Bedside point of care toxicology screens in the ED: Utility and pitfalls

Abstract

Exposure to drugs and toxins is a major cause for patients’ visits to the emergency department (ED). For most drugs-of-abuse intoxication, ED physicians are skeptical to rely on results of urine drug testing for emergent management decisions. This is partially because immunoassays, although rapid, have limitations in sensitivity and specificity and chromatographic assays, which are more definitive, are more labor intensive. Testing for toxic alcohols is needed, but rapid commercial assays are not available. ED physicians need stat assays for acetaminophen, salicylates, co-oximetry, cholinesterase, iron, and some therapeutic drugs that could be used as agents of self-harm. In this review, we look at the potential limitations of these screening tests and suggest improvements and innovations needed for better clinical utilization. New drugs of abuse should be sought and assays should be developed to meet changing abuse patterns.

INTRODUCTION

Self-harm poisoning and toxicological disasters constitute a significant proportion of patient load in the emergecy department. Pesticides and envenomations constitute a substancial proportion of the poisoned patients in developing counties as compared to prescription/recreational drugs in the developed world.[1]

Data from the Drug Abuse Warning Network (DAWN) have shown that a significant number of ED visits are associated with the presence of alcohol and drugs as indicated by history.[2] Some drugs (e.g. cocaine and heroin) may have a higher association with ED visits than others because they produce greater acute toxicity. Alcohol is not tabulated separately by DAWN; however, many studies have demonstrated a high prevalence of alcohol and substance abuse in ED patients, particularly trauma patients. Prevalence rates of approximately 25%, along with other data, suggest that nearly 30 million ED visits per year could be associated with some form of drug use.[3]

Unpublished data from ED visits at our center also indicate that alcohol intoxication remains the foremost reason for substance abuse-related ED visits followed by opioids, but this is fast changing in peripheral hospitals where cocaine- and heroin-related intoxications are increasingly being reported (unpublished data). Prescription drugs are also increasingly being used as agents of self-harm, and the focus has shifted from barbiturates in 70's to benzodiazepines and antiepileptics in 90's.[1]

In most instances, it is difficult to obtain the history from the patients and the management is guided by circumstancial evidence. Clinical examination and routine laboratory test are of limited utility in these cases.[4] POCT in ED is an important too in the hands of treating physicians to diagnose and manage critically ill poisoned patients. A thorough toxicology screening can identify many substances from a single sample but this information is often of no clinical utility because of the turn around time.[4]

Because of considerable limitations in resources and existing technology, it is impossible for any clinical laboratory to provide a full spectrum of toxicological analyses for the impaired or overdosed patient in real time. Given this limitation, it is appropriate to the “toxic screens” to have the greatest impact on patient management.[4] Some of the guidelines for routine screening for suspected toxic exposure have an entirely radical view about routine toxicology screening.

Laboratory Guideline for the Investigation of the Poisoned Patient prepared by the Alberta Medical Association (Alberta, Canada), recommended that “A nonspecific toxicology screen is of limited value in the majority of cases and is rarely indicated”[5] but the others recommend it at least in peripheral centers where a qualified toxicologist may not be available for opinion.[4]

In this review, we look at the basic principles of the toxic screen test, their utility, and limitations. We would also address the potential steps to circumvent the limitations of toxic screen tests.

TOXIC SCREENS OVER THE YEARS

Toxic screen tests have undergone a substantial change since their first use.[6] Conventional methods such as gas chromatography, mass spectroscopy, and liquid chromatography/tandem mass spectrometry (LC/MS/MS) can specifically identify drugs and their metabolites, but their use is hampered by the labor intensive nature and limited availability.[6]

Gas chromatography–mass screening (GC–MS) is an excellent platform for the sensitive and selective detection of a wide range of drugs and poisons. However, there are problems in detecting metabolites,[7] thermolabile compounds, or artifacts.[8,9,10] Therefore, this is not a practical screening test.

Conventional methods for toxic screening require multiple assays and repeated analysis on individual samples, which can be both expensive and time-consuming. LC tandem mass spectrometric analysis (LC/MS/MS) for toxicology screening provides an easy and rapid technique that enables simultaneous multi-drug quantification and identification from various samples such as saliva, urine, or serum. LC/MS/MS quantitative methods can detect and quantify drugs of abuse at levels significantly lower than the current cut-off levels.[5]

The problem with LC–MS-MS technology is that the instrument needs to be guided to acquire data on specific ion transitions at particular collision energies. Therefore, LC–MS-MS is not considered the best choice as a primary screening tool.[5]

Historically, urine has been the most popular matrix for drug testing as it is easy to collect, even in large volumes, and is easy to analyze. This remains true for clinical toxicology drug testing. In the last 10 years, new matrices such as oral fluid and hair are increasing in prevalence for workplace drug testing and medicolegal sectors.[11]

Conventional “Toxic screens” used Radio Immunoassay (RIA) and Enzyme Multiplied Immunoassay Test (EMIT). Today, RIA has become almost obsolete and the most commonly used laboratory based techniques for urine drug testing are Enzyme-Linked Sorbent Immunoassay (ELISA), EMIT, and Cloned Enzyme Donor Immunoassay (CEDIA). All of the modern automated immunological technologies have advanced drug-screening procedures further by providing accurate results at high speeds. Lab-on-a-chip technologies have been developed to consolidate a number of drug tests onto miniature chips and consolidation of drug testing platforms in a lab. These multiplex immunoassays based on ELISA principles can detect multiple drugs of abuse from a single undivided patient sample, leading to more time- and labor-effective screening. The above methods are now automated to meet the demands of a modern toxicology laboratory.[11]

The newer generation immunoassays are simple to perform and have rapid turnaround time but have limitations in the form of false positives due to cross-reactivity from structurally similar compounds. There can also be false negatives if only one specific agent is targeted; there could be failure to detect some drugs or their metabolites within that class.[6]

PITFALLS OF “TOXIC SCREENS”

An ideal “toxic screen” should be able to check for one specific drug or a number of different drugs at once. Urine or saliva preferred samples instead of blood; because urine and saliva are easier to obtain, tests are usually easier to do than blood tests and many drugs show up in either of them.[4] The ease of obtaining the sample, difficulty in substitution, or tampering makes it the practical screening matrix.

Drug abuse and toxic drug consumption differ in different geographic areas due to the production and distribution of these agents coupled with strict rules governing the availability of these agents in a particular country. Since “Toxic screens” using immunoassays screen for a number of drugs, it is better to have them custom-made to the needs of the particular region or country, depending on the prevalent drug culture. Most of the commercially available “toxic screening test” can detect common toxins such as amphetamines (including methamphetamine), barbiturates, benzodiazepines, cannabinoids (THC), cocaine, methadone, opioids (codeine, morphine, heroin, oxycodone, hydrocodone, etc.), phencyclidine (PCP), synthetic cannabinoids, and tricyclic antidepressants. However, toxic alcohols and pesticides are not a common component of most of them.

Alcohol testing is particularly difficult. Alcohol is metabolized at the rate of 0.015% of blood alcohol concentration (BAC) per hour. Thus, a person with a BAC of 0.08% will have no measurable alcohol in the bloodstream within 5½ h of the last drink, rendering breath testing useless. However, alcohol can be detected in urine for several days and ethyl glucuronide (EtG) testing extends the window to 3–4 days. In acute intoxications, a simple breathanalyzer test may be appropriate; however, for delayed testing, ethyl glucuronide (EtG) testing may need to be performed.[12]

Challenge for routine DOA/Tox screening immunoassays is to identify the actual compound and limit false positive results. Increasing structural diversity of common drugs within each class makes it difficult for a single assay to detect all compounds without compromising specificity. Structural similarity in drugs accounts for a high number of false positives.[6] This can be a deterrent for initiating definitive therapy in critically ill patient.

Another problem is that cutoff concentrations optimized for workplace drug testing are not necessarily appropriate for clinical toxicology. Although a true-positive result indicates use, it does not presume impairment or intoxication of the patient at the time of specimen collection.[4]

SUGGESTED SOLUTIONS

Selecting appropriate screening test suitable in a particular setup would solve many problems related to toxic screens. Recognition of the potential causes of poisoned patients presenting in emergency is the first step. “Knowing your enemy” would help the clinician identify the potential toxin. In India, the main cause of self-harm is pesticides followed by prescription drug overdose.[1] Benzodiazepines and anti-epileptics are important prescription drugs used for self harm. Recognition of “toxidromes” can be important in the effective clinical management of ED patients.[13] Proper identification of a particular toxidrome could be used to exclude some drug classes as the cause of the symptoms without urine drug testing. Toxidrome is a collection of physical findings and symptoms that are consistent with a particular drug or class of agents.[4] Although this is an interesting intervention, it is not infallible.[14] Polydrug exposure, delay in presentation, and altered presentation due to halfhearted interventions in periphery may misguide the clinician.[15]

Customized drug testing panels could be established that link specific symptoms to a particular menu of tests, e.g. sympathetics (cocaine and amphetamines), sedatives (benzodiazepines, tranquilizers, and barbiturates), and hallucinogenic agents (THC, LSD, and PCP). Although implementation of such an approach could reduce unnecessary utilization of laboratory tests, the opportunity to identify the causative agent could be missed if the initial clinical impressions were wrong.[4]

The strategy of having a two-tier system may work in a busy ER. Stat testing or initial “Toxic screen” should be rapid, bedside, immunoassay, adequate to identify acute toxicity for the commonly observed toxins for which a specific therapy or antidote may be available. More complicated and time-consuming tests should be reserved for patients with continuing medical problems from toxicological exposure or uncommon symptoms. This would help in early recognition of the common toxic agents and guide early interventions in potentially treatable toxic exposures.

It is important to stress the point that a broad-spectrum screening for toxins is not necessary for patients who are asymptomatic or are clinically improving.[4]

The problem of false positivity by “toxic screens” due to structural similarity in drugs[6] can also be addressed by adapting newer methods. Listing the major cross-reacting substances for each drug class when a positive result is reported by immunoassays may take care of this. This fact can also be highlighted in the package insert that a positive test may indicate a particular class of drug (not an individual drug) and a negative urine drug result does not indicate absence of all drugs of abuse. Test results need to be interpreted in light of the clinical history or “a clinical toxidrome”.[4] Another method suggested is computational molecular similarity model and historical data analysis.[16] This method involves the identification of the active compound by Time of Flight LCMS and then assigning a molecular formula to the compound. The compound such obtained can then be matched to the historical data / d atabases of toxic / hazard ous substances.[16] This information can be further c linically correlated to advise treatment.

Another commonly encountered problem is of having different cut offs for use and abuse.[6] The problem of different set of cutoffs for a particular drug can be sorted by using lower cut offs for routine toxicology screens. It would help pick up even a minimum drug exposure in an emergency setting.

CONCLUSION

“Toxic screens” are important point of care tests in emergency setting. They are useful adjuncts to clinician's assessment of a poisoned patient; however, these tests are not infallible. There is a need for improved immunoassays or more specific technologies to increase the reliability of “Toxic screen tests” in emergency settings.