Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.

Brit. J. Ophthal. (1961) 45, 415.

MONOSEMICARBAZONE OF ADRENOCHROME
(ADRENOXYL) AND CATARACT SURGERY*
EFFECT ON CAPILLARY RESISTANCE AND INCIDENCE OF
HYPHAEMA
BY
H. T. SWAN, A. B. NUTT, G. H. JOWETT,t
W. J. WELLWOOD FERGUSON, AND E. K. BLACKBURN
From the Departments of Haematology and Ophthalmology, Royal Infirmary, Sheffield, and
the Department of Statistics, University of Sheffield

EPINEPLmINE, from which the monosemicarbazone of adrenochrome is

derived, has a powerful action on arterioles and capillaries. It causes the
small muscles of the micro-circulation to contract and this lessens the flow
of blood within the vessels. The part thus played by endogenous epine-
phrine in helping to control the physiological flow of blood is more clearly
defined than any supposed function it has in stopping blood loss. When
there is bleeding from capillary damage, pharmaceutical epinephrine can be
used as a haemostatic for local application, but epinephrine would be of
greater value in capillary bleeding if its effect were more lasting. When
given systemically, it has not proved of any value in reducing blood loss,
and may, indeed, aggravate this by its known action on the mechanism for
dissolving away formed clots (Biggs, Macfarlane, and Pilling, 1947).
Epinephrine itself is a very active chemical, but is readily oxidized to
adrenochrome. This was first isolated by Green and Richter (1937).
Adrenochrome was shown by Roskam and Derouaux (1944) to produce
capillary haemostasis as did epinephrine, and like it was also unstable. In
view of its instability, Braconier, Le Bihan, and Beaudet (1943) elaborated
the monosemicarbazone of adrenochrome (Adrenoxyl) which is said to be
stable and to possess haemostatic properties when given by mouth or by
injection.
Many claims have been made for Adrenoxyl. It is said that the drug
increases capillary resistance in the sub-clavicular region in man and the
lumbar region in the guinea-pig (Prevost, Cotereau, and Parrot, 1947). It
is also reputed to increase' cardiac output with no effect on the blood
pressure or pulse rate (Herve, 1951) and to stimulate the adrenal cortex
slightly (van Cauwenberge, Lecomte, Fischer, Vliers, and Goblet, 1953).
So far as can be ascertained from the literature it has never produced toxic
or allergic side-effects and does not affect blood coagulation, nor does it
* Received for publication August 12, 1960.
t Present address: Department of Statistics, University of Melbourne, Australia.
415
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416 SWAN, NUTT, JOWET7, FERGUSON, AND BLACKBURN
accumulate in the reticulo-endothelial system. Adrenoxyl may be given
by mouth or parenterally.
Delayed hyphaema is a well-known and troublesome complication of
operations for cataract and sometimes causes cicatrization and functional
disorders of the eye. We decided therefore to attempt an assessment of the
value of Adrenoxyl in cataract surgery by observing such changes as it might
produce in skin capillaries, as shown by their resistance to negative pressure.
Concurrently the development of hyphaema was looked for and its relation-
ship to Adrenoxyl therapy and capillary resistance was established.
Because ofthe results obtained, the trial was then extended on more clinical
lines to find out whether Adrenoxyl has a significant influence on the
incidence of hyphaema following cataract surgery.

PART I. EFFECT OF ADRENOXYL ON CAPILLARY RESISTANCE TO NEGATIVE

PRESSURE
Methods
Choice of Patient and Dosage of Adrenoxyl.-The design of the first part
of the trial was based on a preliminary sampling of some unsystematic
records of capillary pressure which were available. These suggested that:
(a) the operation might itself have an effect on capillary resistance,
(b) between-patient variability was so large as to make it desirable to use
each patient as control for himself, i.e. to take observations of capillary
pressure on the same patient when under treatment with Adrenoxyl and
when not under treatment.
In addition these records gave an indication of the size of trial necessary.
Sixteen patients admitted for lens extraction were investigated in the
main trial. Twelve of these were non-diabetic (Cases Al to A6, Bl to B6)
and four were diabetics (Cases A7, A8, B7, and B8). Within these two
groups the patients were paired according to sex but were otherwise taken
in strict sequence on their random admission to hospital. The first of each
pair of patients to be admitted for operation was allocated to the letter A
or B by the tossing of a coin.
The patients in Group A received four tablets (10 mg.) Adrenoxyl every
8 hours for 4 days, 2 days being before the lens extraction, the third being
the day of operation, and the fourth being the first post-operative day.
During the succeeding 4 days Adrenoxyl was withheld. The drug was then
taken in the former dosage for a further 4 days, and stopped for the last
4 days.
The patients allocated to Group B received no Adrenoxyl on the 2 days
before operation, the day of operation, and the day following. During the
succeeding 4 days they received four tablets Adrenoxyl every 8 hours, in
 Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.
ADRENOXYL IN CATARACT SURGERY 417
the next 4 days they received none, and for the last 4 days they received
the drug again in the same dosage. This schedule was what may be called
the mirror image of Schedule A.
The two equal groups of patients were given different schedules of
Adrenoxyl therapy to enable the effect of the operation, if it existed, to be
eliminated in analysis simply by averaging over both groups, a positive effect
on differences in one group cancelling a corresponding negative effect in the
other group.
Operation.-The lens extractions were performed by surgeons who were
members of two surgical teams. The premedication, local anaesthetic, and
nursing were the same in each pair of cases A and B.
Estimation of Capillary Resistance.-This was done by the negative
pressure method advocated by Scarborough (1941), using an apparatus
similar and comparable to his own, but modified to incorporate an aneroid
manometer. The cup of the apparatus had an internal diameter of 20 mm.
and was applied in turn, for exactly 30 seconds, to each of three areas on the
left arm of the patient. The three areas chosen were on the volar aspect
of the forearm as used by Scarborough (1941) and Robson and Duthie
(1950). The figure sought was the negative pressure at which only one
capillary ruptured (" critical pressure "). If no petechiae were produced, the
negative pressure was increased by stages of 50 mm. until more than one
petechia appeared. When more than one petechia was produced at a time,
it was assumed, for the purposes of charting, that the number of petechiae
appearing was proportional to the increase above the critical pressure, pro-
vided this remained within the limits of the 50 mm. increase, and an arbitrary
figure of five was subtracted from the manometer reading for each petechia
after the first. An average was made of the " critical pressures " of the three
areas for each day. The same three areas were tested on each occasion by
the same observer at the same time on each of the 16 days. It was not
known at the time of the examination whether the patient was receiving
Adrenoxyl or not.
Post-operative Complications.-Eye dressings were removed once a day
and any post-operative haemorrhage in the eye was noted at that time.
Results
Statistical Analysis of the Pressure at which Capillaries began to Rupture.-
The data were analysed logarithmically, since there appeared to be marked
differences in level of capillary resistance from patient to patient, variation
increasing with level, and ratios were considered to be a more appropriate
measure of comparison than absolute differences of capillary resistance
(Table I). The logarithm of the average capillary resistance for the three
27
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418 SWAN, NUTT, JOWETT, FERGUSON, AND BLACKBURN
positions (left medial elbow, left lateral elbow, left wrist) was calculated for
each patient on each day, except in the case of Patient A7, whose skin was
ichthyotic, making reasonable estimations impossible except over the left
lateral elbow position, where the skin was relatively normal. This substitu-
tion was a reasonable one, and can be safely assumed not to have affected
the validity of the analysis.
TABLE I
SUMMARY OF LOGARITHMIC AVERAGES

Mean log. Critical Mean log. Critical

Resistance (with Resistance (post-
Mean log. Critical Adrenoxyl) minus operative) minus
Capillary Resistance Mean log. Critical Mean log. Critical
Patient No. (Value in mm. Hg Resistance (without Resistance (pre-
in brackets) Adrenoxyl) operative and day of
(Arithmetic Ratio operation)
in brackets) (Arithmetic Ratio
in brackets)
Al 2-274 (188) -0 035 (0 92) +0-126 (1-34)
A2 2-427 (267) -0-095 (0 80) +0-107 (1-28)
A3 2-302 (200) -0 003 (0 99) +0-051 (1-13)
A4 2-392 (247) +0 004 (1-01) -0-096 (0 80)
Group A A5 2-238 (173) -0-011 (0 98) +0-012 (1-03)
A6 2-430 (269) +0-035 (1-08) -0 092 (0-81)
A7 (diabetic,
LLE only) 2-227 (169) -0-051 (0-89) +0-013 (1-03)
A8 (diabetic) 2-292 (196) -0-055 (0-88) +0009 (1-02)
Mean for Patients in A
Group 2-323 (210) -0-026 (0 94) +0-016 (1-04)
Bi 2-306 (202) +0-061 (1-15) +0-180 (1-51)
B2 2 254 (180) +0 005 (1-01) -0 009 (0 98)
B3 2-297 (198) +0-011 (1-03) +0-043 (1-10)
Group B B4 2-192 (156) +0-031 (1-07) +0-161 (145)
B5 2 534 (342) +0-018 (1-04) +0-046 (1 11)
B6 2-303 (201) -0-071 (0 85) -0-208 (0 62)
B7 (diabetic) 2-467 (293) +0-098 (1-25) +0-114 (1-30)
B8 2-324 (211) +0-089 (1-23) +0-074 (1 19)
Mean for Patients in B
Group 2.335 (216) 0.030 (1-07) +0-050 (1-12)
Mean for All Patients in
Trial 2-329 (213) 0-002 (1-01) +0.035 (1-08)
S1 (diabetic) 2-031 (107) -0-139 (0 73)
Supple- S2 (diabetic) 2-286 (193) +0-020 (1-05)
mentary S3 2-397 (250) +0-018 (1-04)
Grouy S4
P S5 (87)
1-940 (182)
2-259 +0-013 (1.13)
+0-052 (1-03)
S6 2-231 (230) Not Applicable - 0034 (0 92)
Mean for Supplementary
Patients 2-212 (163) -0-012 (0-97)
Mean for All Patients 2-297 (198) 0-021 (1-05)
 Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.
ADRENOXYL IN CATARACT SURGERY 419
The average log. capillary resistance (C.R.) for Adrenoxyl periods, was
compared with the average log. C.R. for non-Adrenoxyl periods, and was
found not to differ significantly. The apparent effect of Adrenoxyl was thus
virtually nil. From the size of the variation it can be asserted that, even if
the trial has turned out negative by chance, any real effect is very likely
(95 per cent. probability) to be less than 6-5 per cent. The difference
between average log. C.R. for Adrenoxyl and non-Adrenoxyl periods was
significantly (5 per cent. level) less in the A group than in the B group and
this different response to the A and to the B dosage pattern must be ascribed
to the effect of the operation on capillary resistance. These results are
summarized in Table I and the analysis of variance test of significance in
Table II.
TABLE II
ANALYSIS OF VARIANCE FOR AVERAGE LOG. CRITICAL CAPILLARY RESIST-
ANCE (ADRENOXYL) MINUS AVERAGE LOG. CRITICAL CAPILLARY RESISTANCE
(NON-ADRENOXYL)
,______________
_-Degrees of
Mean Effect of Adrenoxyl Sum of Squares Freedom Mean Square
60 1 I 60 1 (N.S.)

Difference between Means of A and

B Groups due to Effect of Opera- 12,826 1 12,826
tion (Significant at
per cent. level)
Difference within Groups 32,079 14 2,291
(Unit = 0-001)

Significantly more (5 per cent. level) cases show a rise in average log. C.R.
after the operation than show a fall (twelve rises compared with four falls),
though in patients where there was a fall it was occasionally very marked
(e.g. in Patient B6 who did not develop hyphaema). It was justifiable to
lump the A and B patients together for this comparison in view of the lack
of effect of the drug.
Six cases were available from a previous trial using 5 mg. (2 tabs) 8-hrly
of Adrenoxyl. It was believed that these could fairly be included with the
16 trial cases to assess the effect of the operation. In these six cases, the
records of the capillary resistance for the pre-operative and operative days
were available, but occasional observations were missing for the thirteen
post-operative days. The results for this supplementary group are given in
the lower section of Table I. While the mean log. C.R. is lower than in the
major trial and the average is, if anything, slightly less, the capillary resis-
tance rose in four cases after operation compared with two which fell,
confirming the significance of the comparison above.
 Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.
420 SWAN, NUTT, JO WETT, FERGUSON, AND BLACKBURN
Post-operative Hyphaema.-This occurred in six of the sixteen patients.
Only one patient of the six (A5) developed hyphaema while receiving
Adrenoxyl and without any obvious precipitating cause. Two of these six
(Bl and B5) had been taking Adrenoxyl for 96 and 48 hrs respectively at the
time when the hyphaema was observed but the haemorrhages were imme-
diately preceded by abnormal physical exertion which may have caused
them. Patient Bl jumped out of bed to help a fellow patient in distress
and Patient B5 had a nightmare. The remaining three patients (A4, B4,
A6) were either not receiving Adrenoxyl when the hyphaema developed or
the condition was discovered in the course of the first day of Adrenoxyl
therapy, and could therefore have developed at any time after the previous
daily dressing, before or after the resumption of Adrenoxyl.
No correlation was found between the development of hyphaema and
capillary resistance, even when the figures relating to the day when the
hyphaema was observed were compared with those of adjacent days or with
the mean.
PART II. EFFECT OF ADRENOXYL ON INCIDENCE OF POST-OPERATIVE
HYPHAEMA
Because of the results outlined above, the trial was continued in a modified
form to see whether Adrenoxyl would prevent or reduce the incidence of
delayed hyphaema. The methods used were similar to those in the preceding
section, but were restricted to clinical observation. Adrenoxyl was given by
mouth throughout the stay in hospital of alternate patients undergoing lens
extraction. Consecutive patients admitted for lens extraction were paired
so long as they were of the same sex and had in common the presence or
absence of diabetes mellitus. By random choice one of each pair was given
Adrenoxyl 10 mg. (4 tabs) by mouth 8-hrly for the duration of his stay in
hospital. The other was not given Adrenoxyl, but was observed clinically
with the same care. Forty patients were treated thus with Adrenoxyl and
forty had none. The lens extractions were carried out under similar
conditions in all cases.
Of the forty patients receiving Adrenoxyl, eight developed hyphaema
between the first and 11th post-operative days (Table III, opposite). There is,
however, an increased incidence of cardiorenal vascular disease in diabetes
mellitus, and in diastolic hypertension. In both these conditions abnormal
capillaries are more likely to be present than in non-diabetics and non-
hypertensives (Brown and Roth, 1927). If, therefore, one excludes
hyphaemas occurring in patients with a diastolic blood pressure of more
than 100 mm. Hg and in patients with diabetes mellitus, then six patients
receiving Adrenoxyl developed post-operative hyphaema as opposed to seven
not receiving Adrenoxyl. One of these seven patients already had old
synechiae from previous iritis.
No toxic effects of Adrenoxyl were found.
 Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.
ADRENOXYL IN CATARACT SURGERY 421
TABLE III
DETAILS OF PATIENTS DEVELOPING HYPHAEMA

Case Age ~~~~Post-operative Day of BodPesr

No. Sex Age Adrenoxyl Onset or Recurrence of Diabetes B(omd Pressure
Hyphaema
1 F 79 + 10 280/120
9 M 54 + 6 _ 130/82
15 M 68 + 5,9 _ 140/80
19 M 48 + 1 140/80
23 F 44 + 3,10 140/80
29 F 70 + 1 _ 150/80
57 F 76 + 8 _ 138/60
67 M 72 + 1 + 220/-
4 M 75 - 2 - 160/100
6 F 67 - 2 - 250/130
16 M 79 - 7,9 - 135/85
28 F 69 - 1 - 145/85
32 F 61 - 2,7 + 160/90
38 M 82 - 1 _ 150/90
41 M 69 - 10 _ 220/110
62 M 47 - 1,11 _ 118/100
66 F 53 ' 1* 150/90
70 F 59 _ 3 _ 150/-
80 F 65 5 + 137/70
* Iritis in 1952

DISCUSSION
Adrenoxyl, a relatively expensive drug, has been used widely on the
continent of Europe for the prevention and treatment of haemorrhage, often
with apparently satisfactory results, but there is a paucity of reports in the
literature of the English-speaking countries. We find much of the published
work difficult to evaluate. Thus, for example, Roskam (1954) gives calcium
chloride and thrombase in addition to Adrenoxyl as preventive measures.
So far as ophthalmic surgery is concerned, Bohringer (1952) gave Adrenoxyl
orally and parenterally to prevent hyphaema after cataract operations. He
found delayed hyphaemas after 216 per cent. of 185 cataract operations on
elderly patients not treated with Adrenoxyl, and after 12 1 per cent. of 63
operations on patients treated with Adrenoxyl. So far as other forms of
cataract were concerned, delayed hyphaema occurred in 15-7 per cent. of
77 untreated patients, compared with 12-8 per cent. of 47 patients treated
with Adrenoxyl.
In the first part of the present series where 4 days of Adrenoxyl therapy
alternated with 4 days without Adrenoxyl for each patient, it appears that
the Adrenoxyl as given had no significant effect on capillary resistance; nor
did it prevent the development of delayed hyphaema unassociated with
abnormal exercise in at least one case.
It is of interest to note that, although capillary resistance commonly tended
to rise after operation in our series, it occasionally fell quite markedly; but
 Br J Ophthalmol: first published as 10.1136/bjo.45.6.415 on 1 June 1961. Downloaded from http://bjo.bmj.com/ on January 23, 2020 by guest. Protected by copyright.
422 SWAN, NUTT, JOWETT FERGUSON, AND BLACKBURN
a fall in capillary resistance was not necessarily associated with hyphaema,
and hyphaema also occurred in patients in whom there was no apparent
lessening of capillary strength.
SUMMARY
Sixteen patients undergoing lens extraction for cataract were given
Adrenoxyl in a dosage offour tablets (10 mg.) by mouth 8-hrly in a controlled
trial of the drug.
Adrenoxyl thus given had no statistically significant effect on capillary
resistance as measured by a negative pressure method. No apparent rela-
tionship was seen between the development of delayed hyphaema and changes
in capillary resistance.
There was no apparent difference in the incidence of post-operative
hyphaema in a series of forty pairs of patients, one of each pair receiving
Adrenoxyl by mouth, and the other being treated similarly in all respects
except for the administration of Adrenoxyl.
We thank Miss P. A. Hall, B.Sc., for technical assistance and Dr. J. L. Potter for advice on the
construction of the resistometer apparatus. We are indebted to Sister M. Brown and her staff
for their excellent cooperation in the trials. One of us (E. K. B.) is grateful to the Endowment
Fund of the Board of Governors of the United Sheffield Hospitals for a research grant.

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