Frequency of ClinicalToxicology Test-Ordering (Primarily
Overdose Cases) and Results in a Large Urban General Hospital
George
D. Lundberg,
Clifford B. Walberg, and Violet A. Pantllk
We report one year’s analytical data from a clinical
toxicology laboratory of a large urban hospital. The
laboratory was designed to perform tests on seriously ill patients believed to be suffering from possible
drug overdose. The data describe the types and
numbers of tests requested and percent positive.
Barbiturates, ethanol, a “hypnotic screen,” phenothiazines, and salicylates were the leading requests
and positive findings among the 63 drug determinations studied. The mechanism of organizing a laboratory along “patient-focused”
lines is described and
the clinician-laboratory
interface is discussed. We
believe that these data could be of value to anyone
contemplating
offering a clinical toxicology service
for the first time or in assisting in the reorganization
of their present service.
A profusion
of drug abuse is a phenomenon
of our
time. Many
patients
suspected
of being ill from a
drug(s)
are encountered
daily in emergency
rooms,
clinics,
and doctors’
offices. Whether,
and how, to
substantiate
the presence
of a drug as a factor related to a clinical state continues
to be a major problem
in many clinical settings.
Techniques
for laboratory
identification
of drugs of
abuse have improved
greatly
in recent years. Many
instructive
workshops
in methods
of toxicologic
analysis of human materials
and the increasing
availability of improved
instrumentation
and methodology
have resulted
in greatly
improved
availability
of
drug testing
of body fluids
in many
parts
of our
country.
Nonetheless,
there is still a problem
of what
tests the laboratory
should
make
available,
what
tests the physician
should order, and what a reasonable “turn-around”
time should be.
Analysis
of the “general
unknown,”
a specimen
submitted
to the toxicology
laboratory
with a request for a rapid and definitive
analysis
for “anything the patient
may have taken,”
while perhaps
desirable,
is not yet feasible for practical
clinical use.
Thus, educated
judgments
must be made in ordering
toxicologic
tests.
Department
of Pathology,
University
of Southern
California
School of Medicine;
and the Section of Laboratories
and Pathology, Los Angeles
County-University
of Southern
California
Medical Center, Los Angeles 90033.
Received Nov. 23; accepted
Nov. 26, 1973.
We have reported on the organization
of a clinical
toxicology laboratory
along “patient-focused”
lines1
(1) in which optimal
turn-around
time (i.e., time
from receipt of specimen to report) for scores of clinical toxicological analyses-within
realistic methodological, technical,
instrumental-system
and fiscal restraints-was
the prime
consideration.
Our service
laboratory
is part of the Section of Laboratories
and
Pathology of the Los Angeles County-USC
Medical
Center. It has 16 full-time
employees,
an annual
budget of approximately
$300 000, and is open 24
hours a day, seven days a week for comprehensive,
in-house,
intrinsically-complete,
real-time
response
along patient-focused
lines. This report documents
the first full calendar
year of this laboratory’s
operations in 1972.
How the Laboratory Is Used
Tests are ordered
by following the directions
on a
request
slip, which
details
test availability,
turnaround
time,
proper
specimen,
and generic-trade
name equivalents.
Additional
information
is included in a 20-page
section
of the “Laboratory
User’s
Manual,”
distributed
annually
to 960 using physicians and 350 nursing
stations
and hospital
offices
(2).
For practical
use of the toxicology
laboratory,
future planning,
and clinical research,
the physician
is
asked to indicate
the following
clinical
data:
age,
sex, race, state of consciousness
(awake,
lethargic,
belligerent,
delirious,
coma stages 1, 2, 3, or 4), suspected drug or poison, current
drug therapy,
chronic
drug use (what
drugs),
history,
and diagnosis.
In
most
cases
this information
is actually
entered
on
the request
form, perhaps
because
the format
follows
that of an “Overdose
History and Physical
Examination (Drug Abuse)”
form, which the physician
usually has already filled out.
The
check-off
format
for ordering
tests
was:
Serum: alcohol, quantitative;
barbiturate,
quantitative, long and short acting; hypnotic
screen, qualitative,
including
carisoprodol,
chlordiazepoxide,
di1Lundberg,
G. D., Walberg,
C. B., and
Gupta,
R. C., The
tient-focused
approach to clincal toxicology laboratory
tion. Amer. J. Gun. Pat hou. 57, 262 (1972), (abstract).
CLINICAL
CHEMISTRY,
pa-
organiza-
Vol. 20. No. 2, 1974
121
Table 1. Tests Requested and Number of Positives Found
Drug
Total
requests
Total
positives
Positive,
%
Type”
Sourceb
TAT’
Acetaminophen
Alcohol, ethyl
Alcohol, isopropyl
Quant
Quant
Quant
S
S
S
4
4
4
2
1
50
Spectrophotometric
4624
2261
49
8
8
100
Alcohol, methyl
Quant
S
4
12
1
S.Quant
Qual
S-Quant
S-Quant
S-Quant
U
U
U
U
U
>24
4
>24
4
>24
51
415
121
156
Dichromate oxidation
Dichromate oxidation
& GC6
Dichromate oxidation
& GC
GC
TLC’
GC
13
Barbiturates
Bromide
Caffeine
Carboxyhemoglobin
Carisoprodol
Chioral hydrate
Chloral hydrate
Chlordiazepoxide
Chlorpheniramine
Chlorpropamide
Cholinesterase5
Cocaine
Codeine
Dextromethorphan
Diazepam
Diphenhydramine
Diphenylhydantoin
Doxepin
Ethchlorvynol
Ethchlorvynol
Quant
Quant
S-Quant
Quant
Quant
Quant
Qual
Quant
S-Quant
Quant
Quant
S-Quant
S.Quant
S-Quant
Quant
S-Quant
Quant
S.Quant
Qual
Quant
Quant
4
4
>24
4
>24
>24
4
>24
>24
>24
4
>24
>24
>24
>24
>24
4
>24
4
4
>24
7182
134
1
Ethinamate
S
S
U
B
S
S
U
S
U
S
S
U
U
U
S
U
S
U
U
S
S
Flurazepam
Quant
S
Glutethimide
Heavy-metal screen
Hypnotic screen
Iront
Isoniazid (INH)
Lead screen
Quant
Qual
Qual
Quant
Quant
Qual
S
U
S
S
S
U
Amitriptyline
Amphetamine
Amphetamine
Arsenic
Atropine
screen
194
2
8
33
65
101
37
24
23
24
4
31
4260
62
1
88
59
46
100
28
Method
Gutzeit
TLC & GC
Spectrophotometric
Colorimetric
GC
Spectrophotometric
2
45
100
22
17
77
GC
2
1
50
76
16
21
1
13
8
4
0
11
0
85
50
0
Pyridine reaction
Spectrophotometric
GC
8
5
1
18
1
83
4
0
63
100
18
67
66
3
2
808
532
3
12
55
100
1
3
5
52
0
>24
15
0
0
>24
4
4
4
>24
4
200
4874
66
3
176
37
2
908
32
2
11
62
1
60
42
95
0
19
48
67
6
uv”
uv
Spectrophotometric
uv
Spectrophotometric uv
Spectrophotometric uv
TLC
TLC & GC
GC
Spectrophotometric uv
TLC & GC
Spectrophotometric uv
GC
Diphenylamine reaction
Spectrophotometric
Spectrophotometric
& GC
Spectrophotometric
uv & GC
Spectrophotometric
Reinsch test
TLC & GC
Bathophenanthroline
Spectrophotometric
uv
uv
Fluorescence
(as coproporphyrin)
azepam,
ethchlorvynol,
ethinamate,
flurazepam,
glutethimide,
mebutamate,
meprobamate,
methaqualone, methocarbamol,
methyprylon,
and oxazepam.
Urine: amphetamine,
qualitative
and semi-quantitative; arsenic,
semi-quantitative;
heavy metals, qualitative (Reinsch
test: includes
arsenic,
mercury,
and
antimony);
lead screen
(coproporphyrin),
qualitative; narcotics
and related
bases,
qualitative
and
semi-quantitative,
including
codeine,
heroin (as morphine),
meperidine,
methadone,
morphine,
oxycodone,
pentazocine,
and
propoxyphene;
phenothiazines,
semi-quantitative;
and salicylate,
quantitative. The drugs included
in the “Hypnotic
Screen”
and “Narcotic
Screen”
are listed
on the request
sheet,
in order not to mislead
the physician
into
thinking
the two screening
procedures
detect all possible drugs-a
common
and all-too-frequent
misconception.
122
CLINICAL
CHEMISTRY,
Vol. 20,
No.2,
1974
An expanded
list of available
tests is included
in
the Laboratory
Users Manual,
and any of these tests
may be requested
by writing in a space provided
on
the Toxicology
Request
Form.
The laboratory
responds to all requests
in the stipulated
turn-around
time. A 4-h turn-around
time for appropriate
requests
has eliminated
the use of the designation
“stat.”
If the requests
appear
unreasonable
in the
light of the clinical
data, the pathology
resident
in
the Toxicology
Laboratory
or “on call” queries
the
requesting
clinician
to verify the request
and has the
authority
to cancel the request if unjustified
by clinical circumstances.
Results
There were 89834 patients
admitted
to the LACUSC Medical
Center
in 1972. The number
of patients on whom some toxicologic
test was requested
Table 1. Continued
Drug
Total
requests
Total
positives
Typea
Sourcet
TAT
Meperidine
S-Quant
U
>24
2
1
Meprobamate
Methadone
Quant
S-Quant
S
U
>24
>24
24
2
Methapyrilene
Methaqualone
S.Quant
Quant
U
S
>24
>24
1
Methemoglobin
Methylphenidate
Quant
S-Quant
B
U
Methyprylon
Quant
Morphine
Positive,
%
Method
50
TLC & GC
9
38
2
100
13
0
5
Spectrophotometric
TLC & GC
TLC & GC
38
4
>24
22
2
2
0
9
0
Spectrophotometric
S
>24
10
0
0
GC
S-Quant
U
>24
13
4
31
Narcotic screen
Nortriptyline
Oxazepam
Qual
S-Quant
Quant
U
U
S
>24
>24
>24
1080
1
15
232
1
0
22
100
0
TLC & GC
GC
Paraldehyde
Pentazocine
Phenobarbital
Phenothiazine
Primadone
Procainamide
Quant
S-Quant
Quant
S-Quant
Quant
Quant
5
U
S
U
S
S
>24
>24
4
4
>24
>24
5
2
71
1778
11
2
Propoxyphene
Quinidine
Salicylates
Strychnine
Quant
Quant
Quant
5-Quant
S
S
S,U
U
24
24
4
>24
3
1
3
2
63
362
6
0
3
60
100
89
20
55
0
100
GC
TLC & GC
Spectrophotometric
Forrest test
GC
Spectrophotometric
TLC & GC
1
100
1704
7
849
0
50
0
Colorimetric
TLC & Spectrophoto-
Sulfhemoglobin
Sulfonamides
Trichloroethylene
Quant
Quant
Quant
B
S
S
4
24
>24
22
3
1
0
1
0
0
33
0
metric uv
Spectrophotometric
Spectrophotometric
GC
Warfarin
Quant
5
>24
1
0
0
24205
10092
Total for year 1972
0
Spectrophotometric
& GC
GC
GC
Spectrophotometric
& GC
uv
uv
Fluorimetric
Spectrophotometric
“Type of request: Quant = quantitative;
Qual = qualitative;
S-Quant = semi-quantitative.
Source: S = serum; U = urine; B = whole blood.
‘Turn
around time: The maximum
number
of hours within which the physician
may reasonably
expect
thetimethe
specimen
reachestheToxicology
Laboratory,
which is operated
on a continuous
basis.
d Ultraviolet.
Gas-chromatography.
/ Thin.layer chromatography.
Cholinesterase
is considered
Iron intoxication
is indicated
uv
a result,
measured
ui
from
positive for insecticide
poisoning
when the level is abnormally
low (below 569 U).
and counted as positive when the level in serum is above the normal level.
was 10 100, or about 11% of all admissions.
Almost
all of the tests performed
by the Toxicology
Laboratory were on patients
admitted
to the hospital
for
overdose
or a drug-related
problem.
The total number of toxicologic
tests requested
was 24 205, an average of 2.4 tests per patient,
ranging
from one to as
many as 11 per request.
This represents
an average
of 65 tests on 28 patients
per calendar
day. Of the
total number
of tests requested,
10092 (41.7%) were
positive.
Table 1 tabulates
the 63 different
assays requested, methods
used, turn-around
time, and number
of
positives.
Two qualitative
screen panels for 12 hypnotics and tranquilizers
and 7 narcotics
are listed in
Table 2, showing the frequency
and percent positives
of drugs found. Table 3 lists the tests that appear on
the Toxicology
Request
Form and shows the ordering
frequency
of each.
All presumptives
found by thin-layer
chromatog-
raphy
(TLC) on the hypnotic
and narcotic
screens
are confirmed
by gas chromatography
on the extracts of serum or urine previously
prepared
for the
screening
procedures.
Positive
identification
is followed by quantitation
at a slower turn-around
time
and is either assayed by ultraviolet
spectrophotometnc methods
(in the case of serum),
or gas chromatography
(urine)
with use of internal
standards.
In
general,
assays on serum are quantitative,
and most
assays on urine are considered
semi-quantitative
because they are performed
on casual
(i.e., untimed)
samples.
The individual
requests
for quantitative
or
semi-quantitative
determinations
of drugs included
in the hypnotic
and narcotic
screens,
listed in Table
1, do not include
the number
of quantitative
assays
done on presumptive
cases.
For a total count
of
quantitative
assays performed
for each drug in the
screens,
the number
of positives
listed in Table
2
should be added to those listed in Table 1.
CLINICAL
CHEMISTRY,
Vol. 20, No. 2. 1974
123
Table 2. Panel Screens Listed on Request Form:
Percent Positives of Drugs Found
Hypnotic
screen
Total no. requests
Total no. positives
Carisoprodol
Chlordiazepoxide
Diazepam
Ethchlorvynol
4874
906
4
189
277
50
Ethinamate
Flurazepam
Glutethimide
0
0
86
131
128
36
Meprobamate
Methaq ualone
Methyprylon
Oxazepam
Narcotic
5
0.1
3.9
5.7
1.0
1.8
2.7
2.6
0.7
0.1
screen
Total no. requests
Total no. positives
Codeine
Meperidine
1080
232
43
27
24
Methadone
Morphine
Oxycodone
72
Pentazocine
7
24
Propoxyphene
35
“Percent
Percent
b
18.6%’
of total requests
of total requests
for hypnotic
for narcotic
2l.5%
4.0
2.5
2.2
6.7
0.7
2.2
3.2
screen.
screen.
Discussion
The data presented
indicate
the massive nature of
the drug problem
as reflected
in clearly documented
laboratory
findings
in this hospital.
Clearly,
this
mirrors an enormous
community
problem.
This laboratory
was designed
to perform
tests on
patients
who were seriously
ill from possible
drug
overdose.
It was not intended
to be used for the determination
of therapeutic
concentrations
or for
problems
related to large scale screening
of urines for
drugs for legal or disciplinary
purposes
or patients
who apparently
are not clinically
ill from a drug.
Therefore,
the volume
of work represents
tests performed mainly to assist the physician
in the diagnosis and treatment
of suspected
overdose
cases. The
principal
exceptions
were requests
to measure
diphenylhydantoin
and phenobarbital
in serum, usually so
that therapeutic
concentrations
could be assessed
during
anticonvulsant
therapy.
This fact prompted
us to change the turn-around
time from 4 to 24 h for
these assays.
To request
a given test or panel, the clinician
had
to make a judgment
based on clinical
information.
How good his judgment
was may be indicated
by the
percent
positivity
in tests requested
(Table 1). To be
totally valid from a statistical
standpoint,
as an epidemiologic
screen,
every patient
should
have had
every test performed
on him. For fiscal, technical,
and educational
reasons this was not done. This is a
large teaching
institution,
and at this point in the
development
of clinical toxicology
as a discipline,
we
believe that it is better to allow the clinician
a guided choice as to what he requests,
as a learning
experience, rather than to make available
to him a complete robot-like
“toxicology
screen.”
Although
the Patient-Focus
Clinical
Toxicology
Committee
authorized
134 tests, and methods
were
available
for them, only 63 different
assays were requested.
Of these, 92.2% were those on the check-off
list on the requisition
form (Table 3), while many of
the others constituted
specific quantitative
requests
for drugs listed in the various screens.
We conclude
from this that the request
form is correctly
constituted and that clinicians
are greatly guided in their
ordering
patterns
by a request
form. The large percentage
of positives
for items listed on the request
form may indicate
a judicious
selection
of tests for
routine
ordering
(Table
3), except
for the heavy
metals
and lead screen.
The unreasonably
high request frequency
relative
to the low yield of positives
on these two tests resulted
in their exclusion
from a
revised
request
The
two
panel
form.
screens
(Table
2) were designed
Table 3. Tests Listed on Request Form: Number Ordered Directly by Checking Request Form
Frequency of
Test
No. requested
Alcohol
Amphetamine screen
Narcotic screen
4624
7182
1704
4874
536
1080
Phenoth iazi ne
1778
Barbiturate
Salicylate, serum & urine
Hypnotic screen
Heavy metal screen
Arsenic
Lead screen
Total no. tests
Requested directly
“Based
124
on 10100 admissions.
CLINICAL
CHEMISTRY,
Vol. 20, No. 2, 1974
200
156
176
22310
Positive,
49
59
50
19
24
22
20
1
24
6
%
request, %“
45.8
71.1
16.9
48.3
5.3
10.7
17.6
2.0
1.5
1.7
Percent of total
workload
(24205 tests)
19.1
29.7
7.0
20.1
2.2
4.5
7-4
0.8
0.7
0.7
to
detect drugs having related
pharmacological
effects,
and were those that could be conveniently
separated
and detected
on a single thin-layer
chromatogram.
These
panels
offered
the physician
a convenient
means of ruling in or out a number
of drugs at one
time.
The physician
frequently
ordered
the panel
even though
the causative
drug was already
known.
This had the effect of finding
or ruling out other
drugs not suspected,
but it had the adverse effect of
delaying
the quantitation
of the known drug and frequently
exhausted
the sample.
However,
ruling out
multiple
drugs by TLC screening
was vastly more efficient
and timely
than performing
individual
tests
for each drug included
in the panel.
The accumulation
of reliable
qualitative,
semiquantitative,
and quantitative
drug data in a timeframe closely tied to the clinical data present
on the
form also has produced
a wealth of information
dealing with interpretive
clinical toxicology
(drug levels
vs.
state
of
consciousness),
drug
interactions
(mixtures,
synergism),
pharmacokinetics
in overdose
situations,
and other clinical epidemiologic
data.2’3
Many physicians
still believe that one can treat
overdose
patients
equally
well with or without
toxi-
2Pocock, E. R., Walberg, C. B., and Lundberg, G. D., A clinical
and toxicologic analysis of 1000 consecutive patients suspected of
drug overdosage. Amer. J. Clin. Pathol. 60, 134(1973), (abstract).
3Walberg, C. B., Lundberg, G. D., and Michaels, A. D., The
toxicology of methaqualone
with clinical correlation.
Amer. J.
Gun. Pathou., in press (abstract).
cologic laboratory
support,
while others use the laboratory
aggressively
and completely.
In general,
the
physicians
who depend
least upon the toxicology
laboratory
are those who do not have ready access to
such a capability,
while those who use it freely are
those to whom such facilities
are available
in whose
quality
and rapid
response
they have confidence.
The large number
of requests
for toxicologic
assays
in our hospital
suggests
that the physicians
believe
there is value in these assays for assisting
in the diagnosis and treatment
of many patients.
Our workload is continually
increasing,
which may further reflect the confidence
of the physicians
in the toxicology laboratory.
Although patterns
of drug use and abuse do shift,
there is moderate
stability
among the more common
drug problems.
The epidemiologic
frequency
of specific acute
drug-patient
problems
culminating
in
hospitalization
in the Greater
Los Angeles
area is
clear from our data. Shifting
patterns
may be detected in subsequent
years. Although
the data presented
are derived
from a large-volume
operation,
they
should serve as a guide for the organization
of a program that could offer the most clinical usefulness
for
any hospital
or laboratory
in the United
States that
is contemplating
a toxicology service.
References
1. Lundberg, G. D., Walberg, C. B., and Gupta, R. C., The patient-focused
approach to clinical toxicology laboratory organization. Lab. Med. 3, 14 (1972).
2. Deem, B. A., and Lundberg, G. D., Toward the optimal lab
manual. Med. Lab. Observer, 94-98, September-October
(1973).
CLINICAL
CHEMISTRY,
Vol. 20, No. 2, 1974
125