General anesthesia for dental treatment in a Williams syndrome

patient with severe aortic and pulmonary valve stenosis:

suspected episode of postoperatively malignant hyperthermia
Hikaru Kohase, DDS, PhD,a Ryou Wakita, DDS, PhD,b Syozaburoh Doi, MD, PhD,c and
Masahiro Umino, DDS, PhD,d Tokyo, Japan
TOKYO MEDICAL AND DENTAL UNIVERSITY

A 28-month-old boy (height, 76 cm; weight, 9.4 kg) diagnosed as having Williams syndrome presented for
dental care. We report a case of postoperatively suspected malignant hyperthermia after the administration of general
anesthesia for dental treatment in this patient with severe supravalvular aortic stenosis and pulmonary artery
hypoplasia. Anesthesia was maintained through the inhalation of nitrous oxide and sevoflurane with oxygen. The
patient was hemodynamically stable and no other abnormalities were observed. After the completion of the dental
treatment, he was transferred to the pediatric ward. On arrival at the ward, the patients core temperature increased to
39.5C and tachypnea (RR, 30 breaths/min) was observed. The SPO2 during inhalation was slightly low (92%-93%).
Serum biochemistry revealed an elevated CK level (1345 U/L) but no other abnormal findings. Twelve hours after the
dental treatment, the patients core temperature fell to 37.4C. After hospitalization for 4 days, the patient was
discharged in good condition. In the present case, general anesthesia was employed for dental treatment despite
severe supravalvular aortic stenosis and peripheral pulmonary artery hypoplasia, because conventional dental therapy
was very difficult as a result of the patients mental retardation and hyperkinesia. The present case suggests that the
use of volatile agents that could trigger malignant hyperthermia should be avoided wherever possible. (Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2007;104:e17-e20)

William syndrome (WS), first reported by Williams

et al.,1 is characterized by the following 3 characteristics: supravalvular aortic stenosis, mental retardation,
and elfin face. The incidence of this syndrome is reported to be 1:20,000 to 50,000 children.2 Although a
few reports regarding anesthetic management in patients with this syndrome have been published,3-7 general anesthesia for dental treatment in WS patients with
severe supravulvular aortic stenosis has not been described. Not only careful anesthetic management, but
also the prevention of intra- and postanesthetic complications are required when administering general anesa

Associate professor, Section of Anesthesiology and Clinical Physiology, Department of Oral Sciences, Graduate School, Tokyo Medical and Dental University.
b
Assistant professor, Section of Anesthesiology and Clincial Physiology, Department of Oral Sciences, Graduate School, Tokyo Medical and Dental University.
c
Senior Associate professor, Department of Pediatrics and Developmental Biology, Graduate School, Tokyo Medical and Dental University.
d
Professor, Section of Anesthesiology and Clinical Physiology, Department of Oral Sciences, Graduate School, Tokyo Medical and
Dental University.
Received for publication May 26, 2006; returned for revision Apr 12,
2007; accepted for publication Apr 12, 2007.
1079-2104/$ - see front matter
2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2007.04.013

thesia to patients with WS. Mammi et al.8 reported a

suspected malignant hyperthermia (MH) reaction in a
patient with WS who underwent general anesthesia.
We report a case of postoperatively suspected MH
after the administration of general anesthesia for a
dental treatment in a WS patient with severe supravalvular aortic stenosis and pulmonary artery hypoplasia.
CASE HISTORY
The patient was a 28-month-old boy (height, 76 cm;
weight, 9.4 kg) diagnosed as having Williams syndrome based on elfin face characteristics and supravalvular aortic stenosis but not confirmed by fluorescence
in situ hybridization. His prenatal period and delivery
were uneventful. His parents were healthy and had no
medical history of suspected MH. An inguinal hernia
operation performed under general anesthesia using
sevoflurane and nitrous oxide at the age of 6 months
was uneventful.
A dental examination revealed that the extraction of
3 teeth and the restoration of 4 teeth were required.
Cardiac catheterization confirmed a 4-mm supravalvular aortic stenosis (pressure difference: 70-90 mm Hg)
and peripheral pulmonary artery (PA) hypoplasia (hypoplasia of bilateral PAs, 3-4 mm of stenosis each;
pressure difference: 60 mm Hg).
The patient was admitted to the pediatric ward of our
hospital the day before surgery, and a pediatric cardie17

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Kohase et al.

Table I. Perioperative changes of creatine kinase and body temperature

Operative day

Creatine kinase, IU/L

Body temperature, C

Preop

2POD

3POD

4POD

5POD

132
36.5

36.5

37.2

1345
39.5

1332
39.5

37.4

1439
36.9

1120
36.0

800
36.1

195
36.2

1, emergency period of anesthesia; 2, recovery period of anesthesia; 3, at arrival at the pediatric ward; 4, 2 hours after arrival at the pediatric ward;
5, 12 hours after the dental treatment; , no data available; POD, postoperative days.

ologist conducted the preoperative systemic management. A preoperative echocardiography revealed supravalvular aortic stenosis (pressure difference: 90 mm
Hg) and pulmonary stenosis (pressure difference: 60
mm Hg). In addition, the left ventricular chamber could
not be visualized on echocardiography during left ventricular contraction because of hypercontraction. The
patients preoperative vital signs were as follows: blood
pressure (BP), 120/60 mm Hg; heart rate (HR), 102
beats/min; respiratory rate (RR), 20 breaths/min; and
body temperature (BT), 36.5C. A peripheral blood
examination, including serum calcium (10.5 mg/dL)
and creatine kinase (CK) (132 IU/L) measurements,
was normal. Except for a systolic murmur of Levine
grade III/VI in the third left costal interspace, no remarkable physical findings or symptoms of congestive
heart failure were present.
The patient received nothing by mouth for 3 hours
before the surgery. At 90 minutes before the operation,
1 g of trichloroethanol syrup was administered orally.
Intravenous access was secured 1 hour before entering
the operating room, and 1 g of cefmetazole was administered intravenously. Thirty minutes before the start of
anesthesia, 10 mg of hydroxyzine hydrochloride and 10
mg of pentazocine were administered intramuscularly.
Endotracheal intubation was performed after administration of 1.5 mg of midazolam, 30 g of fentanyl, and
1 mg of vecuronium, and the anesthesia was maintained
through the inhalation of nitrous oxide (50%) and
sevoflurane (1.0%2.5%) with oxygen (47%). Three
teeth were extracted, and 3 teeth were restored. The
duration of the dental treatment was 2 hours. Although
electrocardiography showed ventricular dissociation
during the surgery, the patient was hemodynamically
stable and no other abnormalities were observed. To
avoid hemodynamic changes caused by bucking and
excited movements, the endotracheal tube was removed
prematurely under deep anesthesia and replaced with a
laryngeal mask airway (LMA) after the completion of
the dental treatment. After confirming spontaneous respiration, 0.2 mg of atropine sulphate and 0.5 mg of
neostigmine were administered to reverse the muscle
relaxant. Thereafter, the patient was allowed to breathe

spontaneously for about 45 minutes through a laryngeal

mask. The patients vital signs during this period were
as follows: BP, 120/60 to 110/50 mm Hg; HR, 97 to
105 beats/min; RR, 26 breaths/min; ETCO2, 45 to 48
mm Hg; BT, 36.036.6C. After the patients swallowing reflexes were restored, the LMA was withdrawn
and the patient was allowed to inhale oxygen through a
facial mask. The recovery of consciousness was delayed because of the heavy premedication. At this
stage, the patients SPO2, ETCO2, RR, and BT while
breathing room air were 92% to 93%, 48 mm Hg, 25 to
30 breaths/min, and 37.2C, respectively. Auscultation
revealed normal respiratory sound. He was transferred
to the pediatric ward with oxygen administered. On
arrival at the ward, the patients BT increased to 39.5C
and tachypnea (RR, 30 breaths/min) was observed. No
abnormal muscle symptoms or signs of the upper and
lower limbs were observed. The room air SPO2 was
slightly low (92%-93%). Oxygen was immediately administered again. Surface cooling of the head and armpit areas was performed. Serum biochemistry revealed
an elevated CK level (1345 U/L) but no other abnormal
findings. Urinary catheterization was performed to
monitor output. Neither port-wine urine nor myoglobinuria were observed. The color was yellow transparent and blood gas analysis (pH 7.340, PCO2 49.2 mm
Hg, PO2 97 mm Hg during O2 inhalation) revealed
slightly compensated acidosis. No electrolyte imbalances were detected in serum. Since dehydration was
suspected, Ringers solution was transfused to prevent
dehydration. However, B-mode ultrasonography showed
no respiratory changes of diameter of the inferior vena
cava meaning that CVP (central venous pressure) was
over 10 mm Hg and infusion balance sheet was positive
until this time. There was no evidence of hypovolemia.
Twelve hours after the dental treatment, the patients
core temperature fell to 37.4C. The CK level increased
to 1439 U/L on the second postoperative day and then
recovered to 195 U/L on the fifth postoperative day
(Table I). After hospitalization for 4 days, the patient
was discharged in good condition. Fluorescence in situ
hybridization performed during this perioperative period confirmed the microdeletion of 7q11.23.

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DISCUSSION
Our patient had severe supravalvular aortic stenosis
and peripheral pulmonary artery hypoplasia.
Although valvuloplasty is often selected for supravalvular aortic stenosis, at this stage, the intervention
was considered to carry an increased risk of paradoxical
systemic overload and might have exacerbated the condition of the patient. Conservative therapy was thus
implemented instead of curative surgery.
In the present case, general anesthesia was used for
dental treatment because somatic and emotional stress,
such as pain, fear, excitement, and anxiety caused by
conventional dental treatment could have resulted in
cardiovascular exacerbation, and conventional dental
therapy was very difficult as a result of the patients
mental retardation and hyperkinesia. Curative dental
therapy was necessary because dental caries and subsequent periodontitis could have led to infective endocarditis and other focal infections.
Maintaining a balance between myocardial oxygen
supply and demand is essential for the anesthetic management of patients with WS because WS is characterized by supravalvular aortic stenosis, coronary stenosis,
and peripheral pulmonary artery hypoplasia.3,5 WS patients should be regarded as high-risk patients for anesthesia, particularly if bilateral outflow tract obstruction or
evidence of myocardial ischemia exist.9 Accordingly,
tachycardia, hypertension, and hypotension should be prevented during the perioperative stage.
The patient was heavily premedicated with trichloroethanol, hydroxyzine hydrochloride, and pentazocine
to decrease fear, anxiety, and excitement. Sufficient
sedation was achieved. Rapid induction was smoothly
conducted by the intravenous administration of midazolam and fentanyl. We think this patient required the
heavy premedication and immoblization during treatment, which contributed to eliminating physical stress
during treatment, including bucking at the anesthetic
emergency.
The maintenance of anesthesia was successful, and
no cardiovascular episodes occurred. The anesthesia
was maintained with oxygen, nitrous oxide, and
sevoflurane under manually controlled ventilation. BP,
HR ECG, SPO2, ETCO2, and BT were stable and
within the normal ranges, and no abnormal episodes
occurred during the anesthesia. However, complete
awakening was delayed because of the midazolam,
fentanyl, and heavy premedication. We misinterpreted
the mild as being attributable to hypoxia and hypercapnea to the heavy premedication and early extubation to
avoid systemic stress, whereas they may have been the
initial symptoms of MH.
Propofol is a possible choice of anesthetics in this
patient. Propofol has been found to exert a negative

Kohase et al. e19

chronotropic effect10 and negative inotropic effect in a

dose-dependent manner in human cardiac muscle experiments,11 and to be less likely to induce MH.
Anesthesia was maintained with sevoflurane, because at 6 months of age there had been no episodes,
including of MH, and we were familiar with the agent
in general anesthesia for children. Several articles have
reported that MH is rare12 and even nonexistent in
infancy,13 but otherwise MH reaction occurred in infancy.14 Until we encountered this case, we did not
think that sevoflurane could induce malignant hyperthermia.
Some WS patients have disturbed calcium homeostasis with hypercalcemia or symptoms compatible with
hypercalcemias.15 Myopathic changes have also been
described in some patients.16 Patel and Harrison4 reported excessive masseter spasm after the use of halothane and suxamethonium in WS patients, suggesting a
danger of MH.
Postoperatively, a rapid increase in BT (39.5C),
reduced oxygen saturation, slightly increased ETCO2,
tachypnea, and an elevated CK level were observed. At
this time, shivering, tremors, muscle rigidity, and cyanosis were not observed. These features were suggestive of grade 4 MH, according to the clinical grading
scale by Larach et al.17 MH could not be confirmed, but
appeared likely.
Muscle rigidity including masseter spasm is thought
to be induced by abnormal intracellular calcium release
from sarcoplasmic reticulum in MH. It was not an
inevitable symptom with MH.17 Reduced oxygen saturation increased the ETCO2 mean by increasing oxygen
consumption; hypermetabolization was due to abnormal intracelluer calcium release.
The treatment of suspected hyperthermia in this case
consisted of transfusion and continuous monitoring of
vital signs, including BT, BP, ECG, SPO2, and urinary
output. Dantrolene, a specific, effective agent for MH,
was not used in this case because the patient had grade
4 MH.17
Although no direct evidence of a correlation between
MH and WS has been reported, previous studies have
reported the possibility of MH developing during general anesthesia.3,8 WS is an autosomal dominant condition caused by a mutation in the elastine gene located
at 7q11-23 (microdelation), although the genetic area
affected by WS is also involved in the pathogenesis of
MH.8 The proximity to the WS region of the gene
encoding the L-type voltage-gated calcium channel alpha(2)/delta-subunit (CACNL2A) on 7q11.23-q21.1,
was previously shown to be closely linked to some
forms of MH susceptibility.8
The myopathic changes are closely related to MH
symptoms.18 The increase in CK in the present case

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Kohase et al.

may have been caused by myopathic alterations, with

muscle damage being triggered by the general anesthesia, as described by Patel and Harrison.4
Further examinations concerning MH, including a
muscle biopsy and halothane-caffeine test, should be
performed before the next general anesthesia. Nonetheless, as far as the use of anesthetics in WS patients is
concerned, the present case suggests that the use of
volatile agents that could trigger MH should be avoided
wherever possible.
Our experience in the case reported above suggests
that adequate depth of anesthesia should be maintained
and sufficient analgesics should be administered when
intravenous anesthetics are used for general anesthesia
in patients with WS and that strict postoperative intensive care is needed even for relatively uninvasive care,
such as dental treatment.
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stenosis. Circulation 1961;24:1311-8.
2. Greenberg F. Williams syndrome professional symposium. Am J
Med Genet (Suppl) 1990;6:85-8.
3. Kawahito S, Kitahata H, Kimura H, Tanaka K, Sakai Y, Hirose
Y, et al. Anaesthetic management of a patient with Williams
syndrome undergoing aortoplasty for supravalvular aortic stenosis. Can J Anaesth 1998;45(12):1203-6.
4. Patel J, Harrison MJ. William syndrome: masseter spasm during
anaesthesia. Anaesthesia 1991;46:114-6.
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Williams syndrome. J Anesth 1989;3:227-8.
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Hoyme HE, et al. Sudden death in Williams syndrome: Report of
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Reprint requests:
Hikaru Kohase, DDS, PhD
Section of Anesthesiology and Clinical Physiology
Department of Oral Restitution
Division of Oral Sciences
Graduate School
Tokyo Medical and Dental University
1-5-45,Yushima, Bunkyou-ku
Tokyo, Japan, 113-8549
hkohase.anph@tmd.ac.jp