A. Immunoassays
B. Tiered Testing
C. Broad Spectrum
Testing
D. Selectivity of
Testing
E. Drug Panels by
"Toxidromes"
F.
"Universal" Acetaminophen Screening
LMPG: Laboratory Support for Emergency
Toxicology
(Draft Guidelines)
Part
I. Recommendations
for Drug Testing to Support Emergency Department Toxicology
A. Immunoassays
Immunoassays, which have become the mainstay of stat urine drug testing,
have significant limitations in sensitivity and specificity.
Many emergency physicians are unaware of these limitations, and
will order all available immunoassay tests for every patients suspected of
drug use, irrespective of the presenting signs and symptoms, lack of
clinical significance for some drugs, availability of management measures,
and local prevalence for use and abuse of that drug.
Given the degree of cross-reactivities that many of these drug
assays have, the accuracy of testing for a drug with a low prevalence can
be very poor. The limited number of available immunoassays to drug classes
also limits the utility of this approach.
Furthermore, many clinicians are not even aware of what their own
laboratory drug panel might cover (5).
Recommendations throughout are shown in boxes.
|
Discussion
The Committee feels that it is the joint responsibility of the emergency department and clinical laboratories to provide initial education on the limitations of drug testing to new house officers and to maintain a continuous medical education program to existing practitioners. It is clear that this knowledge is not adequately taught at the undergraduate level, and it is inappropriate to expect that senior residents will have sufficient understanding of these limitations to effectively educate their junior house staff. The laboratory must inform the ED staff when there are changes made to the specificity and performance of commercial drugs-of-abuse immunoassays. They should also discuss the availability of new drug assays or assay platforms (e.g., point-of-care devices), and the appropriateness of implementing such assays in that institution. On the other hand, ED physicians must inform the laboratory staff of changing drug utilization patterns, the appearance of new drugs or analogs such as designer drugs (6,7), or testing and reporting needs that are not currently being met.
Due
to significant limitations in resources and existing technology, it is
impossible for any clinical laboratory to provide a full spectrum of
toxicologic analyses for the impaired or overdosed patient in real time.
Given this limitation, it is appropriate to make recommendations as
to which serum and urine tests have the greatest impact on patient
management, and can be realistically delivered.
|
Table 2. Stat Toxicology Assays Required to Support an Emergency Departmenta
|
Quantitative assays, serum Acetaminophen |
Qualitative assays, urine Tricyclic
antidepressants |
aTurnaround time of 1 h or less.
|
Discussion
A two-tiered
mechanism allows a laboratory to put the majority of their resources in
providing for the needs of the sick ED patient. The Committee has excluded certain drugs from the first tier
of testing because they do not contribute to significant toxicities, or,
are difficult to measure on a stat basis.
Some of these include the phenothiazines, calcium channel blockers,
beta blockers, hypnotics and tranquilizers (chloral hydrate,
ethchlorvynol, glutethimide), some anticholinergic drugs (e.g., atropine),
muscle relaxants (carisoprodol, cyclobenzaprine), some antidepressants
(e.g., fluoxetine), behavorial drugs (clonidine, methylphenidate), date
rape drugs (gamma-hydroxybutyrate, flunitrazepam), certain anesthetics
(e.g., ketamine), and analgesics (fentanyl and analogs).
Many of these drugs will be detected on the broad-spectrum tier of
testing.
Once the patient has stabilized, and if the etiology of the original
clinical problem is still unknown, it may be appropriate for the
laboratory to perform additional tests.
In this situation, the turnaround time may not be as critical as
for the tests in the first tier. Techniques
for a comprehensive urine drug screen profile include thin-layer
chromatography (8), liquid
chromatography with rapid scanning spectrophotometric detection (9),
gas chromatography (GC), GC with mass spectrophotometry (10),
and liquid chromatography/tandem mass spectrophotometry (11).
(A comparison of the advantages and disadvantages of each technique
is beyond the scope of these guidelines.)
Hospitals that do not have adequate resources to perform a
broad-spectrum screening panel can elect to send these specimens to a
reference laboratory or regional toxicology laboratory.
In this situation, laboratory personnel should determine the
reference laboratory’s methodologies used, expected turnaround time, and
assay limitations, and communicate this information to the attending
physician, as this may have impact on the interpretation of results.
It is important to note that the
list of tests shown in Table 2 are analytes the laboratory should make
available on a stat basis, so that when a patient who presents with signs
and symptoms suggesting exposure to one or more of these drugs, the
causative agent can be identified. Table
2 does not imply an ED panel of the tests that should be ordered on all
patients. The ED physician
and toxicologist must decide on the most appropriate plan of action based
on the clinical presentation on a case-by-case basis.
C.
Broad Spectrum Testing
General screening for a broad
spectrum of toxins is not indicated in the ED.
Stat testing for the toxins listed in Table 2 is adequate to
support evaluation of acute toxicity carried out in the ED.
|
Discussion
The toxins identified in Table 2 represent the common agents that will
cause a patient to experience adverse effects to the extent that it leads
to an ED visit. Table 2
represent those agents that can be readily recognized by experienced ED
staff, supported by stat testing provided by the clinical laboratory, for
which a specific therapy or antidote is available.
In the event that a patient presents either in coma or with bizarre
behavior that cannot be explained by one of these toxins, further
evaluation by a trained clinical toxicologist is indicated.
These evaluations usually occur outside the ED setting.
The clinical toxicologist may select from among a broader
assortment of tests for toxicants and tests that are usually provided by a
reference or regional laboratory.
D. Selectivity of
Testing
It is not appropriate for the clinical
laboratory to provide test results for all classes of drugs, simply
because an automated and inexpensive immunoassay is available.
Certain tests may not be indicated because they do not contribute
to significant toxicological sequelae, or have little or no prevalence in
that particular geographic location. There is an additional problem of
diagnostic inaccuracy if used on a general drug screen panel (particularly
with PCP and tricyclic antidepressants, TCAs) because existing
immunoassays exhibit significant cross-reactivity towards other drugs
(e.g., dextromethorphan, diphenhydramine and sertraline for PCP (12)
and phenothiazines, cyclobenzaprine, diphenhydramine for TCAs (13)). As shown in Figure 1, even if the assay has an accuracy of
99%, when it is tested on a population of subjects where the prevalence is
0.1%, the rate of false positive findings exceeds the rate of true
positive findings by 10-fold.
|
|
10,000 Subjects |
|
|
|
Non-abusers |
Abusers |
|
Negative Screen |
9890 True Negative |
0 False Negative |
|
Positive Screen |
100 False Positive |
10 True Positive |
|
Totals |
9990 |
10 |
Fig. 1.
The diagnostic outcome of a test that has an accuracy of 99% and is
used on a population with a prevalence of 0.1%.
Of 10,000 subjects screened, there will be 10 subjects who abuse
the drug in question, and all 10 will have a positive result for the assay
(99% accuracy). Of the
remaining 9990 non-drug abusing individuals, 100 will have a falsely
positive result (99% accuracy). Given
these pretest assumptions, only 9.1% of positive drug screen results (10
out of 110) will be from an individual who abuses the drug in question.
|
Discussion
The prevalence of methaqualone and phencyclidine (PCP) abuse is very
minimal in the U.S. today. In one recent study of drugs used in cases of alleged
sexual assault, ElSohly et al. found no cases of methaqualone and PCP use
among 1179 submitted urine samples (14).
A very low incidence of these drugs was also reported by 877
homosexual men (15).
While tetrahydrocannabinol (marijuana) and lysergic acid
diethylamide (LSD) are more widely abused, many clinical toxicologists do
not want to know if a patient is positive for this drug because they do
not contribute to major acute clinical problems (16).
THC testing may be useful in drug compliance and rehabilitation
programs that are outside the usual objectives of ED testing.
E. Drug Panels by “Toxidromes”
Patients who are drug intoxicated or overdosed often present to the ED with a collection of physical findings and symptoms that are consistent with a particular drug or class of agents. Recognition of these “toxidromes” can be important in the effective clinical management of that patient while in the ED (17). Proper identification of a particular toxidrome could be used to exclude some drug classes as the cause of the symptoms without performing the urine drug testing. Drug testing panels can be established that link specific symptoms to a particular menu of tests (e.g., sympathetic: cocaine, amphetamines; sedative: benzodiazepines, tranquilizers, barbiturates; hallucinogenic: marijuana, lysergic acid diethylamide, phencyclidine). Although implementation of such an approach could reduce the unnecessary utilization of laboratory tests, the opportunity of identifying the causative agent could be missed if the initial clinical impressions were made in error.
|
Discussion
Although the clinical laboratories
are under tremendous pressure to reduce
costs and utilization of laboratory services, elimination of a few drug
tests that are already available (i.e., regularly calibrated and quality
controlled) on the menu of tests on an automated testing platform on urine
collected and sent to the laboratory will not greatly impact the cost of
delivering laboratory services. On
the other hand, a delay in the triage and management of the overdosed
patient due to inappropriate laboratory orders can greatly affect the cost
for treating that patient, and may have an adverse effect on patient
outcomes. There has been at least one study that examined the potential
success of linking toxidromes to particular ED drug screening patterns (18).
When ED nurses, clinical pharmacists and medical residents were
asked to choose among eight toxidromes, the diagnostic accuracy ranged
from 79-88%, with the medical residents scoring the lowest of the group.
Although these figures indicate a reasonable degree of performance,
the critical question is what would the clinical and fiscal impact be for
the 12-21% of patients incorrectly diagnosed, if the toxicological causes
of these cases were not identified. The
inaccuracies in the assessment of toxidromes may be due to presence of
polydrug overdoses, delayed-onset toxicities (19),
or clinical inexperience. The
importance of clinical experience in the ED is a major factor in the
success of toxidrome accuracy and the potential use of specific drug
panels. In a study of
periodicity of drug overdose presentations, Raymond et al. concluded that
EDs are most likely to encounter overdosed patients in the early evening (20).
This is also a time of peak activity in the EDs, when both resident
supervision and tolerance of delays in patient management may be critical.
F. “Universal” Acetaminophen Screening
Acetaminophen overdose is a common clinical problem, with over 111,000 exposures reported to U.S. poison control centers and 40,000 associated ED cases per year. Following therapeutic dosages, the majority of acetaminophen is detoxified by conjugation and excreted in the urine. Toxic ingestion of acetaminophen results in more of the drug being metabolized by the CYP2E1 isoenzyme of cytochrome P450 to N-acetyl-p-benzoquinone imine, a highly reactive intermediate (21). Accumulation of this metabolite leads to fulminant hepatic failure. Therapy with N-acetylcysteine is most effective when initiated within 8-12 hours after ingestion. Unfortunately, the early stages of acetaminophen toxicity are usually asymptomatic or when present, are nonspecific, and can be easily missed (22). Determination of serum acetaminophen concentration will confirm ingestion and with Rumack-Matthews nomogram, allows for the initiation of appropriate therapy (23). Once the first signs of hepatic injury become apparent, (right upper quadrant pain and tenderness, and increases in the concentration of serum aminotransferases), treatment may be less effective. With the eventual development of fulminant liver failure occurs, orthotopic transplantation may be the only remaining therapeutic option.
|
Discussion
In the absence of
specific symptoms to suggest the presence of a disorder, the introduction
of a screening test for a particular population requires careful
consideration before implementation.
In the case of acetaminophen screening, the cost of testing many
patients to identify a small number of acetaminophen-overdosed patients
must be weighed against the cost of treating missed acetaminophen
ingestions that progresses to fulminant liver failure.
The incidence of detectable acetaminophen in blood of patients with
suicidal ingestions or mental status changes ranges from 6-11%.
There have been a few studies conducted to determine the number of
patients who deny ingestion of acetaminophen and yet had a potentially
hepatotoxic acetaminophen concentration.
In the study of Sporer et al. (24),
only 5 out of 1820 patients (0.3%) had a negative history and an
acetaminophen concentration of >50 mg/L. On the other hand, Ashbourne
et al. (25) found 7 of 365 (1.9%) of
patients with occult acetaminophen ingestion at potentially toxic
concentrations. While both
studies suggest that routine screening is warranted, there have been no
outcomes studies to show that this approach is cost effective or provides
medical benefit. Nevertheless,
the Committee felt that assessment of acetaminophen concentrations was
appropriate in any circumstance of suicidal ingestion or repeated overuse.
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