Anuestlzesiu, 1996, Volume 51, pages 575-578

Case reports
Anaesthetic management in maple syrup urine disease

S. Kahraman, MD. Assistant Professor of Anaesthesia, M. Ercan, MD, Resident Anaesthesist, 0. Akku?, MD,
Resident Anaesthesist, 0. ErGelen, MD, Assistant Professor of Anaesthesia, K. Erdem, MD, Professor of
Anaesthesia, Department of Anaesthesiology and Reanimation, T. CoSkun, MD, Professor of Paedeiatrics,
Department of Paediatrics, Hacettepe University, Medical School, 06 100, Ankara, Turkey.

Summary
Two children with n q l r sj'rup urine disease undergoing einergency and clectinc s u r g c ~ yare reported. The arhiinistrntion of
ltetaniine to a 12-month-old boy iiithout neurological prohleriis and propofol infusion to a 5-year-o/d girl I c i t l i a 1ii.stor.j. of'
o f n q l o syrup urino discme and poterztial
convulsions, ~.va.sunecentjul. @Jc) b d i 4 w lhut a , f i d k n o d c ~ d g eof the patliopli~,siolog~
peri-operative prohlcws associated 1i.ith thc3 disease are essentiul, so that paticnts arc not suhjectcd to unnecessarj. risks.

Key words
Complications; maple syrup urine disease.
Anae.stlzetics, iiitravenous; ketamine, propofol.

Decarboxylation in the three neutral branched-chain amino Case liistorj,

acids, leucine, isoleuciiie aiid valine, is accomplished by the
'branched chain 0x0 acid dehydrogenase' enzyme system. Case 1 . A 12-month-old boy, who was found to have classic
Thiamine pyrophosphate is used a s a coenzyme in this maple syrup urine disease on the 4th day of his life. had
reaction. Deficiency of this enzyme system causes maple been adequately managed with relatively few problems until
syrup urine disease, which is named after the characteristic the symptoms of acute gastroenteritis started, after 3 days
odour of maple syrup in body fluids, especially urine. The of which he was admitted to the emergency department.
disease is inherited a s autosomal recessive, with a general On admission he had vomiting, diarrhoea, fever and
incidence near 1:120 000 live births [I]. It is one of the inflammation of his left arm. He was conscious. but was
most commonly seen metabolic diseases in Turkey [2]. The hypoactive with mild dehydration. He was also pale and
characteristic feature of maple syrup urine disease is had acrodermatitis enteropathica. with candida superinfec-
elevation of the concentrations of alloisoleucine, branched- tion around his mouth. He weighed 4600 g; his height was
chain amino acids aiid their ketoacids in blood and tissues 62 cm and his head circumference was 43 cm. which were
and this leads to acute and chronic brain dysfunction [l]. below the 5th percentile for his age and sex. His initial
The concentration of plasma branched-chain amino acids laboratory data are recorded in Tables 1 and 2. At the
can be normalised satisfactorily in children with the disease beginning the patient was fed Milupa MSUD-I (Milupa,
by restricting dietary protein intake and supplementing the Germany) orally but later this formula was discontinued
diet with an amino acid mixture that is free of branched- because of recurrent vomiting and septic arthritis. He was
chain amino acids [3. 41. Early intervention and meticulous then treated with intravenous lluids (3000 m1.m '.day- ' )-

treatment of the condition may prevent neurological decline and antibiotics. Adequate amounts of calories were
and may succeed in preserving the intellect [5]. However. supplied by 10% glucose aiid lipid (1 50 kcal.kg '.day I ) -

severe ketoacidosis. hypoglycaemia. hyperammonaemia. infusions. lrnniediatelp before the operation the patient's
rapid neurological deterioration, cerebral oedema and haematocrit was increased to 31% by red blood cell
death may occur during any stressful situation such a s transfusion. In the operation room the electrocardiogram
infection or surgery. Mental and neurological deficits are (ECG), blood pressure, peripheral oxygen saturation and
common sequelae [I]. temperature of the patient were monitored. Anaesthesia
We report two children with maple syrup urine disease, was induced with ketamine 2 mg.kg I intravenously and
-

one undergoing emergency surgery for septic arthritis and maintained for 25min with boluses of the drug of
the other undergoing elective dental surgery. 0.5 nig.kg I . In total, he needed ketamine I5 nig.
~

Accepted 8 August 1995

0003-2409 96 060575 + 08 318 00 0 @ 1996 The Associdtion of Andesthetists of G t Britain m d Ireldnd 575
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576 Case reports
Table 1. Laboratory values of the patients.

Leucine Isolrucine Valine HbIHct GlucoseNa' K' Ca-- C1- B U N ASTiALT

Patient # pniol.1 pniol.l ~ I pmol.1 'Yo mg Yo mmol.1 mmol.1- mniol.1 mmol.l-' nig YO U . I P

I tPre-operative 1 829 498 787 7.0'22.6 58 139 4.2 8.8 110 11 33,/12
Postoperative 668 320 560 10.4 31.4 105 135.9 3.17 8.8 106 11 33\12
2 Preoperative 303 214 504 8.2 25.7 80 133 4.2 ND 103 5 23,20
Postoperative 316 274 574 8.0 25.2 119 140 4.0 ND 104 8 23 20

i o n admission to hospital.
Hb,Hct, haenioglobin,haematocrit: BUN, blood urea nitrogen; AST. aspartate aminotransferase: ALT, alanine aminotransferase.

Fluids were provided by dextrose 10% in a 1.3 dilution Discussion

with NaC1 0.90/0. Anaesthesia was uneventful with a
normal recovery. During the postoperative period he The severity of clinical presentations of maple syrup urine
was given dextrose 10% (150 ml.kg- '.day-'), NaHCO; disease varies greatly in proportion to the residual activity
(2 mmol.kg-'.day-'), NaCl 5% (15 ml.kg-'.day ') and of the enzyme, branched-chain 0x0 acid dehydrogenase.
KCl (4 mmol.kg- '.day- I). At the 6th hour oral nutrition The classical form of the disease is associated with virtual
was instituted using Milupa MSUD-1. There were no absence of enzyme activity and therefore has the most
complications in the postoperative period. severe biochemical and clinical presentation. On the other
Case 2. The patient was a 5-year-old girl with classic hand, variant forms ('intermittent', 'mild', and 'valine-
maple syrup urine disease who was diagnosed on the second toxic') show variable amounts of residual activity and thus
day of life. She had been admitted to hospital on many vary both clinically and biochemically [6].
occasions for gastroenteritis, upper respiratory tract In the classical form of the disease, the infants who
infections, bronchiolitis, pneumonia and convulsions. Her are normal at birth develop ketoacidosis, poor feeding,
nutritional therapy consisted of Milupa MSUD-2 sup- vomiting, lethargy, hypo- or areflexia and alternating
plemented with natural proteins. She was mentally retarded periods of hypertonicity and flaccidity within the first week
and was scheduled for outpatient dental surgery under of life, since it may take up to a week for blood and tissue
general anaesthesia. On physical examination her weight levels of leucine and 2-ox0 isocaproate to exceed critical
was 19.5 kg (50-75th percentile), and her height was 99 cm concentrations. Later, neurological deterioration will lead
( < 5th percentile). Her weight, compared with her height to seizures, and if untreated, the patients will die within a
was above the age- and sex-matched standards. She had few days or weeks. Early diagnosis and initiation of therapy
crepitations audible at the base of the left lung but physical are essential in order to prevent permanent brain damage
examination was otherwise normal. Her laboratory findings and premature death. In patients with variant forms of the
showed a hypochromic and microcytic anaemia and disease the onset of symptoms is generally delayed and
compensated metabolic acidosis (Tables 1 and 2). Electro- symptoms are less severe [I].
encephalogram showed active paroxysmal abnormalities Management of these patients involves permanent
originating from subcortical areas. reduction of dietary branched-chain amino acids, as well as
She fasted for 3 h prior to the operation. In the operating urgent treatment of acute neonatal illnesses and metabolic
room, after the ECG, blood pressure and pulse oximeter derangements secondary to intercurrent infections in later
monitors were applied, intravenous access was established infancy and childhood [7]. Minor illnesses such as vomiting,
and an infusion (dextrose 10% in 1.3 dilution with NaCl diarrhoea, fever or other causes of stress result in a catabolic
0.9%) was started. Anaesthesia was induced with propofol state with the release of amino acids from muscle proteins.
(2.5 mg.kg ') and atracurium (0.5 mg.kg- I ) . Following
- The latter leads to accumulation of branched-chain
tracheal intubation, anaesthesia was maintained with metabolites, Furthermore, poor oral intake which accompa-
gradually decreasing doses of a propofol infusion nies infection can lead to a relatively fasted state and may
(10-3 mg.kg-'.h-') and NzO/O1(50/50%). The operation increase the concentration of leucine [3].This was suggested
and anaesthesia proceeded uneventfully and at the end of to be a more important determinant of outcome when
surgery the tracheal tube was removed when the patient was compared with the effects of infection itself. Neurotoxic
awake. Five min after extubation, arterial blood gases levels of branched-chain amino acids may be reached within
showed a metabolic acidosis without respiratory compen- hours following infection and patients may eventually
sation (Table 2). Following nasal oxygen administration the present with fasting hypoglycaemia or convulsions [7].
patient was discharged without complications. Cerebral oedema with increased intracranial pressure and

Table 2. Arterial blood gases values of the patients

PCO? POZ Hc~, BE S20

Patient # pH kPa kPa nimol.1 - ' mmol.1 I Yo

1 Pre-operative 7.32 5.2 9.6 19.7 -8.0 93.7

Postoperative 7.40 3.3 11.4 15.0 -8.7 96.5
2 Pre-operative 7.39 4.6 11.7 19.0 - 4.0 97.0
Postinduction 7.41 4.0 14.9 18.7 - 5.0 99.7
Postoperative 7.33 4.6 9.9 18.1 -6.2 92.2
~

Pro?, carbon dioxide pressure; Po2. oxygen pressure; HCOJ,bicarbonate radical; BE, base
excess; Sao~,oxygen saturation.

Anaesthesia, Volume 51, June 1996

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Case reports 511

brainstem compression may occur even in older children conduct of anaesthesia should prevent morbidity and
[7-1 11, mortality.
In the acute phase of the disease administration of a
high caloric regimen supplemented with a mixture free of
branched-chain amino acids appears to be the most effective References
treatment [3,4]. The high caloric content should be [ I ] CHUAKC DT, SHIHVE. Disorders of branched chain amino
provided in the form of intravenous glucose with a acid and keto acid metabolism. In: SCRIVER C R , BEAUDET AL,
concomitant insulin infusion and/or in the form of an SLYWS. VALLED. eds. The niemholic rrnd niolecular hasis
intravenous lipid infusion [ 12- 141. Invasive techniques of inlierited disetrae. New York: McGraw-Hill Inc., 1995:
such as peritoneal dialysis, haemodialysis and venovenous !239-77.
haemofiltration have also proved to be effective [ 15-17], [2] OZALPI, C ~ S K U T N, TOKOLS, DEMIRCIN G. M 6 x H E.
Even in emergency cases pre-operative reduction of Inherited metabolic disorders in Turkey. Journal qf Inlieritc~d
plasma leucine levels and rapid correction of dehydration Metnholic Diseases 1990; 13: 732-8.
and acidosis are essential. When anaesthesia is adminis- [3] THOMPSON J N , FRANCIS DEM, HALLIDAY D . Acute illness in
maple syrup urine disease. Dynamics of protein metabolism
tered, care should be taken to prevent hypoglycaemia due and implications for management. Journal of'Pediatrics 1991;
to pre-operative fasting. During anaesthesia the blood 119: 35-41.
glucose levels and the pH should be monitored and high [4] BERRYGT. HEIDENREICII R, KAPLANP,LEVINE F, MAZURA,
energy intake should be maintained. In addition, avoidance PALMIEKI MJ, YUDKOFFM, SEGALS. Branched-chain amino
of overhydration and an increase in intracranial pressure acid-free parenteral nutrition in the treatment of acute
are of vital importance. Administration of hypertonic metabolic decompensation in patients with maple syrup urine
glucose solutions may constitute an additional stress factor disease. NEW England Jouvnd of Medicine 1991; 321: 175-9.
by precipitating increases in oxygen consumption, CO, [5] KAPLANP. MAZURA, FIELDM. BERLINJA. BERRYGT,
HEIDENREICH R, Y U D K ~ FM, F S E ~ ~ S.
A IIntellectual
. outcome in
production, and noradrenaline excretion. Therefore, in
children with maple syrup urine disease. Jonriirrl qf Prdiatric.Y
these patients, fat emulsions which allow provision of 1991; 119: 46-50.
calories without causing over hydration and haeniodilution [6] LANGEvBtCK U. Pathobiochemical and pathophysiological
may be preferred to glucose loading. Avoidance of analysis of the MSUD phenotype. In: ABIDISA. FEKLW.
overhydration is of particular importance. In this context L A N G E N B ~U,C KSCHAUDER P. eds. Branched-chain rmiino and
Riviello et al. have reported four patients who died because keto acids in Iieciltli rrnd disease. Basel: Karger, 1984: 315-34.
of cerebral oedema [l I]. The authors thought that one of [7] WENDELU. Disorders of branched-chain amino acid
the factors leading to death in these patients might be metabolism. In: FERRANDES J, SAUDUBRAY JM. TADA K, eds.
overhydration and they suggested that a more conservative Inborn metabolic dlrenses. Diagnosis and treatnrent. Berlin.
Heidelberg: Springer-Verlag, 1990: 265-70.
fluid regimen, preferentially using one with colloids, such as [7] LEVIKML, SCHEIMANN A, LEWISRA, BEAUDET AL. Ccrebral
in diabetic ketoacidosis, might diminish the chance of edema in maple syrup urine disease. Juurntil of'Pediatrics 1993;
precipitation of cerebral oedema. 122: 167.
Although there is no single anaesthetic agent that is [8] MANTOVANI JF, NAIDICHTP, PRENSKY AL, Doosou WE,
reported to be contraindicated in patients with maple syrup WILLIAMS JC. MSUD: presentation with pseudotumor cerebri
urine disease, the choice of anaesthetic technique should be and CT abnormalities. Journal qf Pcdiatrics 1980; 9 6 279-81.
individualised to the patient, based on the type of operation [9] LUWAROTTIMS. SIGNORINE, GARIBANDI LR. Cerebral
and associated complications of the disease. The anaes- edema in maple syrup urine disease. Aniericcni Journul of
Disecises o f Clzildren 1982; 136: 648.
thetist should keep in mind that these patients can convulse.
[lo] MIKATI MA, DUUIN GE, D ~ KALOUSTIAN
K VM. Maple syrup
Anticonvulsant properties have been attributed to ketamine urine disease with increased intracranial pressure. Anirrictin
[18-201 but even so the use of ketamine in patients with Journtrl o f Discuses of Children 1982; 136: 642-3.
seizure disorders is controversial at present [21-231. In the [ I l l RIVIELLOJJ JR, REZVANII, DIGEORCEAM. FOLEY-CM.
first patient who was to undergo a short orthopaedic Cerebral edema causing death in children with maple syrup
procedure we chose dissociative anaesthesia with ketamine urine disease. Joitrnd of Pdirtr.ic~.s1991; 119: 42-5.
since he did not have any neurological complications. [I21 WENDEL U, L A N ~ ~ E N BUE,CLOMHECK
K I , BKEMER HJ. Maple
However; in the second patient we decided to use propofol syrup urine disease: therapeutic use of insulin in catabolic
for general anesthesia since she had a history of convulsions states. European Journul of Pcdiufrics 1982: 139: 172-5.
[I31 SIVYDERMAN SE. Treatment outcome of maple syrup urine
and the manipulations would mainly take place in her disease. Actcr Paediairica Jtrponica 1988; 30: 41 7--24.
mouth. There were no complications attributable to [I41 CLOWCL, READET M , SERWER CR. Outcome of early and
anaesthesia in either patient but it should be remembered long-term management of classical maple syrup urine disease.
that ketamine may not be safe to use in those with increased Pmdintrics 1981; 68: 856-62.
intracranial pressure. [I51 GOODMAN SI. Inherited metabolic disease in the newborn.
The second patient had a metabolic acidosis before Approach to diagnosis and management. A d r o i w s in
surgery, therefore she was fasted for only a relatively short Pdicrtrics 1986; 33: 197-224.
time and was given dextrose 10% during the operation in [I61 THOMPSON G N . BUTTWW, SHANNFA, K ~ K HDM. Y Htmmc;
RD, HOWELLSDW. OSBORNFA . Continuous venovenous
order to reverse or prevent worsening of acidosis. However.
hemofiltrdtion in the management of acute decomposition in
acidosis persisted after surgery even though the blood inborn errors of metabolism. Journrrl c!f P r d i t r t ~ k .1991;
~ 118:
glucose was maintained within normal limits throughout. 879 84.
We believe that a stress-induced catabolic state may have [I71 R U T L ~ I XSL. E HAVENS PL, HAYMOWMW. M c L r ~ uRH.
been a factor contributing to our inability to correct the KAN JS, BRUSILOW SW. Neonatal haemodialysis: effective
acidosis, since she did not receive premedication for this therapy for the encephalopathy of inborn errors of
outpatient manipulation. In other words, we suggest that metabolism. JournoI of Pc,ditrtrit~,s 1990: 116: 125-8.
the catabolic effect of stress might have overridden the [I81 S Y B ~ RJW, T K W F JV. Ketamine treatnieiit of status cpilepti-
anticatabolic effect of glucose. A postoperative hyperme- 1983: 58: 203.
CLIS. A/lf,sf/fE.Si(~/[Jg~'
[I91 FISCHERM McD. Use of ketamine hydrochloridc in the
tabolic state secondary to the surgery has also been reported treatment of convulsions. Ancrrsrlicsiu crrici Intc~ri.~ir.c~ C m , 1974;
previously [24. 251. 2: 266-8.
I t is concluded that maple syrup urine disease [20] REIIERBS. TRAPPLS. TRAUTMAU KC. Ketamine suppression
presents significant anaesthetic difficulties and awareness of chemical induced convulsions in the two-day-old white
of the potential anaesthetic problems prior to the leghorn cockerel. Anc.stlie.ritr cintl Ann/gt,.sirr 1980; 5 9 406 9,

Anarsthc.siu, Volume 5 1, June 1996

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578 Case reports
[21] KAYAMA Y, IWAMA K. The EEG evoked potentials and single [23] CORRSEN G, LITTLES, TAVAKOLI M . Ketamine and epilepsy.
unit activity during ketamine anesthesia in cats. Anestlie.~iolug~ Ariesthesin cind Ancilgesici 1974; 53: 3 19-35.
1972; 36: 3 16-28. [24] MORTONH. MSUD news from the clinic for special children.
[22] FERRER-ALLAOO T. BKECHNER VL. DYMONDA, COZENH, Mriple Sjrup Urine Diieuse Nc~~r.slertcv1992: 10: 9-1 1.
CRANDALL P. Ketamine-induced electroconvukive phenomena [25] FUKUTOMI M, KITAMURAS. KAWACHI K, TSUJIT, HASHIMOTO
in the human limbic and thalamic region. Anest/wsiology 1973; K, YOSHIOKA A. Successful repair and postoperative manage-
38: 333-4. ment of tetralogy of Fallot in a patient with maple syrup urine
(1993; 8: 48-51.
disease. Hc,cirt~~Ve~.Fsc~I.r

Anaesthesia, 1996, Volume 51, pages 578-579

Use of liposome-associated bupivacaine in a cancer pain syndrome

N. D. Lafont, MD, F . J. Legros, PhD, L a b o r a t o r y of Physiopathology, Free University of Brussels. R o u t e d e

Lennick 808, 1070 Brussels, Belgium, J. G. Boogaerts, M D , P h D , Head of the D e p a r t m e n t o f Anaesthesiology,
City Hospital, Boulevard Paul J a n s o n 92, 6000 Charleroi, Belgium.

Summary
Bupicacainc. 0.25% encapsulated by multilanzellar liposonies \vas administered epidurally to a patient suffering pain associated
with lung cancer and tlie ej’bct compared with a plain bupicacaine solution q j the same concentration. Complete analgesia was
produced for 4 lz with the plain .solution and 11 11 with the liposon?al,fovniulation. No motor blockade or haemodynaniic instability
uas obserced lvitlz the liposonze-associated bupiracaine.

Key words
Anaestlzerics, local; bupivacaine.
Aiiuestlzetic techniques regional; epidural.
Liposome; drug association.

of local nerve toxicity after 2 and 7 days [13]. When given

in pain management [I]. The action of a long-acting local intravenously, the liposomal formulation of the local
anaesthetic such as bupivacaine is, however, limited to a few anaesthetic appeared to be less neuro- and cardiotoxic than
hours [2].An increase in the drug dose can lead to systemic the equivalent plain solution [14].
toxicity, specifically. a high blood level of bupivacaine In a patient suffering algodystrophic pain of the upper
induces major central nervous system [3-61 and cardiovas- limb, infiltration of the brachial plexus with bupivacaine
cular [7-91 reactions. For these reasons, the recommended associated with liposome produced total pain relief for 40 h
dose of bupivacaine administered epidurally is usually compared with 12 h for the plain bupivacaine solution [ 151.
limited to 225 mg with adrenaline. for a single dose [2]. Epidural administration of liposome-associated bupiva-
A drug delivery system resulting in a longer duration of caine 0.5% in humans led to a 2- to 3-fold prolongation of
action and reduced toxicity would be highly desirable for postsurgical analgesia without motor block [ 161.
the clinical use of local anaesthetics. In a recent editorial. In this case report we have compared the analgesic.
Tucker [lo] pointed out the need for a vehicle to modulate motor and haemodynamic variables after epidural adminis-
perineural block with local anaesthetics. He suggested the tration of equivalent doses of plain and liposome-associated
use of liposomes and biodegradable polymers. bupivacaine in a patient suffering from cancer pain.
We have encapsulated bupivacaine with liposomes and
shown that this resulted in lower and more sustained plasma
levels than the free drug following a single epidural injection C’usc~liistorj.
in rabbits [Ill. A prolonged constant plasma level was After approval of the local ethics committee and written
observed after brachial plexus infiltration of liposome- informed consent, bupivacaine 0.25% without adrenaline
associated bupivacaine [ 121 without any histological sign encapsulated into liposomes was administered via a thoracic

Accepted 15 July 1995