Prior to declaring a patient brain dead, confounding factors which could falsely cause the patient to appear dead must be eliminated. One important confounder is intoxication. Failure to recognize that a patient is intoxicated could lead to an incorrect diagnosis of brain death that in turn can lead to withdrawal of life support – thereby precipitating the patient’s death. So, there is no room for error here.
The two leading guidelines on brain death both recommend the use of urine toxicology screening to exclude intoxication.1,2 Seriously. If you don’t believe it, I’ve reproduced part the latest guideline below:1
The use of urine toxicology screens for brain death determination is inappropriate, for several reasons:
- Urine toxicology screens detect a handful of substances. Numerous substances are often missed on these screens (e.g., oxycodone, fentanyl). Especially with the advent of various designer drugs (e.g., carfentanil), these screens are wholly unable to exclude the presence of any intoxication.
- Urine toxicology screens are largely designed to detect drugs of abuse. However, suicidal ingestions are also common, and these may involve a wide array of substances (e.g., baclofen, valproic acid). Such ingestions will be missed with a urine toxicology screen.
- Urine toxicology screens are not standardized, with some hospitals screening for a broader range of substances than others. One goal of the World Brain Death project is to standardize declaration of brain death across hospitals. Such standardization cannot be achieved if we rely on a toxicology screen that is a hodgepodge of tests that each individual hospital cobbles together based on its own whims.
- Urine toxicology screens are notorious for false-positives due to cross-reactive substances (e.g., a patient taking a few over-the-counter cough and cold medications can have a very scary-looking toxicology panel). A list of common false-positives may be found here.
- Even a “true-positive” urine toxicology result provides little clinical information. The toxicology screen is designed to detect exposure to the substance, not intoxication. For example, let’s imagine a patient who took benzodiazepines, which were subsequently detected on the urine toxicology panel (a “true-positive” result). The patient might have taken a therapeutic dose of benzodiazepines, with no effect on their neurological examination. Or they might have taken a massive ingestion of benzodiazepines. Without any quantitative assessment, the urine toxicology screen doesn’t differentiate between incidental exposure versus lethal overdose.
The utility of urine toxicology screens is hotly debated within the field of toxicology. Most toxicologists seem skeptical of their value. But I think that we should be able to agree that urine toxicology screens are neither sensitive nor specific enough to have a pivotal role in the diagnosis of brain death – a situation where there is no acceptable margin of error.
I don’t believe that this should be a particularly original or unique perspective, but rather my guess is that it will be held by anyone who is educated in the limitations of the urine toxicology screens (e.g., toxicologists and emergency physicians). For example, following the publication of the 2020 guidelines, Drs. Emily Cohen and Robert Hoffman wrote the following letter to the editor detailing the inadequacies of the urine toxicology screen:3
The reply was woefully unable to contest their arguments:4
Indeed, if we search further backwards in the literature, we find a 2017 consensus position statement on this topic by the American College of Medical Toxicology, the American Academy of Clinical Toxicology, and Society of Critical Care Medicine.5 The statement explores numerous limitations of urine toxicology screens (reproduced below). Unfortunately, this statement seems to have been overlooked in the construction of the 2020 guidelines.
Thus, the purpose of this post isn’t to propose anything new or original, but rather to direct attention towards an ongoing and self-evident problem.
The optimal approach to a patient with suspected intoxication is an an ancillary test that is based upon blood flow (e.g., nuclear cerebral blood flow scan). A cerebral blood flow scan will not be affected by any ingestion or intoxication, so it is appropriate and reliable for a patient who may have an undefined intoxication. Unlike the urine toxicology screen, there is robust evidence supporting the adequacy of cerebral blood flow scans for the diagnosis of brain death.
A cerebral blood flow scan has numerous strengths which are worth expounding upon further:
- Testing will not be affected by any intoxication or ingestion.
- A cerebral blood flow scan that shows no blood flow (as interpreted by an attending radiologist) is nearly incontrovertible evidence of brain death.
- Absence of blood flow may allow for prompt diagnosis of brain death (avoiding awkward delays while awaiting send-out laboratory tests or waiting for substances to clear from the blood).
There is no room for error in the diagnosis of brain death. Thus, if there is clinical concern for intoxication, obtaining one additional test (a flow scan) is wholly reasonable. When compared to the numerous scans that we perform on critically ill patients that often have dubious yield, a cerebral flow scan should be worth pursuing if it can help clarify the diagnosis of brain death.
Our primary concern when diagnosing brain death must be to obtain the correct diagnosis. However, for the bean counters out there, it is worth mentioning that a flow scan is probably cost-effective. Obtaining a flow scan may avoid extended periods of observation, which provide no value to the patient and are extremely expensive (the cost of supporting a patient on mechanical ventilation is ~$5,000/day).
An example of how to approach brain death is shown below (further discussion about excluding intoxication is in the IBCC chapter here).
So hopefully this blog might move the needle, perhaps just a wee bit, on the disutility of urine toxicology screening in brain death evaluation. There seems to be a huge disconnect between the way neurologists and toxicologists conceptualize the urine toxicology panel. Attempting to bridge this divide with better communication will improve our care of these critically ill patients.
- 1.Greer D, Shemie S, Lewis A, et al. Determination of Brain Death/Death by Neurologic Criteria: The World Brain Death Project. JAMA. 2020;324(11):1078-1097. doi:10.1001/jama.2020.11586
- 2.Wijdicks E, Varelas P, Gronseth G, Greer D, American Academy of Neurology. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918. doi:10.1212/WNL.0b013e3181e242a8
- 3.Cohen E, Hoffman R. Determination of Brain Death. JAMA. 2021;325(5):492-493. doi:10.1001/jama.2020.23222
- 4.Sung G, Lewis A, Greer D. Determination of Brain Death-Reply. JAMA. 2021;325(5):494. doi:10.1001/jama.2020.23234
- 5.Neavyn M, Stolbach A, Greer D, et al. ACMT Position Statement: Determining Brain Death in Adults After Drug Overdose. J Med Toxicol. 2017;13(3):271-273. doi:10.1007/s13181-017-0606-8