauma with shock and blood loss. Individuals taking concurrent nephrotoxic drugs (often chemotherapy or antibiotics). Individuals with severe acute kidney failure from any cause.

 

Acute Hypersensitivity Reaction to Radiology contrast.

The risks: Acute hypersensitivity reactions are quite common with Radiology contrast agents, as they are to most drugs and also other exposures, such as to food items (eg: peanuts), but most are mild and of no consequence. The reactions that are of most concern are severe reactions, with the most severe being anaphylactic (or anaphylactoid, meaning after the first exposure). This generally manifests as extreme difficulty breathing and very rapid weak pulse, representing shock and systemic and vascular collapse. Any of the IBCAs may cause this reaction, but the now largely antiquated agents, the high osmolar contrast agents had a higher occurrence. All the GBCA agents, regardless of stability or structure, can cause this.

The likelihood: Death following administration of contrast is estimated at approximately 1 in 150,000 following ICBAs, and 1 in 300,000 following GBCAs. Severe acute reactions are estimated at about 1/10 of that or 1 in 15,000 following IBCAs and 1 in 30,000 following GBCAs.

Who are at most risk: Prior major reaction to a contrast agent is considered the highest risk. Asthma and other conditions which are of an acute inflammatory allergic nature are also a high risk. Death from an allergic response appears most likely to occur in individuals in whom risk is perceived to be essentially nonexistent, and it is likely this perception of absence of risk  results in tardy response with life support measures, and subsequent death. The group I am most concerned about are young to middle aged white females. The risk is exceedingly rare, however the importance of this observation is not to dismiss the possibility of a fatal reaction because the subject is young, healthy and has no history of allergies.

 

Nephrogenic Systemic Fibrosis (NSF).

The risks: NSF essentially is restricted to patients with severe kidney failure (category 5, eGFR 0-15) with relatively few occurrences in milder renal failure (category 4, eGFR 15-30). As currently reported, it is a subacute to chronic development disease, with onset as early as 2 weeks, but frequently onset at 2-6 months. The disease is associated with fibrosis development in essentially any organ system. The most devastating changes are in a glove and sock distribution, with the development of red, woody skin, and severe arm and leg joint contractures, which may render the patient wheel-chair bound. The condition is painful. The mortality rate is not clearly defined, but a reasonable estimate is a 30% 5yr mortality.

The likelihood: The disease is primarily limited to individuals in advanced renal failure (most on dialysis) who have received a linear GBCA agent. Approximately 5% of individuals who fit this description develop the disease.

Who are at most risk: Stage 5 renal failure (most often on dialysis), and administration of Omniscan (less so with Optimark and Magnevist).

 

Gadolinium Deposition Disease (GDD).

The risks: All GBCAs may result in GDD. This is like the acute hypersensitivity reactions, and unlike NSF. It generally  arises relatively soon after GBCA injection, from immediately to within 1 month. Common A- symptoms are: brain fog, head pain, burning skin and skin/substrate, sharp pins and needles, boring bone and joint pain, blurred vision and dry eyes, glove and sock distribution of skin discoloration, doughy or firm skin tissue texture, burning pain, pins and needles. 

The likelihood: The incidence is not definitively known, but is relatively rare. A reasonable estimate is moderately severe GDD occurs with an incidence similar to severe acute hypersensitivity reactions, that is 1 in 30,000 individuals, which they may spontaneously recover from if not receiving future GBCAs, and 1 in 300,00 individuals experiencing very severe disease, which is of comparable symptomatology to NSF.

Who are at most risk: individuals of white, central/northern European ancestry (UK through to Russia). Women. History of  auto-immune diseases. These risks are atleast additive, with women of central/northern European ancestry with a history of family or personal auto-immune conditions being at the highest risk. If you already have mild symptoms of GDD, the chance of worsening the condition with a future GBCA injection is nearly 100%.

 

MRI.

The risks: MRI alone is relatively safe. It primarily involves the use of radiofrequency (RF) energy and a fluctuating field powerful magnet. These properties are not associated with cancer development. The major risks associated with MRI is from metal objects either internal to the patient or external. The most dramatic examples are old style high iron-content berry aneurysm clips (on cerebral artery aneurysms) which were pulled off the vessels resulting in intracranial bleeding and death; and large metal objects, like iron-containing oxygen tanks, being pulled into the magnet and crushing the patient, even to death. Probably no example of intracranial clip movement in an MRI and severe injury has occurred since the early 1990s. Following those few experiences, titanium became used as a surgical metal to avoid this life-threatening complication, primarily because of the risk of iron-containing steel being moved in MRIs causing patient injury and death.  Movement of heavy metal containing external-to-patient objects, has continued to occur even to the present time, although it is exceedingly rare. The malfunction of battery operated metal devises has also occurred in MRI. Recently, some patient with GDD report their symptoms worsening even without GBCA when they undergo MRI.

The likelihood: MRI centers go to great length to inquire about metal implants, and comprehensive references exist on-line that they can review to determine risk for each individual patient. Most metals, and even it turns out, most cardiac pacemakers do not pose a substantial risk for patients. It is iron content that is the main culprit for misadventures in MRI, so aluminum (aluminum oxygen tanks), titanium, nickel, are all safe in MRI. Even modern surgical steel has a surprisingly low iron content. Attentiveness is though critical at all times. For example, the MRI magnet is always 'on', unlike with CT where the x-rays are only generated when the system is scanning. Risk of worsening GDD symptoms in MRI even without GBCA injection is unknown. If you have undergone a noncontrast MRI, because you have GDD and did not want to receive another GBCA injection, and experienced worsening of symptoms, then do not undergo any MRI again.

Who are most at risk: Patients with iron containing metal, either surgical or accidental (iron eye splinters in metal workers, bullets and shrapnel from violent injuries). Implanted battery devices have to be assessed for risk/benefit. External devices like RF blankets, loops in external wiring on patients, all may pose some risk of heating and burns. I remain concerned about 7T MRI due to the strength of the magnet and the rapid switching of gradients in such a powerful system. Patients report dizziness and heating at ultrahigh field.

 

 

Nuclear Medicine, PET, PET/CT.

The risks: Nuclear medicine, PET, and PET/CT all involve the administration of radio-active- atom-containing contrast material (termed radiotracers). This means that unlike CT where the radiation exposure is limited to the time that the images are being taken, radiation stays with the patient as long as the radiotracers stay within them. Borrowing from what we now know of GBCAs, this could be a very long time. The radiation dose differs dramatically between the radioactive atoms involved, and inquiry and explanation into the type of atom and the typical radiation dose from the study should be mandatory.

The likelihood: The saving grace of radiotracer based studies is that the volume of agent used is very small, typically in the 1 - 2 ml range. The typical radiation exposure (including the FDG part and the x-ray part) of a PET/CT study is 25 mSv, which far exceeds the risk of 1 in 1,000 cancer of 10 mSV of radiation.

Who are most at risk: As with CT and radiation, children and young adults are the most at risk. Surprisingly little has been written about safety issues with these radiotracer modalities. PET/CT should be limited in the frequency of repetition and also its use in young individuals who do not have life threatening disease. PET/CT is most often used as a diagnostic tool to follow up patients with cancer - it should be remembered that the modality itself can cause cancer, and too frequent use in individuals who have already shown that they have the propensity to develop cancer would seem imprudent. 

 

Ultrasound.

The risks: Ultrasound uses RF waves to generate images. Intrinsically ultrasound is the safest of all the modalities. The concern of risk only enters the discussion when microbubble contrast agents are in use to study vascularity in the body. The risks are blocking small vessels with air bubbles and the organs of concern are the brain and inducing stroke, and heart and inducing heart attack.

The likelihood: The risk of stroke or heart attack are very low with microbubble contrast. Nonetheless should probably only be used sparingly and without frequent re-injections.

Who are most at risk: Individuals most at risk would be individuals who have pre-existent small vessel disease in the brain or the heart. Individuals who have highly reactive vessels to contraction in the presence of irritation may also be at risk, such as Prinzmetal's Angina of the heart or fibromuscular dysplasia with a prominent spastic component.

 

Summary

Individuals undergoing imaging procedures must be aware of the risk of the modality they are being sent to, but also of the risks of the alternatives. This blog provides just a bare bones, skeleton in the closet evaluation describing just the risks, and not the benefits. It may be prudent to print this blog out to bring with you to an imaging study if you are concerned about the risks you may be subjected to. Unfortunately for the present time, most physicians/radiologists do not seem to know about GDD, so this document may be the best overview you have available to determine what risks you are prepared to tolerate. Pay especial attention to the sections who are most at risk to determine the risk profile you are in and what risk you are willing to take.

 In the not too distant past, and for many years, I would have recommended MRI with GBCA for most cancer indications for essentially everyone. Most of my career I have spent generating comparisons of risks/benefits for MRI and CT, and often came down on the side of MRI (and often with GBCA). But if you are a white middle aged woman with a history of autoimmune disease, CT, even with the cancer risk, may be a modality that you prefer the risks to take the chance on. If you are the same type of person and feel you already have mild symptoms of GDD from an earlier GBCA injection, then you should never get another GBCA injection again, so either MRI without GBCA (recognizing some patients still might experience a worsening of symptoms from MRI alone), or getting a CT would make the safest and most sense > unless ultrasound can have an adequate accuracy for the indication you are being investigated for. 

    It may seem that if you have GDD from a GBCA that you should have undergone a CT with IBCA. The problem is one cannot go back in time and go with an alternate strategy. In the 2005-2010 range I spent much of my efforts into imaging safety looking at medical radiation. During that time I had a number of interactions with mothers whose children had undergone CT and 2-3 years later developed leukemia, and perished. There is no doubt that those mothers would have liked to opt for another imaging modality - such as MRI with GBCA and the risk of GDD. Determination of what risk you are prepared to accept is a very personal matter - but you have to understand what those risks mean.

 

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