Estimation of lean body mass in children A. M. Peters

British Journal of Anaesthesia 106 (5): 719–23 (2011)
doi:10.1093/bja/aer057
Estimation of lean body mass in children
A. M. Peters 1,2,3*, H. L. R. Snelling 2, D. M. Glass 1 and N. J. Bird 4
1
Department of
Department of
3
Department of
4
Addenbrooke’s
2
Nuclear Medicine, Harley St Clinic, London, UK
Nuclear Medicine, Royal Sussex County Hospital, Audrey Emerton Building, Eastern Road, Brighton BN2 5BE, UK
Radiology, University of Cambridge, Cambridge, UK
Hospital, Cambridge, UK
* Corresponding author. E-mail: a.m.peters@bsms.ac.uk
Editor’s key points
† Lean body mass (LBM) is
often used to guide
anaesthetic drug doses in
adults.
† This study shows that
these relationships are
similar in adults and
children.
† Therefore, estimated LBM
may be better than body
weight to guide drug
dosing in children.
Methods. Patients comprised three groups: prospective kidney transplant donors from two
separate centres (centres 1 and 3) and children referred to a further centre (centre 2) for
the routine clinical measurement of glomerular filtration rate (GFR). GFR and extracellular
fluid volume (ECV) were measured using Cr-51-EDTA. LBM was directly estimated (eLBM) in
adults using an equation based on height and weight. ECV in children was estimated
(eECV) from another equation based on height and weight, converted to eLBM using the
relationship between eLBM and ECV determined in the adults from centre 1 and then
compared with adult data from centre 3.
Results. In children, the ratio of eECV to ECV was 1.04 (SD 0.18). In centre 1, eLBM (kg) was 3.81
(SD 0.55) times greater than ECV (litres) in men (n¼50) and 3.77 (0.77) times greater in women
(n¼51). eLBM in children was therefore derived by multiplying eECV by 3.8. In children, eLBM
showed a close linear correlation with measured ECV (eLBM¼3.50ECV+2.0; R 2 ¼0.857),
similar to adults (eLBM¼2.82ECV+14.5; R 2 ¼0.582). In all groups, eLBM/weight correlated
inversely with weight.
Conclusions. In terms of the relationships between eLBM, ECV, and weight, children are similar
to adults. Therefore, drug dosage in children should also be based on eLBM rather than weight.
Keywords: drug therapy,
pharmacology, clinical
drug
dosage
calculations;
children;
pharmacokinetics;
Accepted for publication: 15 February 2011
The doses of some anaesthetic agents, especially watersoluble drugs, are routinely based on lean body mass
(LBM), estimated from height and weight using equations
that are different for men and women.1 2 However, these
equations, which are based on previously described relations
between total body water (TBW), LBM, height and weight,3 4
are not applicable to children, often giving nonsensical estimates for LBM, including negative values.
An equation based on height and weight has been
described previously for estimating extracellular fluid volume
(ECV) in children.5 Taking this a step further and assuming
that the relation between ECV and LBM is the same in children
as in adults, we present here an equation based on height and
weight for estimating LBM in children. This required us to first
establish the relation between ECV and LBM in adults.
Methods
Subjects and study design
Pre-existing anonymous clinical data sets of subjects from
three separate institutions were retrospectively analysed.
The opinion of the Local Research Ethics Committee was
that this study is in the domain of service improvement
rather than research and therefore did not require formal
ethical review by an NHS REC. Patient characteristics are
summarized in Table 1.
The principle underpinning the study design is the
assumption that ECV is proportional to LBM in both adults
and children. If the proportionality constant (conversion
factor) could be determined in adults, it could be used to
multiply an estimate of ECV (eECV) to give LBM in children,
because an equation has previously been described for estimating ECV in children from height and weight.5
The three patient groups consisted first of an adult group
from one institution (centre 1) in which the conversion factor
was determined using measured ECV and LBM estimated
from height and weight (eLBM); secondly, a group of children
in which the conversion factor was then used to derive eLBM
from eECV; and thirdly, a further adult group with which to
compare childhood eLBM with adult eLBM and their respective relationships with measured ECV in order to validate the
conversion factor.
& The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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† The relationship between
LBM, body weight, and
extracellular fluid volume
in children is unclear.
Background. In adults, dosages of some anaesthetic agents are based on lean body mass (LBM)
rather than body weight. Our aim was to derive an equation for estimating LBM in children.
BJA
Peters et al.
Table 1 Patient characteristics of adults and children by centre, shown as mean (SD) (range)
Centre 1
Men (n550)
Centre 3
Women (n551)
Men (n593)
Women (n5102)
Age (yr)
44 (14) (19 – 70)
48 (12) (21 –76)
48 (12) (24 –69)
48 (12) (21 – 71)
Weight (kg)
81 (12) (60 – 114)
68 (12) (52 –103)
86 (11) (55 –120)
70 (7) (42 –110)
Height (cm)
179 (6) (169 –191)
164 (7) (149 – 176)
179 (6) (164 – 191)
164 (7) (146 –178)
BMI (kg m22)
25 (3) (18 –34)
25 (4) (20 – 37)
27 (3) (19 –35)
26 (4) (19 –40)
Centre 2
(children; n569)
Age (yr)
5.9 (3.5) (0.5– 13)
Weight (kg)
21.5 (10.7) (4.3– 48)
Height (cm)
1.1 (0.2) (0.6– 1.6)
BMI (kg m22)
16.5 (3.2) (12.6 – 26.7)
Measurement of GFR and ECV
GFR was measured from three or four blood samples obtained
between 120 and 240 min after bolus injection of Cr-51-EDTA
using the conventional slope –intercept method.6 It was
scaled to a BSA of 1.73 m2 (GFR/BSA), using the equation of
Haycock and colleagues7 to calculate the BSA from height
and weight, and corrected for the single-compartment
assumption using separate Brochner-Mortensen equations
for adults and children.6 Using BSA, corrected GFR/BSA was
then ‘descaled’ to give absolute, one-compartment-corrected
GFR.
GFR per unit ECV (GFR/ECV) was expressed exclusively as
the terminal rate constant (a2) of the same Cr-51-EDTA
clearance curve with correction for the single-compartment
assumption using the equation described by Bird and colleagues:8
corrected
720
GFR
= a2 + (a22 × 15.4) ml min−1 ml−1
ECV
(1)
(Note that whilst one-compartment GFR overestimates ‘true’
GFR, a2 underestimates true GFR/ECV.)
Then,
ECV =
GFR
(GFR/ECV)
(2)
In a recent study, this method gave ECV in good agreement
with ECV simultaneously and independently measured in the
same individual from multisample iohexol clearance.8
Estimation of LBM
LBM was estimated in both groups of adults from height
(H; cm) and weight (W; kg) using the equations described
by Boer:2
Men : eLBM = 0.407W + 0.267H − 19.2 (kg)
(3)
Women : eLBM = 0.252W + 0.473H − 48.3 (kg)
(4)
LBM was also estimated using the formulae of James1
W 2
Men : eLBM = 1.1W − 128
(kg)
H
W 2
Women : eLBM = 1.07W − 148
(kg)
H
(5)
(6)
It was shown by Boer2 that ECV, measured as the bromide
space, displays a linear, proportionate relation with eLBM.
The current study confirms this for adults with respect to
eLBM based on both the Boer equations and the James
equations (Fig. 1).
For the estimation of LBM in children, it was assumed that
the observation of Boer2 with respect to the proportional
relationship between ECV and LBM in adults can be extrapolated to children. Using the Boer equations, the proportionality constants (conversion factors) were found to be 3.81
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The adults from centre 1, in whom the conversion factor
was derived, comprised 101 healthy prospective kidney
transplant donors (50 men and 51 women). The children
(aged up to and including 13; n¼69; all with non-cancerous
conditions) to whom the conversion factor was applied were
from another institution and referred for the routine clinical
measurement of glomerular filtration rate (GFR). Only children with a GFR/ECV of .4.5 ml min21 litre21 (range 4.5 –
10.4 ml min21 litre21) were included. [Note that in children,
GFR is more appropriately scaled to ECV rather than to
body surface area (BSA).]5 The second group of adults comprised 195 healthy prospective kidney transplant donors
(93 men and 102 women) from a third institution (centre
3). In order to avoid bias, the adult data from centre 1
were used only to establish the relationship between eLBM
and measured ECV for the purpose of estimating LBM in
the children and thereafter not further utilized.
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Lean body mass in children
Centre 1
y = – 0.96 + 0.29x
R 2 = 0.583
20
ECV (litre)
ECV (litre)
30
Centre 3
30
10
20
10
0
0
0 10 20 30 40 50 60 70 80
eLBM (Boer) (kg)
Centre 3
30
ECV (litre)
10
y = 3.13 + 0.20x
R 2 = 0.571
20
10
0
0
0 10 20 30 40 50 60 70 80
eLBM (James) (kg)
0 10 20 30 40 50 60 70 80
eLBM (James) (kg)
Fig 1 Dependence of measured ECV on eLBM in adults from centres 1 (left panels) and 3 (right panels). eLBM was estimated using Boer’s
equations (upper panels) and James’ equations (lower panels). Results between the two centres are similar. The two sets of equations
gave almost identical values. Note the linear and proportionate (regression lines pass close to origins) relationships between ECV and eLBM.
(SD 0.55) in men and 3.77 (0.77) in women. Using the James
equations for LBM, the corresponding values for men and
women were 3.86 (0.54) and 3.81 (0.83), respectively. Exclusion of obese subjects (BMI.30 kg m22; 4/50 men and 7/51
women) had little effect on these values, which became,
using Boer’s equations, 3.84 (0.55) and 3.86 (0.79). Given
these near-identical values between the two sets of
equations (Fig. 1), the Boer equations were subsequently
used for estimating LBM in children, inserting a value of 3.8
into the equation that estimates ECV (litre) from height (H;
cm) and weight (W; kg)5
eECV = 0.0215 × W 0.6469 × H0.7236
(7)
eLBM = 3.8 × eECV
(8)
and so
Although
sponding
centre 3
(0.51) in
not used, it is re-assuring to note that the correconversion factors based on the adults from
and Boer’s equations were 4.03 (0.46) and 3.73
men and women, respectively, similar to the
values recorded from centre 1. Corresponding values with
the exclusion of subjects with BMI.30 kg m22 in this population (15/93 men and 13/102 women) were 4.06 (0.47) and
3.78 (0.48), respectively.
Results
Extracellular fluid volume
In children, there was good agreement between eECV and
measured ECV (Fig. 2), with a mean ratio of 1.04 (SD 0.18),
supporting the validity of equation (7). Adult ratios were
also close to unity with mean values in centres 1 and 3 of
1.02 (0.19) and 1.05 (0.13), respectively. Mean measured
ECV/weight in children was 0.222 (0.038) litre kg21, significantly higher (P,0.001) than in both men and women
from centre 3, in whom corresponding values were 0.187
(0.011) and 0.184 (0.015) litre kg21, respectively. Mean
measured ECV/eLBM in children in children was 0.259
(0.042) litre kg21, intermediate between men and women
in whom the corresponding values were 0.251 (0.011) and
0.274 (0.015) litre kg21, respectively.
721
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y = – 0.70 + 0.28x
R 2 = 0.572
20
ECV (litre)
0 10 20 30 40 50 60 70 80
eLBM (Boer) (kg)
Men
Women
Centre 1
30
y = 3.00 + 0.21x
R 2 = 0.582
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Peters et al.
A
130
1.8
120
1.2
110
0.6
100
Children
Men
Women
90
0.0
eLBM (kg)
Difference (litre)
2.4
–0.6
–1.2
–1.8
80
70
60
50
–2.4
40
–3.0
30
20
–3.6
0
2
4
6
8
10
10
12
Average (litre)
0
0 10 20 30 40 50 60 70 80 90 100 110 120130
Weight (kg)
B
90
Children
Men
Women
80
70
Across children and adults from centre 3, there was a nonlinear relation between weight and eLBM that approached
identity in very small individuals (Fig. 3A). Childhood data
appeared continuous with data from women but men had
a higher eLBM per unit weight and per unit measured ECV
(Fig. 3A and B).
In children, measured ECV showed a close linear correlation with eECV [from equation (7)] and therefore, from
inspection of equation (8), inevitably also with eLBM
[eLBM¼3.50.ECV (litre)+2.0 kg; R 2 ¼0.857; Fig. 3]. Importantly, the relationship between measured ECV and eLBM in
children was similar to the corresponding relation in adults
[eLBM¼2.82ECV (litre)+14.5 kg; R 2 ¼0.582; Fig. 3].
In all three subject groups, eLBM/weight showed strong
negative correlations with weight (Fig. 4), as would be anticipated from inspection of Figure 3A.
60
eLBM (kg)
Lean body mass
50
40
30
20
10
0
0
5
10
15
20
25
Extracellular fluid volume (litre)
Fig 3 (A) Relations between eLBM (kg) and weight (kg) in children, women, and men. The line is identity. (B) Relationships
between eLBM (kg) and measured ECV (litre) in children (bold
line: eLBM¼3.50ECV+2.0; R 2 ¼0.857), women, and men. The
regression line (fine line) is for all adults and is eLBM¼2.82
ECV+14.5 (R 2 ¼0.582). In both (A) and (B), eLBM was based on
Boer’s equations in adults and equation (8) in children.
Discussion
Several techniques have been described for estimating LBM
in children, including sophisticated techniques that
measure TBW or use dual absorption X-ray absorptiometry,
to simple techniques, such as waist circumference and skin
fold thickness, as summarized by Ellis9 and by Wells and Fewtrell.10 The current paper, however, is the first to estimate
LBM in children from an equation based exclusively on
height and weight. This is of potential value, as the adult
equations based on height and weight are not applicable
to children, giving negative values, for example, in very
small children (data not shown).
Because it assumes that LBM is directly proportional to ECV,
the described technique is analogous to estimating LBM from
TBW.3 4 Its validity therefore depends on the accuracy of the
data from the adults from centre 1, in whom the relationship
722
between measured ECV and eLBM was first established. ECV
per unit eLBM (ECV/eLBM) in these adults was 268 ml kg21 in
men and 275 ml kg21 in women, with respective coefficients
of variation (SD/mean) of 14.6% and 17.6%. These values of
ECV/eLBM are lower than the corresponding values of 303
and 302 ml kg21 obtained using bromide in men and
women by Boer,2 but this can be explained by the bromide
space being higher than the distribution volume of
Cr-51-EDTA. Boer’s coefficients of variation, however, were
lower at 5.3% and 6.3%, respectively. The corresponding coefficients of variation for the men and women from centre 3
were 10.8% and 14.6% (see the Results section). The estimation of LBM may become inaccurate in obese subjects,1
but the exclusion of these (BMI.30 kg m22) had little effect
on the conversion factor used in equation (8).
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Fig 2 The Bland– Altman plot of measured ECV and eECV in children. Bias is not significantly different from zero. Dashed lines are
mean (1.96 SD). There were only three patients with BMI.25 kg
m22, and these are shown as filled symbols.
BJA
Lean body mass in children
1.0
Children
Men
Women
0.9
eLBM/weight
0.8
0.7
0.6
0.5
0.4
0
20
40
60
80
100
120
140
Weight (kg)
Conflict of interest
In a recent previous study, a conversion factor of 3.9,
based on Boer’s equations, was reported.11 However,
although close to the factor reported in the current study,
this value was obtained on a population of adults referred
for clinical measurement of GFR rather than a healthy population; moreover, women and men were not separated.
The validity of the current technique depends on the validity of the assumption that the relationship between ECV
and LBM is the same in children as in adults. It is highly
likely that the relationship between LBM and TBW is the
same between children and adults, so the critical assumption
is that TBW is distributed between intracellular and extracellular spaces in an identical manner. There are limited
data on this point, but support is provided in the current
study by the data illustrated in Figure 3, which show the continuity that exists between children and women with respect
to both eLBM and measured ECV. We would suggest that
with the appearance of male hormones, LBM per unit body
weight increases, thereby accounting for the way in which
data points for men were displaced upwards relative to children and women in Figure 3A and B.
The validity of the approach also depends on the accuracy
with which ECV can be estimated from height and weight in
children. The finding that the ratio of estimated to measured
ECV in these children was almost unity supports the validity
of equation (7) for estimating ECV from height and weight
in children. Moreover, it is unlikely that the factor of 3.8 in
equation (8) has been underestimated; otherwise, points in
small children in Figure 3A would lie above the line of
identity between eLBM and weight. There were only three
children who could be considered approaching obesity
None declared.
References
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2 Boer P. Estimated lean body mass as an index for normalization
of body fluid volumes in man. Am J Physiol 1984; 247: F632– 5
3 Hume R, Weyers E. Relationship between total body water and surface
area in normal and obese subjects. J Clin Pathol 1971; 24: 234–8
4 Womersley J, Boddy K, King PC, et al. Estimation of the fat-free
mass of twenty subjects from measurements of total body potassium, body density, skinfold thickness, and height and
weight. Proc Nutr Soc 1972; 31: 35A
5 Bird NJ, Henderson BL, Lui D, et al. Indexing glomerular filtration
rate to suit children. J Nucl Med 2003; 44: 1037– 43
6 Fleming JS, Zivanovic MA, Blake GM, et al. Guidelines for the
measurement of glomerular filtration rate using plasma
sampling. Nucl Med Commun 2004; 25: 759–69
7 Haycock GB, Schwarz GJ, Wisotsky DH. Geometric method for
measuring body surface area: a height-weight formula validated
in infants, children and adults. J Pediatr 1978; 93: 62 –6
8 Bird NJ, Michell AR, Peters AM. Accurate measurement of extracellular fluid volume from the slope/intercept technique after
bolus injection of a filtration marker. Physiol Meas 2009; 30: 1371– 9
9 Ellis KJ. Selected body composition methods can be used in field
studies. J Nutr 2001; 131: 1589S–95S
10 Wells JCK, Fewtrell MS. Measuring body composition. Arch Dis
Child 2006; 91: 612– 7
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723
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Fig 4 Relationships between eLBM/weight (y) and weight [x (kg)]
in children (bold line: y¼0.91 – 0.0024x; R 2 ¼0.241; P,0.001),
women (lower fine line: y¼0.95 – 0.0039x; R 2 ¼0.541) and men
(upper fine line: y¼1.03 – 0.0033x; R 2 ¼0.785). As in Figure 3,
eLBM was based on Boer’s equations in adults and equation (8)
in children.
(BMI.25 kg m22), and their points in the Bland –Altman
plot (Fig. 2) are not outliers.
The adult dosages of some agents in current anaesthetic
practice, especially water-soluble, are based on eLBM. The
justification for this is evident in Figure 3, which shows first
a non-linear relationship between eLBM and weight and secondly that, in general, men have a higher eLBM per unit
weight than women. In children, eLBM per unit weight
decreases with increasing weight, as it does in adults. In children, eLBM also shows a relation with measured ECV that is
similar to adults (Fig. 3). The rationale for basing drug dosage
on eLBM in adults is therefore equally applicable to children.
Exactly when a child becomes an adult is unclear. The
study in which equation (7) was developed5 suggested
13–14 as the age cut-off between children and adults,
based on the finding that BSA (1.35 m2), GFR, and ECV all
abruptly stopped increasing at around this age. Figure 3A in
the current study shows discontinuity between children and
adults, with respect to the relationship between eLBM and
measured ECV, arising at a body weight of 50 kg, another
potential cut-off point.
In conclusion, it is suggested that the dosages of drugs
that are based on eLBM in adults should also be based on
eLBM in children, obtained using equation (8), given above.