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530
Proc. roy. Soc. Med. Volume 61 May 1968
200
blood and tissue uptake difference at this time
may be postulated to be due to alteration in
tissue blood flow. Ten minutes later, with
vaporizer still set at '2', the marked decrease in
alveolar ventilation was reflected by a fall in
halothane uptake by the blood. Tissue uptake
was greater than blood uptake, which was consistent with the fall in arterial halothane from
25 6 to 21-0 mg/100 ml. Despite the maximal
vaporizer setting for a period of ten minutes the
blood uptake was only 11-1 mg/min because the
alveolar ventilation was low. The associated fall
in cardiac output to 460 of the control value led
to the low uptake of 8-6 mg halothane per minute.
HEART RATE
160
20
20
L/nmin
-
...._______. RESPIRATORY
-
RATE
X
,v
2
-'ALVEOLAR
*
VENlTILATION
1.5
L/.,i.
CARDIAC OUTPUT
1
14
0.5 *
mg/100ml
25
-BLOOD HALOTHANE
15
-
10
ARTERt~L/
'/
TISSUE RALOTRANE
MIXED VENOUS
35.1
311.6
6.611.1
36.9
212. 4
31.6
mg/min
ARTERIAL HALOTHANE
UPTAKE
Dg/miD
S
IErr
2
10
20
TIME (.in.)
4 |r
30
a.e
ON
FF
<
40
Fig 1 Halothane uptake in a 20 kg dog during closed
circuit anaesthesia with vaporizer inside the circuit and
spontaneous respiration
saturation at a constant inspired halothane concentration prolonged administration would be
required (Duncan & Raventos 1959). The results
are consistent with the view that tissues of high
lipid content and high blood flow take up large
amounts of halothane rapidly. The low mean
halothane value for omentum, despite its high
lipid content, is probably due to its low blood
flow. The range of variation of uptake by the
different tissues may be explained by the variation
in minute ventilation and body weight among
the dogs.
Halothane uptake in the dog: Fig 1 shows the
data for uptake of halothane by a 20 kg dog
during closed circuit anxsthesia. Previous studies
on halothane uptake have been made during
constant inspired halothane concentrations
(Mapleson 1962, Eger & Guadagni 1963). During
closed circuit ancesthesia with the vaporizer
inside the circuit, the major factors in halothane
vaporization are the vaporizer setting, alveolar
ventilation and halothane temperature. From
Fig 1, after ten minutes' exposure with the
vaporizer set on '1', blood and tissue uptake
were virtually the same. After a further ten
minutes with the vaporizer set at '2', halothane
uptake was high since alveolar ventilation and
cardiac output were near control levels. The
REFERENCES
Duncan W A M & Raventos J
(1959) Brit. J. Anasth. 31, 302
Eger E I It & Guadagni N P
(1963) Anesthesiology 24, 299
Kety S S (1951)Pharmacol. Rev. 3, 1
King N W & Broughton G
(1967) Brit. J. Ana'sth. 39, 515
Larson C P, Eger E I II & Severinghaus J W
(1962) Anesthesiology 23, 349
Mapleson W W
(1962) Brit. J. Anarsth. 34, 11
Nunn J F & Hill D W
(1960) J. appl.Physiol. 15, 383
Wolfson B, Ciccarelli H E & Siker E S
(1966) Brit. J. Anesth. 38, 591
Professor J P Payne
(Research Department of Anacsthetics,
Royal College of Surgeons of England, London)
Alcohol in Blood and Urine
The use of a gas chromatograph combined with an
internal standard and an integrator offers the most
convenient method yet developed for the accurate
measurement of ethyl alcohol concentration in
biological fluids. In practice those fluids most
commonly analysed are blood and urine and a
suitable gas chromatograph consists of a moving
phase source, an injection port and vaporizer, a
stationary phase, a detector and a recorder.
The moving phase is nitrogen, although other
gases such as argon can also be used. The nitrogen
which passes through the instrument at a constant
rate purges the injection port and vaporizer of the
volatile components of the sample to be analysed
and carries them on to the stationary phase, a
4 ft (I 2 m) copper column of 025 in (6 mm)
internal diameter packed with porous polymer
beads of 80 to 100 mesh (Poropak Q) maintained
at a temperature of 171°C. The various com-
is
Section of Ancesthetics
ponents of the sample are selectively adsorbed on
the column, to be shortly released in the inverse
order of their affinity for the column material.
After release they pass through a hydrogen flame
detector where a complex ionization process
occurs. As a consequence carbon atoms are given
up in proportion to the amount of organic
material present. These carbon atoms are counted
as they pass through the detector and appropriate
signals are transmitted to the recorder where they
are transcribed in the form of a peak. The area
under the peak is an accurate representation of the
concentration and if the signals are fed into an
integrator greater precision in measurement can
be achieved.
Technique
Before analysis, the blood or urine sample is
diluted with an aqueous solution of propanol (25
mg/100 ml) in the ratio of 1: 10; 2 V1 of the diluted
sample is injected into the entry port of the
chromatograph. Both ethanol and propanol are
eluted and appear as separate peaks within five
minutes of injection. The peaks are charted and
the areas under each are computed and recorded
by the integrator. Since the areas are directly proportional to the concentration, the ratio of the
concentration of alcohol to that of propanol can
be calculated.
The dilution of the sample decreases the rate at
which blood solids accumulate on the column;
the presence of propanol provides an internal
standard and eliminates the need to measure the
injected volume precisely since the important
factor is the ratio of alcohol to propanol. For
calibration purposes a suitable concentration of
ethyl alcohol is made up by weight in water. A
sample of this standard is diluted with the aqueous
solution of propanol and injected into the chromatograph exactly as the blood sample. When the
ratio of alcohol present to that of propanol is
obtained the alcohol concentration in the unknown sample can be derived as follows:
concentration
of known
standard
x
ratio of
unknown
sample
ratio of known standard
concentration
of unknown
sample
Duplicate analysis is usual. Typical chromatograms derived from the analysis of five separate
samples from the same blood specimen are shown
in Fig 1. With a mean level of 262 mg/100 ml the
range is from 259 to 266 mg.
531
ETH. PROP. RATIO MEAN
,
-2t8
231
1
07Lt
CONC. OF
WATER
1 0725
STANDARD
273
255
1071
252mg/100mi
232
206
1-126
265 mg/100ml
277
252
1 099
259
312
280
1i114
262
314
278 1 129
266
315
285
260
BLOOD
CONC OF
ALCOHOL
1 105
.
i
MEAN 262
Fig 1 Typical gas chromatograms showing the extraction of ethanol from water and blood. The amount of
alcohol in the water was known and forms the control.
The remaining peaks were derived from five separate
aliquots of the same blood sample injected consecutively
quate and the handling technique is straightforward. The difficulties arise when attempts are
made to calculate blood values from the results
obtained on urine analysis. For this purpose a
conversion factor of 1-33 has been recommended
in the Report of a Special Committee of the
British Medical Association (1965). But although
Payne et al. (1966) demonstrated good agreement
when this ratio was used in a laboratory study of
the uptake, distribution and elimination of
alcohol in healthy volunteers, it was emphasized
that such a ratio was only valid when the alcohol
level in urine had passed its peak and when the
bladder had been emptied within the preceding
thirty minutes. Furthermore their later work
(Payne et al. 1967) and that of others (Morgan
1965, Stevens et al. 1966) showed that the ratio of
1-33 was not reliable outside the laboratory. In the
Belfast investigation (Morgan, personal communication) 213 of the 518 accused motorists had a
urine:blood ratio greater than 1 40, the overall
ratio being 1 38. In the more detailed study carried
out by Payne and his colleagues the urine:blood
ratio was 1 -41 and 19 ofthe 35 suspects had a ratio
greater than 1-33. These findings support the contention of Froentjes (1963) who, on the basis of a
ratio of 1 52 obtained from more than 7,000 paired urine and blood samples, argued that a
realistic ratio would be 2:1 for medico-legal
purposes.
Urine Analysis
The analysis of urine presents no special problems; the difficulties of collection are minimal, the
volume of the sample is usually more than ade-
The significance of these observations lies in the
fact that under the Road Safety Act of 1967,
which has made it an offence to drive with more
than 80 mg alcohol per 100 ml blood, 107 mg
532
Proc. roy. Soc. Med. Volume 61 May 1968
16
Table I
Details of 12 volunteers with blood alcohol levels in the 50-80 mg/100 ml range
Subject Age
1
29
43
2
20
3
28
4
23
5
28
6
7
49
8
28
46
9
10
51
33
11
18
12
Weight
(kg)
86
88
70
70
67
73
60
71
71
60
83
69
First
urine
(U,)
159
99
100
93
91
156
139
82
141
89
140
109
Time
interval
(min)
45
21
18
17
30
60
22
26
19
24
65
Second
urine
(U2)
1540
90
91
79
15
106
88
1320
1300
76
1250
86
1210
Blood
(B)
71
57
50
59
61
70
80
54
71
79
73
62
U2/B
2 17
1-58
1 82
1-34
1*44
1-88
1-63
1-41
1-76
1.09
1-65
1-71
0 Urine level above the statutory limit
alcohol in 100 ml urine has been taken as the
equivalent of 80 mg per 100 ml in blood. This, in
effect, means that despite the evidence to the
contrary the ratio of 1-33 has been accepted by
Parliament and that in the interests of justice
accused motorists will be well advised to insist on
blood analysis.
It has been implied that the high urine:blood
ratios are a function of relatively high alcohol
levels in blood and urine and that around the
critical level, i.e. 80 mg alcohol per 100 ml blood,
urine analysis is marginally more helpful to the
accused driver than blood analysis (Enticknap
1967 a, b). These assertions were made on the
basis of studies on eight subjects but the evidence
is not convincing. Scrutiny of Enticknap's data
reveals that not only was there no evidence that
the urine values used to determine the urine :blood
ratios had been collected after the peak concentration of alcohol had been reached but also that,
even when second urine samples had been
collected, no corresponding blood samples appear
to have been obtained. The validity of Enticknap's
ratios therefore must be seriously in doubt.
In our own experience high urine:blood ratios
are just as common when the alcohol level in the
blood is low. Of 12 volunteers who had blood
alcohol levels in the 50-80 mg range no fewer
than 11 had urine:blood ratios greater than 1V33
(Table 1). Moreover, in 5 of the 12 volunteers
the urine alcohol level was substantially above
107 mg/100 ml although the blood level was well
below the statutory limit. In all 12 subjects the
urine samples had been collected after the peak
concentrations had been reached and in 9 the
samples had been taken within thirty minutes of
the earlier collection.
The implication of these observations is
serious. Almost certainly innocent men and women
risk conviction if urine analysis is used alone, so
long as the value of 107 mg of alcohol in 100 ml
urine continues to be taken as the equivalent
of 80 mg in 100 ml blood.
Blood Analysis
The analysis of blood is more complicated than
that of urine. Controversy exists about the
method of collection and discrepancies between
the alcohol levels in capillary and venous blood
samples collected simultaneously have added to
the disquiet.
Although by implication preference has been
expressed for capillary blood samples collected
either from the finger-tip or from the ear-lobe
(Road Safety Legislation 1965-6) little formal
guidance has been given about the method of
collection. Many doctors favour the ear-lobe
because of its dependent position and its plentiful
blood supply but the ear stab can be embarrassing
as well as painful for the suspect, and for this
reason a finger prick is sometimes preferred.
Unfortunately, finger blood flow is not uniformly
adequate and even when the pulp of the finger
is stabbed the blood flow may be meagre. Under
these circumstances the temptation to apply
pressure must be resisted, as the ensuing
himatocrit disturbance will almost inevitably
distort the results of analysis.
Once the site of puncture has been decided,
selection of a suitable skin sterilizing agent is
important. Although in practice the use of an
alcoholic solution, such as tincture of iodine or
methylated spirits, is unlikely to lead to any
significant effect on the alcohol concentration in
the blood, there are theoretical objections which
can be avoided by the use of a nonalcoholic
antiseptic.
The choice of a container for the blood sample
presents further difficulties. With the accepted
methods of collection capillary blood is exposed
to the atmosphere for a varying period of time at
body temperature and the possibility of loss of
alcohol by evaporation has to be considered.
This risk seems to be lowest when blood is
allowed to flow freely into polypropylene plastic
pots. Loss can also occur by a leak past the seal
or by adsorption of alcohol on the materials used.
17
Section ofAnwsthetics
Clotting is a particular hazard of capillary
sampling, since the sample is usually too small to
allow the use of liquid anticoagulants. In
practice, the containers are usually coated with a
heparin or fluoride-oxalate solution and allowed
to dry. This has not proved entirely satisfactory
and our own experience indicates that about 7 %
of samples are clotted. One further source of
error remains to be considered. It has recently
been shown that when alcohol is added to blood
withdrawn from volunteers, the alcohol content
of the plasma is about 40 % higher than that of an
equal volume of red blood cells (Payne et al.
1967). Since separation of plasma from red cells
is not uncommon in blood collected in capillary
tubes, the need for careful mixing before analysis
is obvious.
This observed difference between the alcohol
content of plasma and red blood cells from the
same sample has been confirmed in vivo in 20
volunteers given varying quantities of alcohol to
drink (Payne, Hill & Wood 1968) and raises new
problems of a more fundamental nature.
When the distribution of alcohol taken by
mouth is in equilibrium in the body, the tissue
levels, including those in the lungs and in the
kidneys, reflect the plasma concentration. In
particular, the tension of alcohol in the alveolar
gases is directly proportional to the plasma
concentration. But since substantially more
alcohol is present in plasma than in red cells, it
follows that, for any given plasma concentration,
the whole blood concentration must vary inversely
with the number of red blood cells present. On
this basis it seems reasonable to question the
validity of blood:breath and urine:blood ratios.
The potential sources of significant error
encountered in the analysis of capillary blood by
gas chromatography emphasize the need for a
standard protocol for the withdrawal and
handling of blood for the determination of the
alcohol content. Until such a protocol is established there is every justification for insisting on
the use of venous blood when blood alcohol
determinations are required.
Dr J B Enticknap (East Ham Memorial Hospital,
London) said that there was not, in his view, any
conflict between his results and those of Professor
Payne, as his own were specifically obtained under
field conditions in which it was most unlikely
either that the bladder was emptied or the postabsorptive peak reached. These conditions most
closely resembled those in which an actual arrest
might be made at a low blood level and accounted
for his findings of urine blood ratios as low as
0-3. He also felt that with more development there
was a future for quantitative breath tests.
REFERENCES
British Medical Association (1965) The Drinking Driver. London
Enticknap J
(1967a) Brit. med.J. ii, 49
(1967b) Brit. med. J. iv, 11O
FroentjesW (1963) In: Alcohol and Road Traffic. Ed. J D J Havard.
London; p 179
Morgan W H D (1965)J. forens. Sci. Soc. 5, 15
Payne J P, Foster D V, Hill D W & Wood D G L
(1967) Brit. med. J. iii, 819
Payne J P, Hill D W & King N W (1966) Brit. med. J. i, 196
Payne J P, Hill D W & Wood D G L (1968) Nature (Lond.) 217, 963
Road Safety Act (1967) HMSO, London
Road Safety Legislation 1965-6
(1965) Cmnd 2859. HMSO, London; p 12
Stevens P J, Mason J K & Bowden C H (1966) Med. Sci. Law 6,96
533
Professor Payne denied that breath analysis had
any place in the determination of blood alcohol
concentrations. In his opinion breath analysis
provided a useful screening test but nothing more.
Dr B M Wright (National Institute for Medical
Research, Mill Hill, London) said that Professor
Payne's view that breath analysis was of no
practical value was not shared by any other
worker in the field. It was based on experiments
carried out in his laboratory, using a method that
had not been used before for this purpose, which
gave results different from those of other workers,
many of whom had obtained excellent correlation between breath and blood alcohol. Professor
Payne's observations about the differing alcohol
content of plasma and red cells were interesting
but the relevant question was the relationship
between plasma and whole blood. Available
evidence suggested that the alcohol content of
plasma was only about 10 % more than that of
whole blood. The suggestion that the plasma-red
cell difference could account for variations in the
breath/blood relationship was fallacious, because
what mattered in this case was not the actual w/v
concentration but the partial pressure of alcohol,
which was uniform through the blood.
There was no doubt that substantial and unexplained variations in the breath/blood ratio did
occur but, nevertheless, the only published
evidence (Wright, 1965, Brit. med. J. ii, 1430)
suggested that in practice breath analysis with a
reliable instrument such as the 'Breathalyzer' gave
as accurate an estimate of blood alcohol as blood
analysis under operational conditions.
Professor Payne admitted that the variations in
blood/breath ratios reported by his own group
might not be acceptable to Dr Wright who had
developed his own method of measuring alcohol
in breath; nevertheless their results had never been
publicly challenged. While it was true that the
technique of infra-red analysis which had been
used to determine the alcohol content of breath
was not the usual method, it was well recognized
for its reliability and accuracy; if it had not been
534
Proc. roy. Soc. Med. Volume 61 May 1968
18
previously used in alcohol studies by other
workers, this was surely a reflection on them
rather than on the method. There was no virtue in
using a less reliable method simply because everyone else used it. Dr Wright was being naive in
talking about the many workers who had obtained excellent correlation between breath and blood
alcohol levels. Certainly a few groups of workers
had obtained a reasonable measure of agreement
but this was scarcely surprising since they all had
the same built-in error.
Professor Payne questioned the reliability of
Dr Wright's statement that the alcohol content of
plasma was only about 10 % more than that of
whole blood. Published papers gave values for
plasma between 15 and 25% higher than whole
blood, and these were broadly in agreement with
the 18 % value obtained by his own group (Payne
et al. 1968, Nature (Lond.) 217, 963). Dr Wright's
comment about the plasma/red cell difference
implied a lack of understanding of the problem.
For any given blood concentration of alcohol the
plasma concentration will vary directly with the
hmematocrit. Since the alveolar tension of alcohol
reflects the plasma tension which in turn is directly
related to the plasma concentration, it follows
that different alveolar tensions can be obtained for
the same blood level.
(1960, J. appl. Physiol., 15, 383) who determined
this in man. It was felt that using this assumption
was more accurate than using minute ventilation
which would have resulted in artificially higher
values of halothane uptake by the blood.
Dr R M A McClelland (King's College Hospital
Medical School, London) asked whether Dr Cervenko's figure of 0-68 for alveolar ventilation ratio
was an assumption based on human work.
Dr Cervenko replied that it was. The value used to
calculate alveolar ventilation from minute ventilation in the dog had been taken from Nunn & Hill
Dr Gavin Robinson (Glasgow) asked if levels of
halothane in skeletal muscle had been measured.
Dr Cervenko said that this had not been done.
The President asked why carbon tetrachloride had
been used as a solvent for halothane.
Dr Cervenko replied that, using the chromatographic column described, several extracting
solvents had been tried. Carbon tetrachloride was
found to be the one with the best characteristics,
namely rapid elution with little tailing, good
separation from ether and halothane, low water
solubility and economy.
The President asked Professor Payne whether
capillary or venous blood gave the greater
advantage to the accused motorist.
Professor Payne replied that the choice of site
would depend on a number of factors including
the stage of absorption and the state of the circulation. He pointed out that, after uptake had
ceased, the arterial, capillary and venous blood
concentrations of alcohol were virtually the same
but, while alcohol was still being absorbed, the
peripheral venous blood usually contained less
than capillary and arterial blood, especially if the
peripheral blood flow was reduced, for example
in arterial disease of the lower limbs.
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