Brit. J. Anaesth.

(1971), 43, 96

MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA REQUIRING

SURGERY UNDER GENERAL ANAESTHESIA
A Case Report
BY
JOHN W. CROOKE, J. F. TOWERS AND W. H. TAYIOR

SUMMARY
An 8-year-old boy with homocystinuria required a prolonged dental operation under
general anaesthesia. The successful management, without subsequent thrombo-
embolism, is described. The patient showed a partial response to treatment with
pyridoxine over a two-year period. The response was marked by a reduction in the
plasma and urinary homocystine levels and by decreased platelet adhesiveness. It is
suggested that a similar regime of pre-operative and operative management should be
considered in all affected patients undergoing surgery, since there was no increase in
platelet adhesiveness by the third postoperative day, as would normally have occurred.

Advances in diagnosis and therapy have resulted are frequently myopic and exhibit ectopia lentis;
in the increased survival of patients affected by have metaphyseal changes in the long bones; a
rare diseases. Such survival may in turn present tendency to thromboses and embolic episodes;
complications of management which were pre- convulsions; mental retardation; a high colour to
viously unknown. the cheeks; fine fair hair; knock knees; flat feet,
An example of such a disease is homocystinuria, and kyphoscoliosis. Gerritsen and Waisman
first described by Field and associates (1962), and (1966) state that diagnosis is suggested by the
independently in the same year by Gerritsen, presence of (1) ectopia lends, (2) mental retarda-
Vaughn and Waisman (1962). Studies of patients tion, (3) convulsions, (4) fine sparse hair. The
with this metabolic disorder reveal a strikingly diagnosis is confirmed by demonstration of homo-
high incidence of thrombo-embolic complications, cystine in the urine.
associated with a high mortality. These may At present treatment of homocystinuria is
occur spontaneously and, in particular, after directed toward reducing the homocystine con-
surgery often of a minor nature. tent of the urine and plasma by the administra-
Carson and colleagues (1965) presented ten tion of a diet with a low methionine content, or
cases who between them suffered more than ten of pyridoxine which acts as a co-enzyme in the
thrombo-embolic episodes; there was a fatal out- metabolic pathway of methionine (Gerritsen and
come in three cases. Henkind and Ashton (1965) Waisman, 1966; Komrower, 1969). Opportunity
reported two postoperative deaths due to to consider the operative and anaesthetic manage-
thrombo-embolism following ocular surgery. Har- ment of homocystinuria was taken when an
court (1969) reported that episodes of thrombo- 8-year-old boy known to have the disorder was
embolism are common following general anaes- referred for treatment of a dental abscess.
thesia. McDonald and associates (1964) have
demonstrated increased platelet adhesiveness in JOHN W. CROOKE, M.B., B.S., B.SC(PHYSIOI_),
affected patients, and it is to be expected that F.F.A.R.C.S.; J. F. TOWERS,* M.R.C.S., L.R.CP.,
such adhesiveness would increase in the post- F.D.S.R.C.P.S., F.F.DJLC-S.; W . H . TAYLOR, M.A., D.M.,
MJLC.P.; Department of Anaesthesia, University of
operative period. Liverpool, and the Departments of Oral Surgery and
Sufficient numbers of cases of homocystinuria Chemical Pathology, The United Liverpool Hospitals
(Royal Infirmary), Liverpool 3.
have now been described to show that the disease * Present address: Department of Oral Surgery, St
carries definite stigmata; thus affected children George's Hospital Group, London.

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 MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA 97

CASE REPORT adhesiveness. The results in table I would suggest that

treatment with pyridoxine has caused a marked diminu-
The patient was born in November 1960. and is the tion in the percentage of adhering platelets. The normal
youngest surviving child of a family in which three value of non-adhering platelets is 72 per cent or higher
male children died in infancy. One older girl and two for each of the methods used.
older brothers survived. Of the three who died, one The clinical features, as distinct from the biochemical
was stillborn, another died at 6 weeks of cerebral and haematological features, have not changed as a
thrombosis, and the third at 16 months of broncho- result of the treatment with pyridoxine; the malar flush,
pneumonia. The other surviving children do not pre- skin lividity and mental retardation are still just as
sent the clinical picture of homocystinuria. prominent.
Homocystinuria was diagnosed at the age of 7 years
as a result of a screening survey of partially sighted TABLE I
children, carried out by the Schools Medical Officers Response of plasma and urinary homocysiine levels,
of the City of Liverpool. Th; patient was known to and platelet adhesiveness, to treatment with pyridoxine
have had two attacks of epilepsy at the age of 10 hydrochloride.
months, and ectopia lends was diagnosed at the age
of 4 years 9 months. At this time two urine samples
were examined by two different laboratories and homo-
cystine was not found.
On examination, at the age of 7 years, he was 118
cm in height and weighed 22.5 kg, both measurements
being within the normal range for his years. He had
the typical fair hair of the disease with marked lividity 1§
of the skin, a malar flush (fig. 1) and slight knock knees. ?1
1
He was also severely mentally retarded.
I
Before 121
treatment 204 47*
Nov. 1967 250 3.2 148 60*
Jan. 1968 350 0.5 113
Mar. 1968 750 1.3 98 72*
May 1968 1000 1.6 65
Apr. 1968 1200 1.6 48
June 1969 1200 43.5
Pre-op 72 f
Post-op
(3 days) 76t
Homocystine is normally absent from plasma and
urine. Normal non-adhering platelets =72 per cent.
• Estimated by the rotating bulb method;
t Estimated by the glass bead method (Dacie and
Lewis, 1968).

Anaesthetic technique.
The operation was planned for the morning, the
drinking of water being allowed and encouraged up to
3 hours before in order to avoid pre-operative dehydra-
tion. The patient weighed 25 kg, and was premedicated
with atropine 0.4 mg intramuscularly to ensure a dry
mouth for surgery, and to encourage a fast pulse and
high cardiac output Sedatives were avoided to allow
rapid recovery postoperatively. Anaesthesia was induced
with thiopsntone 100 mg, tubocurarine 17.5 mg, nitrous
FIG. 1 oxide and oxygen, after which a 6.5-mm non-cuffed
orotracheal tube was carefully passed, thus avoiding the
An 8-year-old boy showing the high col- additional risk of trauma often associated with nasal
our, malar flush and fair hair typical of intubation. A moist throat pack was used. The correct
patients with homocystinuria. selection of tube fize allowed intermittent positive
pressure ventilation without a leak, and anaesthesia was
Treatm:nt was begun with pyridoxine hydrochloride maintain^ with nitrous oxide and oxygen. Halothane
in November 1967, to which there has been a partial 0.25-0.5 per cent was added for the first hour, from a
response (table I). The dosage of pyridoxine has cur- Fluotec vaporizer outside the circuit, to improve vaso-
rently been increased to 1200 mg daily in order to see dilatation and peripheral blood flow.
if further lowering of the plasma and urinary homo- Immediately after induction an intravenous infusion
cystine level can be achieved. was set up, using an indwelling No. 18 gauge l i in.
In addition to the biochemical features, the patient needle in the dorsum of the left hand. 250 ml of Mac-
also showed the characteristic increase in platelet rodex "70^ 6 pjr cent in 5 per cent dextrose, i.e.
a*

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 98 BRITISH JOURNAL OF ANAESTHESIA

aDproximately one-eighth of the patient's estimated needed in all quadrants of the mouth, made it
blood volume, was infused over the next 10 min. This
volume did not cause any alteration in the pulse rate necessary to use general anaesthesia. It was there-
(120 beats/min), and prevented the moderate fall in fore important to consider if our usual pre-
systemic blood pressure which would otherwise have operative preparation needed modification, and
been anticipated, the blood pressure remaining steady
at 110/75 mm Hg. which anaesthetic technique was best suited to
During the course of the anaesthetic the systolic the operative and postoperative requirements.
pressure and pulse rate were each prevented from
falling below 100 mm Hg and beats/min by injection On the basis that the chances of intravascular
of two further increments of atropine 0.2 mg intra- thrombosis would be reduced if those factors
venously- A further 5.0 mg of tubocurarine were known to stimulate it were diminished, the pre-
required. The patient's legs were moved and his calves
massaged every 5-10 min, and the operating table operative preparation, the conduct of the anaes-
inclined slightly head-down for 2-3 roin on three thetic and the management of the early
occasions in an attempt to improve peripheral venous postoperative periods were designed to promote:
return.
On completion of the surgery muscle relaxation was (i) reduction in blood viscosity and platelet
reversed with atropine 0.48 mg and neostigmine 2.0 adhesiveness; (ii) maintenance of high cardiac
mg which were given together intravenously. Follow- output and rapid circulation time; (iii) reduction
ing extubation the blood pressure was 120/70 mm He
and pulse 112 beats/min. The drip was discontinued of vascular resistance and improvement of peri-
before the patient left the theatre. A total volume of pheral perfusion; (iv) good venous return; (v)
325 ml of Macrodex had been infused (approximately
one-sixth of the estimated blood volume). The blood quick recovery and early postoperative ambula-
loss was minimal. The duration of the operation was tion.
1 hr 30 min and of anaesthesia 1 hr 55 min. The patient
was returned to the ward conscious and co-operative. It was decided that the intravenous infusion of
A quarter-hourly blood pressure and puke chart was Macrodex (dextran with a weight average mole-
kept for the next 2 hours, and then 4-hourly. cular weight of 70,000) during operation would
Operative technique. help to satisfy the first requirement, as well as
Dental procedures were carried out as follows. promoting venous return. Bennett and associates
(1) Fillings were inserted in three permanent molar
teeth (1966) demonstrated that infusion of dextran 70
6 / 6 diminished platelet adhesiveness in normal men.
/ 6
Bygdeman (1967, 1969) confirmed the above re-
/E sults and showed that the optimal effect on
(2) Six teeth i -c-n i TVC VftTC extracted and the
o r.l;/ ub. platelet "stickiness" was achieved with dextran
socket walls approximated with gut sutures. 77.5 (a special sharp fraction with a weight
Two hours postoperatively the patient was ambulant,
able to drink, and had passed 90 ml of urine. His Hood average molecular weight of 77,500). Dextrans
pressure was 125/70 mm Hg and pulse 100 beats/min. about this molecular weight were more effective
Monitoring of pulse and blood oressure was continued
for a further 24 hours and both remained steady. He than dextran 40 solutions. Bennett, Dhall and
was given a fluid intake of approximately l i 1. for each Matheson (1968) showed that infusion of Macro-
of the first two postoperative days. Recovery was dex (dextran 70) in patients undergoing abdom-
uneventful, and he has remained well since.
inal surgery caused a significant reduction in
DISCUSSION platelet adhesivness, as measured on the third
With the knowledge of fatalities in previous cases postoperative day, when compared with normal
in this disease (Carson et al., 1965; Henkind and controls. The role of platelets in thrombosis is
Ashton, 1965), due thought was given to the discussed by Hampton (1969) who mentions the
prevention of postoperative thrombosis. Since it importance of other plasma factors which may
is not known whether general anaesthesia of itself effect platelet behaviour. Ham and Slack (1967)
increases the tendency to intravascular throm- suggest that maximum platelet adhesivness occurs
bosis, the fact that it may is sufficient ground for much sooner than the tenth postoperative day, as
its avoidance if local anaesthesia is possible and was widely thought, and that adhesiveness in-
practicable. Trauma of any degree appears to be creases before new platelets are formed in res-
potentially dangerous, and should therefore be ponse to stress.
reduced to a minimum. It is of special interest that treatment with
In this case the fact that the patient was men- pyridoxine achieved a normalization of the
tally retarded and that dental treatment was platelet adhesiveness up to the time of surgery.

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 MANAGEMENT OF PATIENTS WITH HOMOCYSTINURIA 99

However, of greater interest is that following TRAITEMENT DES PATIENTS AVEC

surgery the platelet adhesiveness did not increase HOMOCYSTINURIA, D E V A N T ETRE OPERES
as was expected but in fact decreased. It is sug- SOUS ANESTHESIE GENERALE:
DESCRIPTION D ' U N CAS
gested that this decrease was brought about by
the regime which was instituted as part of the SOMMAIRE

anaesthetic technique and, further, that this Un garcon de huit ans, avec homocystinuria devait
subir une intervention dentaire prolongee sous anes-
decrease in platelet stickiness contributed to a th6sie locale. Les auteurs decrivent la conduitc qu'ils ont
prevention of thrombotic complications and the suivi ayec succes, sans thrombo-embolisme ulteneur.
patient's uneventful recovery. Le patient avait durant une periode de deux ans reagi
partiellement au traitement a la pyridoxine. La response
se manifesta par une reduction des taux urinaires et
ACKNOWLEDGEMENTS plasmatiques dTiomocystine, et par une adherence
We wish to thank Dr Colin Bray and Mr John Kecnan thrombocytaire riduite. On suggcre de suivre une con-
for their estimation of platelet adhesiveness, and Mrs duite pre'-operatoire et operatoire du meme genre chea
S. Simpson and Mr D. Kilshaw for the homocystine tous les patients atteints, qui doivent ctre op6res,
determination. puisqu'au troisieme jour apres l'operation il n'y eut pas
We are indebted to Pharmacia Ltd. for financing the d'augmentation de l'adherence des thrombocytes, telle
printing of the colour plate. qu'elle se produit normalemcnt.

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BEHANDLUNG VON PATIENTEN MIT
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Bygdeman, S. (1967). Experimental studies on the anti- mufite eine langer dauernde Zahnoperation in Voll-
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