"TOX SCREENS - 1996"

Toxicology Screens ("Tox screens") are probably the most misunderstood tests performed by the Clinical Lab. A common misperception is that a tox screen is a test that can rule out poisoning. No such test exists anywhere. There are more poisonous substances in the world than there are named diseases. It is clearly impossible to test for them all.

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. As a result, laboratories typically offer more than one kind of tox screen, and even the same kind of tox screen may show considerable variation in the substances actually detected in different laboratories. Typically, a laboratory will offer several different tox screens as well as other more specific toxicological testing. For example, Table 1 shows the various toxicological tests offered at Yale-New Haven Hospital. Clearly, it is important to know what is available before simply ordering a "tox screen."

One of the most common tox screens involves thin layer chromatography (TLC) on an extract of urine, or less commonly gastric aspirate or serum (1-6). Extracted compounds are identified by their relative mobilities (Rf values) 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. The 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. A positive urine screen may provide guidance for selection of the appropriate serum assay when the history is unclear.

Some laboratories offer a urine tox screen that is actually a panel of immunoassays for drugs of abuse. These panels detect only the drugs included in the panel. Moreover, a positive result only indicates recent use, and is not necessarily indicative of active intoxication. Urine tox screens do not allow 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 is less sensitive, due to the lower drug concentrations found 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 several relatively specific assays for drugs most commonly seen in overdose situations (1,3-10). The latter are not truly screens, but panels. The specific compounds detected in a panel or GC assay will vary from lab to lab. The assays employed 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 they are designed to look for. No information will be obtained on drugs not specifically included. Thus, a "negative" serum tox screen should not be construed as having ruled out poisoning.

A few laboratories may 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. Over 99% of significant poisonings involve a relatively small number of drugs readily identified in a good toxicology laboratory 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. The TLC screen is supplemented with immunoassays for opiates, phencyclidine (PCP) and cocaine metabolite. The immunoassays are run daily, but the TLC screens are run only Monday through Friday (cutoff time, 9 AM). In the TLC screen, we attempt to identify any compound which we detect. Clearly, an adequate history will help in making accurate identifications of uncommon compounds. Specific urine immuno-assays are also available 24 hours a day for amphetamines, benzodiazepines, barbiturates, methadone, PCP, opiates or cocaine metabolite. One of these tests should be requested instead of the "tox screen" if you are concerned about the presence of a specific drug, or if the information is needed urgently. (Requests for multiple individual immunoassays require Laboratory Medicine Resident consultation to establish a clinical indication for each requested drug.)

Cocaine and THC

Both cocaine and tetrahydrocannibinol (THC) 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. Our Toxicology Laboratory offers a urine test for this cocaine metabolite, but does not test for THC or its metabolite.

Serum Overdose Panel

A serum overdose panel is also offered and is available on a STAT basis. The drugs specifically looked for and quantified are 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., theophylline, 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 "TCA screen" or the "barbiturate screen," as appropriate. These are slower tests that provide quantitative information. One of the latter tests may be ordered directly, if it is important to identify the presence of the drug at therapeutic concentrations.

The TCA screen is a semiquantitative screening immunoassay. Results are reported as ranges. Clomipramine and doxepin exhibit only partial cross-reactivity, so that reported results represent only about half of the actual levels of these two drugs. Low levels of 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, such as fluoxetine and trazodone, are not detected.

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 history is often unreliable, the overdose panel is recommended in all cases where 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 will detect many drugs that the overdose panel will not detect. We recognize that no single policy will be suitable for all situations. If contacted, we will attempt to optimize our approach to the specific problem (call Chemistry, extension 5-2444, and ask for either the Toxicology Supervisor or the Lab Resident).

Abused Drug Screens

The urine toxicology screen serves as our primary screen for abused drugs. 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 only carries out drug testing for medical purposes, we nonetheless are required to comply with these principles. We confirm all positive results by an alternate method before they may be reported, except in medical emergencies. Positive immunoassays are confirmed by TLC, or by gas chromatography/mass spectroscopy (GC/MS) in certain instances. This means that results cannot be confirmed and officially reported until 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. Confirmed results may not be obtainable on specimens of less than 30 mL total volume. 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 pager or listed office phone number). We regret that these policies, required by law, may cause some inconvenience.

Heavy Metals

Depending on the laboratory, a "heavy metal screen" is usually 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. The metals included in the panel may vary with the laboratory. With the exception of lead, it is extremely uncommon to find elevated levels of heavy metals in persons who are not occupationally exposed. The yield of screening is extremely low in patients 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. Specimens for heavy metal screening should be collected in containers provided by the laboratory (5-2444). They 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 (5-2444) prior to collection.

Utility of Tox Screens

Tox screens are generally ordered with the intention of ruling in or ruling out poisoning in a patient. 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 substances 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 and poisons not detected by the screen. A tox screen may be useful in several ways as seen in Table 2.

At present there are few drugs for which specific treatments or antidotes are available. If a major overdose of one of these drugs is suspected 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 interventions 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 methemoglobinemia.

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 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 consult service and can sometimes set up special tests when indicated. Please direct your questions to the Laboratory Medicine Resident (5-2444) or to the Director of Toxicology, Dr. Pete Rainey (5-2445).

References

1. Weisman RS, Howland MA, Vereby K. The toxicology laboratory. In: LR Goldfrank et al., eds., Goldfrank's Toxicologic Emergencies. Norwalk, CT:Appleton-Lange, 1994. pp. 99-108.
2. Davidow B, Petri NL, Quame B. A thin-layer chromatographic screening procedure for detecting drug abuse. Am J Clin Pathol 50:714-719, 1968.
3. Berry DJ, Grove, J. Emergency toxicological screening for drugs commonly taken in overdose. J Chromatograpy 80:205- 219, 1973
4. Decker WJ. Rapid screening procedures for drugs. Clin Toxicol Bull 3:169- 173, 1973
5. Helliwell M, Hampel G, Sinclair E, Huggett A, Flanagan RJ. Value of emergency toxicological investigations in differential dianosis of coma. Br Med J 2:819-821, 1979
6. Widdop B, "Drug analysis in hte overdosed patient" in The Poisoned Patient, CIBA Foundation Symposium, new series, Vol 26, pp 219-237, Elsevier, New York, 1974
7. Bailey DN. Results of limited versus comprehensive toxicology screening in a university medical center. Am J Clin Path 105:572-575, 1996.
8. Oserloh JD. Utility and reliability of emergency toxicologic testing. Emerg Clin North Am 8:693-724, 1990.
9. Hepler BR, Sutheimer CA, Sunshine I. The role of the toxicology laboratory in emergency medicine. J Toxicol Clin Toxicol 19:353-365, 1982.
10. John D, Byers J. Cost effective drug screening in the laboratory. Clin Toxicol 18:459-469, 1981.
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., Handbood of Workplace Drug Testing. Washingtion:AACC Press, 1995. pp. 321-353.
13. Kwong TA et al. Critical issures in urinalysis of abused substances: Report of the substance abuse testing committee. Clin Chen 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.

Table 1

Table 1. TOXICOLOGY TESTS AT Y-NHH
TEST	SUBSTRATE	DRUGS ROUTINELY DETECTED
Toxicology screen (M-F; cut off 9 AM)	Urine	Amphetamines, antihistamines, barbiturates, benzodiazepines (some), caffeine, cocaine and metabolites, codeine, decongestants, (ephedrine, pseudoephedrine, phenylpropanolamine), diuretics (some), hydroxyzine, methadone, meperidine (Demerol), morphine, nicotine, phenothiazines, propoxyphene, quinine, tricyclic antidepressants. (Other drugs may be detected if they are specifically requested and an authentic standard is available.)
Specific Immunoassays (daily, STAT)	Urine	Amphetamines, barbiturates, benzodiazepines, cocaine metabolite, methadone, opiates, phencyclidine (PCP).
Overdose panel (STAT)	Serum	Acetaminophen, acetone, amitriptyline barbiturates, clomipramine, desipramine, doxepine, ethanol, imipramine, isopropanol, methanol, notriptyline, salicylates.
Specific Assays (daily, STAT)	Serum	All tests in overdose panel, plus caffeine, carbamazepine, carboxyhemoglobin, chlordiazepoxide, cholinesterase (insecticides), diazepam, digoxin, ethchlorvynol, ethylene glycol, iron, lead, lidocaine, lithium, methemoglobin, N-acetyl-procaineamide, phenobarbital, phenytoin, primidone, procainamide, quinidine, theophylline, thiocyanate, valproic acid.

Table 2

Table 2. INDICATIONS FOR A TOX SCREEN
To establish a primary or contributing diagnosis. To confirm and document a clinical diagnosis. To determine prognosis (qualitative data usually needed). To confirm brain death (by ruling out drugs as a cause of a flat EEG). To determine whether to undertake specific interventions. To determine whether to admit a patient.