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Muscle weakness in critically ill children

B.L. Banwell, MD; R.J. Mildner, MD; A.C. Hassall, MSc; L.E. Becker, MD; J. Vajsar, MD; and
S.D. Shemie, MD

Abstract—Objective: To establish the incidence of muscle weakness in critically ill children. Methods: Neuromuscular
examinations were performed in 830 children without identified antecedent or acute neuromuscular disease (age 3 months
to 17 years 11 months) admitted for ⬎24 hours to a pediatric intensive care unit (ICU) over a 1-year period. Results:
Fourteen of 830 (1.7%) patients had generalized weakness. Four failed repeated attempts to extubate. Multiple organ
dysfunction occurred in 11 patients and sepsis in 9. Most children received corticosteroids, neuromuscular blocking agents,
or aminoglycoside antibiotics. Eight of the 14 children were solid organ or bone marrow transplant recipients. Muscle
biopsy showed evidence of acute quadriplegic myopathy in all three patients in whom biopsy was performed. Three
patients died. In survivors, significant weakness persisted for 3 to 12 months following ICU discharge. Conclusions:
Muscle weakness is an infrequent but significant feature of critical illness in children. Transplant recipients seem to be at
particular risk.
NEUROLOGY 2003;61:1779 –1782

The development of muscle weakness in critically ill
adults has been well documented.1-6 In adults with
sepsis and multiorgan failure, the incidence of severe
muscle weakness, often manifesting as failure to
wean from mechanical ventilation, approaches 70%.5
Several forms of intensive care–acquired weakness
have been described: critical illness polyneuropathy,7
acute quadriplegic myopathy (AQM) also termed
critical illness myopathy,8,9 necrotizing myopathy,10
and prolonged neuromuscular blockade.11 Clinical
features are failure to wean from mechanical ventila-
tion, severe skeletal muscle weakness or quadripare-
sis, and reduced or absent tendon reflexes.
Associated risk factors include critical illness, status
asthmaticus, organ transplantation, exposure to cor-
ticosteroids, prolonged neuromuscular blockade, sep-
sis, and multiorgan failure.1,3,11-15
Documentation of muscle weakness in critically ill
children is restricted to small case series,16,17 case
reports,18-21 and occasional inclusion of pediatric pa-
tients in adult intensive care unit (ICU) series.20-22
We prospectively evaluated the incidence, clinical
features, and prognosis of children in whom signifi-
cant weakness developed during the course of their
ICU admission.
Methods. Subjects. All children, ages 3 months to 17 years,
admitted to the pediatric ICU at the Hospital for Sick Children for
⬎24 hours during the 1-year study period were examined two to
three times weekly by the ICU fellow and ICU physiotherapist.
Any patient meeting one or more of the following criteria was
identified as a case: 1) muscle weakness defined as Medical Re-
search Council (MRC) grade ⱕ4 in any one muscle group; 2) re-
duced or absent tendon reflexes; or 3) inability to wean from
mechanical ventilation (in patients without evidence of pulmonary
disease or severe CNS dysfunction). Patients with pre-existing
neuromuscular disease, acute Guillain-Barré syndrome, botulism,
or spinal cord injury were excluded. Patients exposed to neuro-
muscular blocking agents were tested every 24 hours, using the
train of four repetitive nerve stimulation, until a qualitatively
observable muscle response was elicited. They were identified as
cases only if muscle weakness, areflexia, or failure to wean from
ventilation persisted after neuromuscular blockade resolved. All
patients identified as cases underwent a detailed neurologic exam-
ination performed by the study neurologist.
Electrodiagnostic studies were offered to all patients. They
included electromyographic (EMG) studies with concentric needle
electrodes from at least one proximal and one distal muscle in the
lower extremities and standard nerve conduction studies from
several nerves in both upper and lower extremities.
Muscle biopsy was offered to all patients with clinical and
EMG evidence of myopathy. Open muscle biopsy was performed

Drs. Banwell and Mildner contributed equally to this work.

From the Departments of Pediatrics (Neurology [Drs. Banwell and Vajsar], Critical Care Medicine [Drs. Mildner and Shemie, A.C. Hassal], and Neuropa-
thology [Dr. Becker]), Hospital for Sick Children, Toronto, Ontario, Canada.
Received November 26, 2002. Accepted in final form September 5, 2003.
Address correspondence to Dr. B.L. Banwell, Department of Pediatrics (Neurology), Hospital for Sick Children, 555 University Ave., Toronto, Ontario,
Canada M5G 1X8; e-mail: brenda.banwell@sickkids.ca

Copyright © 2003 by AAN Enterprises, Inc. 1779

Table Clinical features of children identified with muscle weakness

MOD

Patient no. Age, y Diagnosis ICU stay, d Max score Days Episodes of sepsis

1 12.5 DKA 13 3 8 1
2 10.6 HT 6 2 2 0
3 15.7 Trauma 28 — 0 2
4 15.0 HT 39 3 12 1
5 1.6 HT 41 3 14 1
6 2.7 Asthma 8 — — 0
7 16.7 S-J 8 2 6 1
8 13.7 Seizures 27 — — 1
9 12.1 BMT 12 3 2 0
10 17.5 Myocarditis 26 4 2 1
11 16.5 BMT 14 5 3 1
12 17.5 OLT 9 3 1 0
13 2.6 HT 26 4 3 0
14 17.3 BMT 36 3 11 1

ICU ⫽ intensive care unit; MOD ⫽ multiple-organ dysfunction; DKA ⫽ diabetic ketoacidosis; HT ⫽ head trauma; S-J ⫽ Stevens–John-
son disease; BMT ⫽ bone marrow transplant; OLT ⫽ orthotopic liver transplantation.

from a clinically affected muscle, processed using standard meth-
ods, and stained using conventional histochemical techniques.
Muscle was also processed for electron microscopy. In addition to
children identified by the above methods, the medical records
were reviewed for all children who succumbed during the 1-year
study period for whom autopsy muscle specimens were obtained.
For autopsy cases, sampled muscles included the diaphragm, in-
tercostal, and one limb muscle (gastrocnemius or deltoid).
Identified patients underwent a weekly neuromuscular assess-
ment in the ICU and after transfer to the ward by either the ICU
fellow or the neurologist. All patients were referred for outpatient
follow-up with the study neurologist after hospital discharge.
The study was approved by the Ethics Review Board of the
Hospital for Sick Children, Toronto.
Results. Patient characteristics. During the 1-year
study period, 1,553 children between 3 months and 17
years 11 months old were admitted to the ICU; 848 were
admitted for ⬎24 hours. Twelve children were excluded
because of a pre-existing neuromuscular disorder and six
due to Guillain-Barré syndrome. Of the 830 eligible pa-
tients, 16 patients were identified by the ICU fellow and
therapist and referred to the neuromuscular specialist.
Two of these patients were excluded: one due to parental
refusal to partake in the study and one due to extreme
patient irritability that precluded accurate examination.
Thus, of the 830 eligible patients, 14 (1.7%) children with
acquired weakness were identified: 5 boys and 9 girls. The
mean age of the cohort was 12.32 years (range 1.6 to 17.5
years). The age distribution of the cohort was bimodal,
with 3 children under age 3 years and the remaining 11
children age 10 or older. The incidence of neuromuscular
weakness in very young ICU patients (between 3 months
and 3 years old) was 0.7% (3/406 eligible ICU patients),
whereas the incidence in older children (ⱖ10 years) was
5.1% (11/214 eligible ICU patients ⱖ10 years old). None of
the 210 ICU patients between ages 3 and 10 was identified
as a case.
The table highlights the admission diagnoses, age, num-
1780 NEUROLOGY 61 December (2 of 2) 2003
ber of ICU days, MOD scores, and number of septic epi-
sodes for each of the 14 patients. Multiorgan failure was
documented in nine children, nine required inotrope sup-
port, and seven received aminoglycoside antibiotics. Nine
patients were treated with corticosteroids for 4 to 11 days,
with total cumulative doses ranging from 0.5 to 260 mg/kg
for an individual patient. Nine children required neuro-
muscular blockade with vecuronium or pancuronium, five
of whom required brief infusions or single doses and four of
whom received continuous infusions lasting ⬎24 hours
(range 61 to 312 hours). All 14 children required mechani-
cal ventilation, with mean time on ventilator of 260 hours
(range 11 to 552 hours). Twelve of the 14 patients (86%)
were ventilated for ⬎5 days. Eight of 14 (57%) children
identified in our series were solid organ or bone marrow
transplant recipients.
Neuromuscular features. Patients were identified with
muscle weakness between day 4 and day 26 after ICU
admission. All 14 patients had generalized weakness in-
volving all four limbs with reduced or absent tendon re-
flexes, four patients failed repeated efforts to wean from
mechanical ventilation, and two patients had additional
clinical features of focal compression neuropathies (pero-
neal neuropathy in one patient, femoral and peroneal neu-
ropathies in a second patient). Wasting of proximal and
distal muscles was prominent in 8 of the 14 patients.
Electrodiagnostic studies were declined in seven pa-
tients, including one child with clinical features of pero-
neal nerve compression. Four of the five children
undergoing needle EMG showed myopathic findings with
short-duration, low-amplitude motor unit potentials and
small polyphasic potentials with an early recruitment pat-
tern. The EMG in the fifth child was normal, possibly
because this study was performed when the child was al-
ready showing improvement in muscle strength. Motor
and sensory nerve conduction studies were done in seven

Figure. (A) Normal sarcomere morphology (longitudinal
section) in healthy control muscle. Note the clearly delin-
eated A band (marked A) containing myosin thick fila-
ments and the well-defined M band (m) in the center of
the A band. The I band (I), made up of actin thin fila-
ments, emanates from the Z disk (Z). (B) Muscle from Pa-
tient 14 shows complete absence of the A band due to loss
of myosin thick filaments. The I band (I) is present. The Z
disk (Z) is thickened and is no longer an exact register with
adjacent sarcomeres. (C) Transverse section of healthy con-
trol muscle. (C, inset) Note the hexagonal array of thin fila-
ments (arrowhead) surrounding a central thick filament
(arrow). (D) Transverse section of muscle from Patient 14.
(D, inset) Note the nearly complete absence of myosin thick
filaments. Only thin filaments are present (arrowhead).
⫻40,000 (A through D); ⫻400 (insets, C and D).
children. In four, including the one with normal EMG,
decreased size of compound muscle action potentials with
otherwise normal data were apparent. One patient with
leukemia (treated with vincristine) had normal strength
until admission to the ICU for complications of bone mar-
row transplantation. Nerve conduction studies demon-
strated findings characteristic of a demyelinating
polyneuropathy with slow nerve conduction velocities and
prolonged distal latencies in several nerves. Needle exam-
ination in this patient was declined, and there were no
prior nerve conduction studies available. Electrophysi-
ologic confirmation of compressive neuropathies of the
femoral and peroneal nerves was demonstrated in one pa-
tient. Nerve conduction studies were normal in two pa-
tients, but testing had been delayed by parental request in
one child until he was already showing significant muscle
strength recovery and was performed very early in the
course of illness in the second child, prior to the time of
maximal neuromuscular weakness. Consent for further
studies in this child was declined. Therefore, electrodiag-
nostic studies were classified as myopathic in four pa-
tients, were normal in two, showed compressive
neuropathies in one child, and demonstrated a mild demy-
elinating polyneuropathy in one patient.
Serum creatine kinase levels were significantly elevated
to 2 to 100 times the upper limit of the reference range in
three patients. Total and free plasma carnitine levels were
normal in all 14 children at study inclusion. In one patient,
subsequent carnitine deficiency (total carnitine 12 mmol/L
[reference range 32.0 to 84.0 mmol/L], free carnitine 6.2
␮mol/L [reference range 26.0 to 60.0 mmol/L]) developed
during her ICU stay. Mild electrolyte imbalance occurred
in patients with renal failure, but significant hypomag-
nesemia or hypophosphatemia was never documented.
Thyroid function studies were normal in all 14 children.
Muscle biopsy was performed in three patients, and
scattered basophilic atrophic fibers with loss of ATPase
reactivity were present in all three specimens. Immunocy-
tochemical studies demonstrated loss of myosin immunore-
activity and prominent calpain expression in affected
fibers. Electron microscopy confirmed selective loss of my-
osin thick filaments, consistent with acute quadriplegic
myopathy.8 In one patient (Patient 14), these findings were
present in the majority of fibers (figure).
Skeletal muscle specimens (diaphragm and limb mus-
cles) obtained at autopsy were reviewed from 16 cases,
none of whom were identified as having ICU-acquired
weakness prior to death. One autopsy case, a 3-year-old
girl, demonstrated scattered atrophic fibers with patchy
ATPase reactivity and loss of myosin immunoreactivity in
all three muscles studied, consistent with AQM. Autopsy
was not performed for Patient 14, the only patient enrolled
in the study to die during her ICU admission.
Patient outcome. The mean length of hospitalization
following discharge from the ICU was 37.2 days (range 5 to
113 days) for the 12 patients for whom this information
was available. One patient was transferred to another in-
stitution (length of subsequent hospitalization unavail-
able), and one patient, who had profound muscle weakness
(grade 0/5 in all limb muscles) and areflexia, succumbed in
the ICU without ever recovering any voluntary contraction
of her limb muscles. Two patients died within 3 months of
discharge from the hospital: one of presumed cardiac ar-
rhythmia and one due to pulmonary complications of graft-
versus-host disease after bone marrow transplant. In the
month prior to death, both patients had proximal muscle
weakness of a severity such that they were unable to climb
stairs.
Of the 11 surviving patients, 9 were available for
follow-up and 2 patients were discharged to facilities out-
side Ontario. At 3 months after hospital discharge, one
child was normal and eight had persistent proximal weak-
ness of the upper and lower limbs (strength on at least two
muscle groups MRC grade ⱕ4). Two of these children were
unable to walk independently. Two patients had multiple
assessments. One patient regained normal strength and
activity level at 8 months. The second patient had normal
strength but reduced endurance at 18 months after hospi-
tal discharge.
Discussion. The incidence of muscle weakness
(1.7%) in this prospective-based study of critically ill
children is lower than that reported in some adult
ICU series (20 to 76%),5,23,24 most of which included
only patients with sepsis, multiorgan failure, or pro-
December (2 of 2) 2003 NEUROLOGY 61 1781
longed ICU admission. Retrospective studies of un-
selected adult cohorts have shown an incidence of
neuromuscular complications of 0.2 to 0.5% of all
ICU admissions.1,14
The incidence of neuromuscular weakness was
lower in very young children than in children over
age 10 years. Given the inherent difficulty in exam-
ining very young critically ill children, it is possible
that weakness in infants and toddlers may have
been underappreciated. It is also possible that the
risk for neuromuscular complications of critical ill-
ness increases with age, particularly after puberty.
Prolonged immobilization and pharmacologic de-
nervation (neuromuscular blockade) of muscle result
in myosin thick filament loss, consistent with acute
quadriplegic myopathy, in experimental animal mod-
els.25,26 Electron microscopy confirmed myosin thick
filament loss in the three children for whom biopsy
was performed and it has recently been reported to
be the major pathologic finding in adults with ICU-
acquired muscle weakness.27
Several comments about our identified cohort can
be made. Children with muscle weakness had longer
ICU admissions (20.9 vs 7.38 days) compared with
the ICU population as a whole. All 14 children were
ventilated, 12 (86%) for ⬎5 days. By comparison,
only 32% of all children requiring ventilation over
the study period (246/779) required ⱖ5 days of respi-
ratory support. Whether prolonged ICU admission
and mechanical ventilation contributed to, or were
consequences of, muscle weakness cannot be deter-
mined by the current study.
Transplantation was the admitting diagnosis for
eight of the children identified in our study. Trans-
plant recipients represented 9.6% of the eligible ICU
population but accounted for 57% of our identified
cohort. This suggests that children admitted to the
ICU following transplantation should be carefully
monitored for neuromuscular complications. Recent
publications have documented acute quadriplegic
myopathy in adult transplant patients.13,28
Acknowledgment
The authors thank Mr. Vern Edwards for technical assistance.
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 Muscle weakness in critically ill children
B. L. Banwell, R. J. Mildner, A. C. Hassall, et al.
Neurology 2003;61;1779-1782
DOI 10.1212/01.WNL.0000098886.90030.67

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