TOX SCREENS--1999

Toxicology Screens ("Tox screens") are often perceived as being able to rule out all poisonings. Unfortunately, it is simply not possible to test for all poisonous substances in the clinical laboratory. A more achievable goal is to offer testing that can rule out the presence of the most commonly encountered poisons. Even this much more modest goal is not readily achieved with a single test. Typically, a laboratory will offer several different toxicology screens, as well as other more specific toxicological testing. For example, Table 1 shows the various toxicological tests offered at Yale-New Haven Hospital. This menu may differ substantially from one institution to another, and the range of compounds detected by a toxicology screen of urine or serum may vary widely between laboratories.

     One of the most common toxicology screens involves thin layer chromatography (TLC) of an extract of urine, or less commonly gastric aspirate or serum (1-5). Extracted compounds are identified by their relative mobilities and by distinctive reactions with various developing sprays. In principle, almost any extractable compound can be identified by this approach. In practice, most labs reliably identify only 20-40 compounds, depending on the details of the method and the skill of the person interpreting the chromatograph. This technique detects only relatively high concentrations of analytes and does not provide quantitative information. Accordingly, this approach is primarily used on urine, where drug concentrations are greater than in serum and where quantitation is not critical. Identification of a drug or its metabolites in urine only indicates exposure to the substance in question and does not necessarily correlate with the patient's condition at the time of collection. For example, a positive result only indicates recent use, and is not necessarily indicative of active intoxication. A positive urine screen may provide guidance for selection of the appropriate serum assay when the history is unclear. Urine tox screens using either TLC or immunoassays do not provide unequivocal drug identification. If they are used for drug abuse testing, all positives should be confirmed by an independent method.

    TLC analysis of serum rarely provides information not provided by the same procedure applied to urine and it is less sensitive owing to lower drug concentrations in serum. Therefore, serum is rarely analyzed by this technique. Serum tox screens are generally done by gas chromatography (GC) or are a composite of relatively specific assays for drugs most commonly seen in overdose situations (1,3-9). The latter are not truly screens, but rather are performed as panels. GC assays and panels can be carried out more quickly than TLC procedures, so that answers can be obtained on a STAT basis. Moreover, they provide quantitative data that are more suitable for clinical correlation. However, these procedures detect only those drugs which are specifically assayed for. Thus, a "negative" serum tox screen should not be construed as having ruled out poisoning.

     A few laboratories offer tox screens on serum or urine using gas chromatography/ mass spectroscopy (GC/MS) or high performance liquid chromatography/ultraviolet spectroscopy (HPLC/UV) coupled with computer searching of spectral libraries. However, over 99% of significant poisonings involve a relatively small number of drugs (10) which can be readily identified by simpler techniques. Identification of less commonly encountered poisons rarely affects management (11). As a result, the practical utility of these costly, high tech approaches is limited.

Urine Toxicology Screen
      The Toxicology Laboratory (a section of the Yale-New Haven Hospital Clinical Chemistry Laboratory) offers a TLC "tox screen" for urine samples Monday through Friday (Table 1). In this screen, we attempt to identify all compounds detected. Clearly, patient history will help in making accurate identifications of uncommon compounds. Specific urine immunoassays are also available 24 hours a day for benzodiazepines, PCP, opiates, and cocaine metabolite. One of these tests should be requested instead of the "tox screen" if you are concerned about the presence of one of these specific drugs, or if the information is needed urgently.

Cocaine and THC
     Both cocaine and tetrahydrocannibinol (THC, the active ingredient in marijuana) are rapidly cleared from the body. The use of each drug is therefore inferred by the detection of longer-lived metabolites which are concentrated in the urine (specifically, benzoylecgonine for cocaine and THC carboxylic acid for THC). Because of their longer half-lives, these inactive metabolites may be detected after all drug effects have ceased. Thus, a negative test rules out recent drug use, but a positive test may be difficult to interpret. Benzoylecgonine is generally detectable for 2-3 days after cocaine use (12). The THC metabolite may be detected for several weeks after exposure in regular users (12), making the test essentially useless for confirming that someone is currently under the influence of marijuana. The Toxicology Lab at YNHH offers a urine test for cocaine metabolite, but does not test for THC or its metabolite.

Serum Overdose Panel
     A serum overdose panel is available on a STAT basis for the following: alcohols (methanol, ethanol, isopropanol and acetone), acetaminophen, barbiturates, salicylates and tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine, clomipramine and doxepin). We also offer individual assays for a number of drugs not in the overdose panel (e.g., theo-phylline, digoxin, ethylene glycol, carboxyhemoglobin (carbon monoxide), etc.).

     In order to provide rapid turnaround, a cascade approach is used for tricyclic antidepressants (TCAs) and barbiturates, when requested as part of the overdose panel. An initial screening immunoassay is used to determine whether these drugs are present in toxicologically significant amounts. Because the various TCAs and barbiturates exhibit different levels of cross-reactivity, these screening assays provide only qualitative information. While toxic levels of these drugs will give a positive screening result, therapeutic levels may or may not, depending on the cross-reactivity of the specific drug involved. This is particularly true for the barbiturates which exhibit a wide range of cross-reactivity. Accordingly, negative screening results for barbiturates are reported as "not present at a toxic level." Positive screening results are followed up with the specific screen; these are slower tests which provide quantitative information and may be ordered directly, if it is important to identify the presence of therapeutic drug concentrations.

     The TCA screen is a semiquantita-tive screening immunoassay. Results are reported as ranges. Clomipramine and doxepin exhibit only partial cross-reactivity, such that reported results represent only about half of the actual levels of these two drugs. Low levels of TCA cross-reactivity also occur with a number of structurally related drugs, particularly amoxapine, maprotiline, carbamazepine, phenothiazines, and antihistamines. These may produce positive results in the absence of tricyclic antidepressants; usually such results are in the low (0-300 ng/mL) range. Note that other types of antidepressants are not detected, including selective serotonin reuptake inhibitors (SSRI's; e.g., fluoxetine, paroxetine, sertraline), monoamine oxidase inhibitors (MAOI's; e.g., phenelzine, tranylcypromine), bupropion, trazodone and venlafaxine.

     The overdose panel was designed to assist in the management of patients with intentional overdoses. Because multiple drug ingestion is common in intentional overdose and the history is often unreliable, the overdose panel is recommended in all cases where an intentional overdose is a possibility. On the other hand, the overdose panel is rarely indicated in other situations, where a test for a specific drug or a urine toxicology screen is usually the preferred approach. The urine toxicology screen can detect many drugs that the overdose panel does not detect. We recognize that no single policy will be suitable for all situations. The lab will always attempt to optimize our approach to the specific problem (call Chemistry, extension 8-2444, and ask for either the Toxicology Supervisor or the Lab Resident).

Abused Drug Screens
     The urine toxicology screen serves as our primary screen for drugs of abuse. The increasing popularity of drug testing in the workplace has resulted in the passage of many laws to protect the rights of those being tested (12-16). Although the toxicology laboratory carries out drug testing for medical purposes only, we are obligated to comply with these laws. We confirm all positive results for abused drugs by an alternate method before reporting, except in medical emergencies. Positive immunoassays are confirmed by TLC, or by gas chromatography/mass spectroscopy (GC/MS) in certain instances. This means that initial results cannot be officially reported until confirmed by the next run. For emergency room and other acutely ill patients, a positive immunoassay result may be reported by telephone to the requesting physician, but will not appear in the patient's records until the result has been confirmed. For patients requiring laboratory documentation of drug use for immediate referral to a detoxification program, a special report may be issued prior to confirmation. This report will clearly indicate that this is a preliminary, unconfirmed result for medical use only.

     Specimens which are positive by immunoassay but negative by confirmatory testing will receive a final report of "negative". Although immunoassays can be performed on as little as 0.5 mL of urine, TLC requires at least 30 mL to confirm weak positives. For immunoassay-positive, TLC-negative specimens for which a definitive answer is critical, confirmatory testing may be done by GC/MS. Confirmation by GC/MS requires 1-2 weeks.

     We are also required to limit access to these results to those physicians directly involved in the care of the patient. To protect the privacy of those tested for drugs of abuse, results of drug tests are not entered into the computer data base, and are not available at computer terminals. Results must be obtained either from the patient's medical record or by contacting the laboratory. If you contact the laboratory, we must be able to confirm that you are a physician (for example, by calling you back on your listed office phone number). We regret that the need to meet legal requirements may cause some inconvenience.

Heavy Metals
     A "heavy metal screen" comprises either the Reinsch test (a relatively insensitive urine spot test for antimony, arsenic, bismuth and mercury) or a panel of tests on blood or urine for specific heavy metals. With the exception of lead, it is extremely uncommon to find elevated levels of heavy metals in persons who do not have a readily documented source of exposure. For heavy metal screening, a 24-hour urine is the preferred specimen. (Note that the routine urine toxicology screen does not include testing for heavy metals.) For lead testing, whole blood is preferred. Care must be taken during specimen collection to avoid contamination from environmental sources.

     The Toxicology Laboratory offers testing for lead in capillary and venous blood on Monday and Thursday. Other heavy metal testing is sent to a reference laboratory. Urine for heavy metal screening should be collected in containers provided by the laboratory (8-2444). Urine will be tested for lead, mercury, arsenic and cadmium. Turnaround time is 3-5 days. Requests for heavy metal screening should be discussed with the Laboratory Medicine Resident (8-2444) prior to collection.

Utility of Tox Screens
     Tox screens are generally ordered with the intention determining if poisoning has occurred but a negative tox screen does not rule out poisoning. Even the most comprehensive tox screen can reliably identify only a relatively small percentage of over 10,000 highly toxic sub-stances and over 6 million compounds of lesser toxicity. Moreover, a positive tox screen does not rule out other contributing etiologies, especially trauma due to falls while intoxicated or poisons not detected by the screen.

     A tox screen may be useful in several ways as seen in Table 2.

     Unfortunately, there are few poisonings for which specific treatments or anti-dotes are available. If a major overdose of one of these drugs is suspec-ted and the risk of the indicated intervention is less than the risk of waiting for laboratory confirmation, it may be appropriate to initiate therapy immediately, without waiting for lab results. Such interven-tions may include the use of naloxone for opiates, acetylcysteine for acetaminophen, deferoxamine for iron, vitamin B6 for isoniazid, vitamin K for warfarin, pralidoxime and/or atropine for organophosphates, nitrites and thiosulfate for cyanide, ethanol for methanol or for ethylene glycol, oxygen for carbon monoxide, and methylene blue for methemoglobi-nemia. Some antidotes are relatively benign but quite expensive (e.g., digoxin immune Fab for digoxin, or fomepizole for ethylene glycol or methanol). Here the risks of delaying therapy while awaiting drug levels need to be balanced against the cost of the intervention.

     If intervention is attended by significant risks, knowing the amount of drug present is required to decide whether to initiate therapy. Such higher risk interventions include hemodialysis or hemoperfusion for intoxication with methanol, ethylene glycol, salicylate, ethchlorvynol, lithium or theophylline intoxication. In all cases where a specific intervention is undertaken to reduce drug levels, a specific test for that drug should be requested before and after therapy to allow assessment of therapeutic efficacy.

     The Toxicology Laboratory provides a consultation service and can set up special tests when indicated. Please direct your questions to the Laboratory Medicine Resident (8-2444) or the Director of Toxicology, Dr. Pete Rainey (8-2445).

Pete Rainey, M.D.

References

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10. Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emer Med 16:443-497, 1998.

11. Kulig K. Initial management of ingestions of toxic substances. N Engl J Med 326:1677-81, 1992.

12. Green KB, Isenschmid DA. Medical review officer interpretation of urine drug test results. In Liu RH, Goldberger BA, eds., Handbook of Workplace Drug Testing. Washington:AACC Press, 1995. pp. 321-353.

13. Kwong TC et al. Critical issues in urinalysis of abused substances: Report of the substance abuse testing committee. Clin Chem 34:605-632, 1988.

14. Chamberlain RT. Legal issues related to drug testing in the clinical laboratory. Clin Chem 34:633-636, 1988.

15. AMA Council on Scientific Affairs. Issues in employee drug testing. JAMA 258:2089-2096, 1987.

16. Osterloh JD, Becker CE. Chemical dependency and drug testing in the workplace. West J Med 152:506-513, 1990.