James T. O’Donnell PharmD (Rush University Medical Center) and James J. O’Donnell PhD (Rosalind Franklin University of Medicine and Science),
The field of pharmacology is an important area of medicine that focuses on the effects of drugs in different biological systems. This field of study is especially relevant when considering drug-related side effects and adverse events in patients. Even with advancements in medication development, the potential for a drug-related side effect is always possible. Most side effects are considered minor and mostly just inconvenient, but there are drugs that can have serious and potentially deadly side effects. A pharmacologist is an expert in this arena and can provide useful interpretation of how these effects occurred and why the clinical manifestation appears as such.
As a pharmacologist, we have spent our careers studying the intricate interactions between the human body and drugs. We are frequently sought out to provide expert opinions in medical settings that involve drug complications. Medication errors are common in clinical settings and can contribute to serious side effects causing significant patient harm. A medication error can include prescription, omission, unauthorized drug, improper dosing, incorrect dose preparation and drug administration into the wrong place in the body. Depending on the severity of the error, the mistake can go unnoticed or contribute to damage and even death of the patient. While sometimes devastating, medication errors can provide a unique opportunity to learn more information on the effects of the administered drug and its impact on particular tissues.
We have been consulted in numerous interesting cases that demonstrate that even drugs deemed generally safe for use can show serious side effects if certain factors go wrong. If the drug dosing is incorrect, if the drug is not administered properly, if too much drug is given (overdose), if the patient has a condition in which the drug is contraindicated (not supposed to be used); these all can negatively impact how the drug effect will be seen in the patient and how serious unwanted, toxic side effects can be. There are two cases that we were asked to provide expert opinions on that showed very significant and debilitating effects of a generally safe class of drugs used for imaging (radiology) procedures. In both cases, the patients experienced medication errors in which they were incorrectly administered contrast agents in their myelography imaging procedures. The summaries provided below highlight the acute and long-term complications which developed. Following the summaries, we have provided our interpretations on how these drugs may have caused the injuries and our commentary on medication errors in myelography procedures.
While these toxic reactions are rare, more information is needed on the understanding of long-term ramifications following such incidents. There is relatively no information available on residual toxic effects, since the majority of available reports discuss acute findings in these cases, and an unfortunate majority of patients that receive overdoses or inadvertent (accidental administration into the body/spinal cord) injections of contrast agents die.
Myelography is a type of radiographic (X-ray or CT scan) imaging examination that doctors use to see inside the spinal cord and assess for spinal cord injury, cysts, tumors and other abnormalities. Myelography is generally regarded as a safe procedure with minimal possible risks when dosed and administered correctly. To perform the procedure, the doctor injects a contrast agent – a drug that acts as a type of dye – into the patient’s spinal canal to visualize the images of the spinal cord. Myelographic dyes temporarily change the way the imaging interacts with the body. Contrast agents make certain structures or tissues in the body appear more defined compared to the surrounding tissue. By improving the visibility of specific organs, blood vessels or tissues, contrast agents aid doctors in the diagnosis of medical conditions. Contrast materials are delivered into the body in one of three ways. They can be swallowed (taken by mouth or orally), administered by enema (given rectally) or injected into a blood vessel (vein or artery; also called given intravenously or intra-arterially). Intrathecal (spinal canal) iodinated contrast agents are commonly employed during myelography imaging procedures and are considered to be generally safe and effective when administered correctly.
CASE #1 (CH)
This first case involves a middle-aged woman – CH. CH was scheduled for a myelogram procedure. During her procedure, she was administered an intrathecal injection overdose of Isovue-M, a non-ionic iodinated contrast agent. CH was administered 2-3 times the recommended dose of Isovue-M and two times the recommended maximum dose for the myelogram procedure. Following the procedure, CH developed altered cognitive (thinking) ability, memory loss and seizure activity while hospitalized. Upon discharge she was released with ongoing medical problems including “altered mental status”, “contrast-induced seizures” and “status epilepticus”. A brain scan was performed 18 hours’ post-procedure which showed that the Isovue-M contrast agent was in spaces surrounding the brain, and images of the cerebral spinal fluid (CSF) were 200x higher than normal. Moderately high contrast agent in CSF was still observed two days later. It was clear to us that excessive levels of the contrast agent was exposed to brain tissue for an extended period of time. This brain exposure to toxic levels of the contrast agent was responsible for the serious effects that CH experienced immediately following the procedure. Unfortunately, CH suffered permanent damage from this toxic exposure and continues to experience significant medical complications including cognitive deficits, seizures, impairments in memory function, and significant hearing loss.
It was clear that the high levels of ISOVUE-M resulted in profound levels of the contrast agent to enter into the brain. The drug manufacturer specifically warns against entry of the drug into the brain and states that entry of a large or concentrated amount of the contrast agent increases the risk of neurotoxicity. Her reported side effects were consistent with those listed by the manufacturer for adverse events for the nervous system. Given the greatly excessive dose that CH received, the drug was able to access the brain causing significant and irreversible contrast neurotoxicity – death of brain cells – contributing to each of the neurologic and cognitive deficits experienced. As stated earlier, most patients do not survive, so the medical community does not have a lot of experience in assessing and predicting residual and long-term toxicities from such overdoses.
CASE #2 (DP)
This second case involves a middle-aged man – DP. DP was scheduled for a myelogram procedure as part of a workup for brief episodes of vertigo, or the sudden sensation that your head is spinning. During his procedure, he was inadvertently administered an intrathecal overdose of Conray, a non-ionic iodinated contrast agent that is not to be used (contraindicated) in this type of procedure. Following injection, DP exhibited signs of contrast-induced neurotoxicity including lower limb disturbances, seizure activity, cognitive dysfunction and memory loss. He also presented with burning and prickling sensations, tingling and spasms. It was quickly determined that he had been administered the incorrect contrast product for intrathecal use in myelography. Conray contrast media is never to be administered intrathecally and contraindicated for use in myelography. In attempts to remove the contrast agent, attempts were made to flush and drain the drug out of his system. DP was also treated with Keppra, an anti-epileptic drug, to control his seizure activity. DP was released four days following the procedure. Following discharge, he continued to experience persistent cognitive impairment, including the inability to concentrate and multitask, and dull tension-like headaches. He continues to exhibit neuromuscular impairments, including overactive or overresponsive reflexes, dizziness, unsteadiness, generalized weakness and muscle spasms.
In this case, it was immediately acknowledged that the wrong drug was delivered and emergency steps were taken to remove the drug from the central nervous system. Due to the known pharmacology of Conray contrast agent, intrathecal use and direct application in the CNS is contraindication -never to be used. The manufacturer warns against the use of intrathecal administration and states serious neurological adverse events, including death, convulsions, cerebral hemorrhage, coma, paralysis, seizures and brain edema. The accidental administration of a highly toxic and contraindicated agent resulted in direct entry of the agent into the brain and significant and irreversible contrast neurotoxicity.
Medical errors resulting in neurotoxicity
In the first case, the medication error that occurred resulted in the wrong dose of ISOVUE-M being delivered causing a significant overdose of the contrast agent. In the second case, the medication error that occurred resulted in the wrong contrast agent being injected into the spinal cord of the patient, one that was not to be used in this type of procedure. Both medication errors resulted in significant neurotoxicity causing permanent damage to brain structures and subsequent clinical manifestations.
The exact mechanisms underlying neural insult following contrast agent administration remains uncertain. It seems likely that these contrast agents were able to access the brain, either directly or by crossing through the blood brain barrier, and then acted to disrupt normal brain signaling and caused brain cell death. These agents are poisonous to the brain. Complications that result in aberrant brain activity can also lead to permanent damage. A causal relationship is often suggested between seizure-like behavior and deficits in cognitive abilities, i.e., impaired thinking and memory dysfunction. Both patients immediately experienced seizure activity following their procedures. It is likely that the seizures contributed to memory loss. The severity and permanent dysfunction that both patients continued to display support our opinions that the contrast agents contributed to significant damage of brain structures involved in information processing, thus leading to permanent memory impairment. Persistent damage to sensory and motor capabilities also most likely reflect damage to components of the spinal cord and brain regions involved in motor control.
A critical point in these cases is that contrast agents are CYTOTOXIC – meaning that they kill cells. If enough of the cells are killed or damaged, the function of that cell or brain structure, or region of the brain is damaged. Unfortunately, and notoriously, brain tissue and function does not regenerate like many other systems in the body.
The neurotoxicity experienced by both patients is multifaceted and caused by:
- Toxic nature of the drug’s pharmacology/chemistry
- Relative dispersion of the agent in the brain
- Cell death and damage to important CNS structures
The permanent contrast-induced damage to specific brain structures, e.g., mesial temporal, occipital and temporal cortical structures, likely correlates to cognition, memory, vision and hearing problems observed in these patients. Given the toxicity of the contrast agent and the exposure of the agent to the brain during this procedure, it is highly probable that the adverse reactions, both transient and permanent, are contrast-induced toxic reactions. Recall that both patients were being seen by doctors for issues unrelated to any neurological impairment. A reasonable, clinically valid, and scientifically sound explanation of their current neurological deficits is the acute neurotoxicity, from which both patients did not fully recover.
These cases highlight the devastating effects of medication errors. While these patients are fortunate to be alive, the long-term effects are serious and debilitating. More than 100,000 medication errors are reported to the FDA each year and most of these are preventable. In the cases discussed above, it appears that proper oversight on many levels was overlooked leading to these tragic drug induced injuries. In the hospital, dosing and drug administration should be quality checked by multiple people to ensure that patients are not at risk for potential life-threatening complications due to medication errors.