bio-impedance vector analysis in malawian children...
TRANSCRIPT
UNIVERSITY OF GRONINGEN
Bio-impedance vector analysis in Malawian children with
severe acute malnutrition A diagnostic study in a low- income setting
Report written by Jacintha Kool (s2099837) under supervision of Dr. P.F. van Rheenen,
Pediatric Gastroenterologist at the University Medical Center Groningen (UMCG) and Dr.
W.P. Voskuijl, Paediatrician and Senior Lecturer at the Department of Paediatrics, College of
Medicine, Queen Elisabeth Central Hospital (QECH).
2
SUMMARY
Background/objectives: Severe acute malnutrition (SAM) is diagnosed according the criteria
of the WHO guidelines. Measurement of weight, length/height and mid upper arm
circumference (MUAC) and determination of edema is required to distinguish between two
phenotypes: kwashiorkor and marasmus. Bio-electrical impedance vector analysis (BIVA) is a
known method to measure body composition but it has not been investigated yet whether this
method can help to assess the nutritional status of children with SAM. This study aims to
identify changes in body composition during the stabilization of children with SAM.
Methods: Firstly the use of BIVA in correlation with de traditional anthropometry was
analyzed in a cross-sectional study design. Secondly the changes in bio-electrical impedance
between the start and end of the stabilization treatment phase were recorded in a longitudinal
design.
80 participants with SAM (43 male), between 6 months and 8 years old, were admitted to a
Nutritional Rehabilitation Unit (NRU). The BIVA parameters , normalized by height, are:
resistance (R/H), which reflects body fluids and reactance (Xc/H), which reflects the amount
of soft tissue.
Results: A sufficient negative correlation is seen between MUAC and R/H ratio in patients
with kwashiorkor (r = -0,440, p = 0,003) and a stronger correlation in patients with marasmus
(r=-0,644, p = 0,001) during the stabilization. The Z-scores of weight-for-height/length only
correlates with the R/H value of children with kwashiorkor (r=0,621, p= >0,001). Secondly,
BIVA demonstrated the difference between marasmus and kwashiorkor at the start (p<0,001)
and end (p<0,001) of the stabilization phase. Kwashiorkor (p<0,001) as well as marasmus
(p<0,001) show a significant change in BIVA parameters after the stabilization.
Conclusion: BIVA can detect significant changes in body composition during the stabilization
of children with SAM. Further studies should evaluate whether BIVA is a useful add-on to the
traditional anthropometry to guide therapy SAM in a low-income setting.
SAMENVATTING
Achtergrond: Ernstig acute ondervoeding (SAM) wordt gediagnostiseerd volgens de criteria
van de WHO richtlijnen. Het vaststellen van gewicht, lengte, midden-arm omtrek (MUAC)
en oedeem is noodzakelijk om onderscheid te maken tussen de twee fenotypes van SAM:
kwashiorkor en marasmus. Bio-elektrische impedantie vector analyse (BIVA) wordt al
gebruikt om lichaamscompositie te meten. Het is echter nog niet onderzocht of deze methode
gebruikt kan worden bij het inschatten van de voedingstoestand van kinderen met SAM. Deze
studie tracht verschillen in lichaamscompositie vast te stellen, tijdens de stabilisatie van
kinderen met SAM.
Methode: Allereerst werd in een cross-sectional study design de relatie tussen het gebruik van
BIVA en klassieke antropometrie geanalyseerd. Daarnaast wordt de verandering in BIVA
gedurende de stabilisatiefasen een longitudinaal design vastgelegd.
80 deelnemers met SAM (43 mannelijke) in de leeftijd van 6 maanden tot 8 jaar werden
opgenomen op een hervoedings afdeling (NRU).
De BIVA parameters, genormaliseerd voor lengte, zijn: weerstand (R/H) die de
vochthuishouding weerspiegeld en reactantie (Xc/H) die de hoeveelheid zacht weefsel
weerspiegeld.
Resultaten: Een duidelijke correlatie is te zien tussen MUAC en R/H ratio in patiënten met
kwashiorkor (r = -0,440, p = 0,003) en een sterkere correlatie in patiënten met marasmus r=-
0,644, p = 0,001). De Z-scores van gewicht voor lengte/hoogte correleren alleen met de R/H
waardes van de kwashiorkor kinderen.
BIVA toonde ten tweede aan dat er verschil zit tussen kwashiorkor en marasmus aan het
begin (p<0,001) en eind (p<0,001) van de stabilisatie fase. De BIVA parameters van
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patiënten met zowel kwashiorkor (p<0,001) als marasmus (p<0,001)zijn na stabilisatie
significant veranderd.
Conclusie: BIVA kan tijdens de stabilisatie significante verschillen vaststellen in
lichaamscompositie van kinderen met SAM. Verdere studies moeten onderzoeken of BIVA
een bruikbare aanvulling is op de huidige klassieke antropometrie om de behandeling met
SAM te kunnen volgen.
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TABLE OF CONTENTS 1. INTRODUCTION ............................................................................................................................... 5
1.1. Background/ rationale .................................................................................................................. 5
1.2. Objective ...................................................................................................................................... 6
2. METHODS .......................................................................................................................................... 6
2.1. Setting and study design ............................................................................................................... 6
2.2. Participants ................................................................................................................................... 7
2.4. Statistical methods ...................................................................................................................... 10
3. RESULTS .......................................................................................................................................... 11
3.1. Participants ................................................................................................................................. 11
3.2. Descriptive data .......................................................................................................................... 13
3.3. Main results ................................................................................................................................ 13
4. DISCUSSION ................................................................................................................................... 16
4.1. Key results of research questions ............................................................................................... 16
4.2. Methodological limitations ......................................................................................................... 16
4.3. Comparison with other studies ................................................................................................... 16
4.4. Implications for paediatric practice ............................................................................................ 17
5. CONCLUSION ................................................................................................................................. 18
6. ACKNOWLEDGEMENT ................................................................................................................. 18
7. REFERENCES .................................................................................................................................. 18
Appendix A. Standard Operating Procedure ......................................................................................... 21
Appendix B photo report information sheet for guardians .................................................................... 24
Appendix C BIVA-CRF ........................................................................................................................ 28
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1. INTRODUCTION
1.1. Background/ rationale
1.1.1. Epidemiology and topical underlying causes of Severe Acute Malnutrition
Despite the first millennium development goal (MDG) target 1 c: “cut the proportion of
people who suffer from hunger in halve between 1990 and 2015”, childhood malnutrition is
still a major global health problem. It is contributing to childhood morbidity, mortality,
impaired intellectual development, suboptimal adult work capacity, and increased risk of
diseases in adulthood. (1) It is estimated that 19 million preschool-age children, mostly from
the WHO African Region and South-East Asia Region, are suffering from severe wasting
(weight for Height/length <-3SD)
Globally, nearly half of under-five deaths are attributable to malnutrition. In 2013 3.1 million
deaths – half of under-five deaths worldwide- occurred in Sub-Saharan Africa (2). Malawi, a
sub-Saharan African country with 16 million inhabitants, is one of the world’s poorest
countries. It ranks 174 out of 187 countries in the 2013 Human Development Index(3). 1/7th
of the children younger than 5 years is malnourished. For every 1000 live births 68 children
were dying before the age of 5 in 2013. The global mortality rate is 46 children per 1000 live
births(2).
Malawi is experiencing frequent food shortages due to the vulnerable agriculture sector, the
most important sector in the economy. More that 80 percent of Malawians are smallholder
farmers. (4) Food security can be easily effected by natural disasters such as annual dry spells
and flooding. At the start of this year, 2015, heavy floods destroyed about 25000 of hectares
of crops. It is estimated that 695 600 people experienced acute food insecurity during the
previous lean season, December to March 2015(3). It is expected that this number will be
much higher next lean season. Children between six months and five years old are especially
vulnerable to changes in food intake. Those who also live in households with lack of
environmental hygiene and unequal gender relations are of high risk to get severe acute
malnutrition (SAM)(5).
1.1.2. Measuring Severe Acute Malnutrition
Traditionally, the severity of malnutrition is determined with the use of anthropometry (which
includes the measurement of weight, height, en mid upper arm circumference (MUAC)). This
method is based on historical data of the World Health Organization on nutrient requirements.
Few of the recommendations are supported by evidence from clinical trials.(6,7)
Anthropometric observations in children with Severe Acute Malnutrition (SAM) are
frequently not correctly reflecting the actual nutritional status. Disturbances are seen when
edema is present and this causes overestimation of body weight. Secondly, dehydration can
lead to underestimation of bodyweight, while the presence of dehydration is often difficult to
recognize.(8,9) Dehydration is a common feature in children with SAM, caused by impaired
gut function (carbohydrate malabsorption) and osmotic diarrhea. Currently, simple bedside
clinical observations are the only tools to assess hydration status, but these signs are difficult
to interpret in children with SAM (4,5). Sunken eyes and wrinkled skin can been seen in a
malnourished child with and without dehydration. Signs that that are typical for dehydration
in a malnourished child are also seen in septic shock, for example cold hands and feet and
diminished urine flow (7).
It has been proven that the early identification and treatment of SAM could improve long term
as well as short term outcomes and it is vital to identify and manage underlying clinical
conditions during treatment of SAM as well (10).
6
A method that more accurately distinguishes between nutritional status and hydration status
would assist health workers in deciding what treatment is needed to stabilize children with
SAM. Those that are admitted with dehydration need rehydration with ReSoMal first, while
those without dehydration can be treated with therapeutic formula straight from the start(7).
1.1.3 Bio-electrical impedance
Bioelectrical impedance vector analysis (BIVA) allows to differentiate between soft tissue
mass and fluid mass, and might be able to give information about the body composition. It
measures electrical properties of the different body tissues at the bedside. (11-13) The use of
BIVA to diagnose SAM children in a low-income setting is not yet described in recent
published studies.
1.2. Objective
This study aims to evaluate the use of BIVA in the assessment of body composition in
children with SAM in Malawi. BIVA is compared with the traditional clinical assessment of
the nutritional status. The following research questions will be answered:
(A) Is the improvement in nutritional status measured by traditional anthropometry in
agreement with the changes in body composition measured by BIVA?
(B) Is the clinical distinction between kwashiorkor and marasmus reflected in differences in
bio-electrical impedance between those groups?
(C) Does the bio-electrical impedance within one person change between the start of
treatment and the moment of transition?
2. METHODS
2.1. Setting and study design
2.1.1. The F75 study
The present study is an add-on study to the “F75 trial”. The F75 trial is a multicenter
randomized double-blind intervention trial that is currently being executed in two hospitals in
Kenya and one hospital in Malawi. The BIVA-study is only performed on the nutritional
rehabilitation unit (NRU) in Queen Elizabeth Central Hospital (QECH) in Blantyre (Malawi).
This unit is one of the biggest malnutrition wards in Africa where up-to-date clinical care is
combined with research that varies from basal to clinical-epidemiological (10,16-18).
The standard clinical care for children with SAM in a NRU consist of three distinct phases. In
‘phase 1’ or ‘stabilization phase’ a low protein, liquid diet (F75) is introduced with a reduced
energy intake (80-100 kcal/kg/day). Once a child has stabilized, it moves up to the ‘transition
phase’. In this phase a child will either get therapeutic foods (RUTF) with supplemental F75
or a milk formula known as F100. F100 is a liquid formula with a higher energy density and
protein content than F75. The caloric intake is increased daily to a maximum of 130
kcal/kg/day. Recovery mainly takes place in phase 2, or the rehabilitation phase. The focus is
to achieve catch-up growth with either RUTF or F100. The total amount of days to recover
varies per patient (6).
The F75 trial wants to evaluate the outcome of a revised formulation of F75 milk with
reduced carbohydrate composition and without lactose, compared to the current formulation
of F75 during the initial stabilisation period amongst children with SAM.
7
Figure 1: implementation of BIVA-study in F75-study, illustrated by patient X. The patient is
admitted to the hospital on day 0 and gets stabilized the with F75-milk. The first BIVA test
takes place the next day and de second BIVA test takes place when clinical signs show
improvement and the patient is ready to receive more calories in the transition phase: F100
of RUTF with supplemental F75. When no complications occur, the patient can rehabilitate
in phase 2.
2.1.2. Design of the BIVA-study
The BIVA study consists of two parts:
In the first part a cross-sectional design is used in order to compare the pattern of impedance
of SAM children with the anthropometric measurements. The measurements are performed on
day 1 as shown in table 1.
The second part of the BIVA-study is performed in a longitudinal design. BIVA patterns,
measured on the first day of stabilization, are compared with those measured on the last day
of stabilization. 2. The follow-up stopped as soon the patient died or when the participation of
the F75-study ended.
The Malawian research site of the F75-trial in the NRU started recruiting patients as of
December 2014. The aim is to recruit 320 patients. The BIVA study recruited patients
between February 9 and April 9, 2015. The follow up of patients ended April 18 when the last
participant was discharged from the QECH. The sample size was based on a convenience
sample. It was anticipated that approximately 100 children with SAM could be included in the
F75 trial in a 10 week period.
2.2. Participants
All of the children admitted to the NRU suffered from SAM. The WHO guideline (7)
distinguishes two clinically phenotypes:
- Marasmus: weight-for-length/height ≤ -3 Z-scores OR - a mid-upper-arm circumference
of <11.5 cm (WHO growth standards).
- Kwashiorkor: nutritionally induced bilateral edema. Other features of kwashiorkor can
include fatty infiltration of the liver and hepatomegaly, discolored sparse hair, flaky
desquamated, discolored skin and anorexia.
All children between 6 months and 8 years old with SAM were screened on the eligibility
criteria for the F75 study. They had to have medical complications as defined in the current
WHO guideline for the management of SAM (6) or had to fail an appetite test in absence of
complications. A known allergy to milk products was a reason to exclude the patient.
Patient
nummer
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day6 Day 7 Day 8
X Phase
1
BIVA
test 1
BIVA
test 2
Transition
phase:
F100 or
RUTF
(+F75)
Phase
2
F100
or
RUTF
discharge
F75 F75 F75
8
After receiving informed consent from the guardian the patient was enrolled in the F75 trial.
A F75 study patient was excluded from the BIVA-study when one of the following was found
during physical examination:
1. open skin lesions on the sticker placements
2. inability to stretch the limbs due to a cerebral palsy
3. significant body asymmetry as in amputations, unilateral hemiparesis, and
neuromuscular conditions that produce localized changes in perfusion or tissue
atrophy(19)
After enrollment of the patients in the BIVA study they were followed as long as they were
part of the F75 study. Participation of the F75 study stopped as soon as they were discharged
from the hospital.
2.3 Data source & measurement
Figure 2A: image of BIVA device in practical use, Figure2B: graphical interpretation of the BIVA
parameters.
2.3.1. Interpretation of BIVA
Resistance (R) and reactance (Xc) are the output variables of interest in bio-impedance vector
analysis (figure 2A and B) (20). R gives information about ionic solutions of soft tissue that
represents the total amount of intra- and extracellular fluid. Xc gives information about cell
membrane integrity that represents the lean tissue mass. The combination of these two
components is Impedance (Z-vector). An RXc graph allows an evaluation of the soft tissues
trough patterns based on percentiles of their electrical properties without prior knowledge of
body weight. As described in figure 2B, vector shortening or lengthening indicates a change
in hydration status, while upward or downward bending of the vector indicates a change in
soft tissue mass.
As a relatively short duration of the stabilization phase is anticipated, we expect the R
component to show bigger absolute differences from baseline compared to Xc. We therefore
2B
9
decided to use the R component divided by height (R/H ratio) as the primary outcome of the
analysis
See appendix A for a detailed description of the Standard Operating Procedure (SOP) and
additional appendix B for a illustration of the BIVA procedure that was used to inform the
guardians and patients.
2.3.2. F75-CRF
Four trained clinicians completed a Case Report File (CRF) on a daily basis for all study
patients of the F75-trial. The BIVA-CRF is based on these reports and additional BIVA data
were added by the author of this report. (see appendix c for the complete BIVA-CRF). Table
1 shows the source of each variable.
F75 trial day 0 BIVA-study
day 1
BIVA study
transition *1
Discharge
F75-CRF
- age
-gender
- date/time of
admission
- Upper arm
circumference
- length(49-84 cm) height (85-110 cm)
-weight (kg)
- edema score *2
- clinical hydration
status *3
-Weight (kg)
-edema score
- Upper arm
circumference
- clinical
hydration status
- date
- admission
pathway:
moved back to
phase 1:
yes/no
- HIV-status
- medical history
- complications at
admission *4
- number of days
with diarrhoea
- number of days
requiring
rehydration fluids
(ReSoMal of IV
fluids)
- total days of
stabilization
phase *5
- study outcome
- Numbers of
episodes of
new-onset
severe clinical
deterioration
*6
BIA-device
- Number of
feeding
moments*7
- BIVA-output 1
*8
- Number of
feeding
moments
BIVA-output 2
Table 1: BIVA-CRF variables were collected on four moments of the inhospital treatment, out
of two different sources.
10
Definitions of variables in BIA Case Report File
1. The criteria for stabilization and ready to move to ‘transition phase’ (WHO
guidelines):
- Absence of any WHO danger or emergency signs: obstructed breathing, respiratory
distress, cyanosis, shock (delayed capillary refill plus fast & weak pulse plus
temperature gradient), severe anaemia (Hb<5g/dl), congestive cardiac failure,
impaired consciousness, convulsions, severe dehydration, profuse watery diarrhea,
vomits everything, hypothermia.
- If there is edema at baseline, loss of edema Tolerating full prescribed volume of F75
feeds and observed to be completing the feeds.
2. Edema score: If there is edema at baseline, loss of edema is defined as improving from
a severe +++ edema (severe: generalized bilateral pitting edema including feet, legs,
arms and face) to ++ edema (moderate: no upper arm or upper leg edema and no facial
edema) or from ++ edema to + (mild: only feet/ankle edema) or none;
3. Hydration status is based on the frequency of diarrhea (3 or more loose/watery stools
in last 24) and/or vomiting, the AVPU-consciousness score: alert, response to Voice,
response to Pain, Unconsciousness, and the component is the capillary refill >2 in the
fingernail:
4. Complications at admission: shock, severe pneumonia, diarrhea, malaria, febrile
sepsis, or other.
5. Total days that a patient was treated in the stabilization phase: excluding number of
days when the child is moved back to the stabilization phase (from the 'transition
phase') during a clinical deterioration;
6. New-onset severe clinical deterioration accompanied by one or more of the following
features: shock (fast and weak pulse and limb versus core temperature gradient and
capillary refill time>3 seconds), respiratory distress (severe sub- or intercostals
recessions/in drawing, hypoxemia (SaO2 < 94% in room air) or requiring oxygen;
impaired consciousness (Blantyre coma score<4) or hypoglycemia (<3.0 mmol/l);
7. Feeding moments on a NRU take place every three hours.
8. BIVA output variables: Reactance (Xc), Resistance (R), Phase angle (PhA).
2.4. Statistical methods
Pearson’s correlation is used to evaluate the relationship between the BIVA parameter R/H
ratio and MUAC. The correlation between the R/H-ratio and he weight-for-length/height Z-
score is calculated with the Spearman’s correlation. The weight-for-length/height Z-score is
calculated with the NCHS/WHO normalized reference values(21). The difference in BIVA
output variables between kwashiorkor and marasmus and between the beginning and end of
the stabilization phase is calculated with a BIVA software package (Piccoli 2002) (22). This
software package plots the two mean components R/H and Xc/H in a confidence ellipse. Two
mean vectors have a significantly (P , 0.05) different position in the R–Xc plane when the
95% confidence ellipses are not overlapping. The independent Hotelling’s T2 test is used for
the difference between kwashiorkor and marasmus and the paired one-sample Hotelling’s T2
test will be used to calculate the difference between the start and end of the stabilization
phase. Hotelling’s T-test is a multivariate extension of the Student-T test.
11
3. RESULTS
3.1. Participants
In a total period of 9 weeks 80 patients could be tested at baseline and 60 patients at the end
of the stabilization phase.
86 participants were seen between the 5th
feeding moment and the 7th
feeding moment and
could be examined for eligibility for the BIVA study. 5 patients were excluded due to two
reasons: 4 patients were not able to stretch their limbs due to a cerebral palsy and 1 patient
with kwashiorkor suffered from desquamated skin. These exclusion criteria are displayed in
figure 3A en 3B.
Out of 81 eligible patients who were recruited 80 patients underwent the first BIVA test. One
guardian refused because her child was too upset. Figure 4 displays a flow diagram that gives
an overview of the inclusion of participants.
A B
Figure 3A: Not able to stretch the limbs due to cerebral palsy. Figure 3B: open skin lesions on
sticker placement.
12
Figure 4: enrolment of participants in BIVA-study
F75 study -recruitment n = 95
Assessed for eligibility n = 86
Total recruited n = 81
Not assessed for eligibility: n=9
Researcher not available
n = 9
Excluded n = 5:
Unable to stretch limbs n=4
Open skin lesions n = 1
Data available for cross-sectional
analysis n = 80
Withdrawal n = 1
Child was too upset
Data available for cohort analyses
n=60
Lost to follow-up n = 20
Died in phase1 n =9
Absconded n =1
Withdrawn n =1
No researcher n = 9
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3.2. Descriptive data
Demographic and
Clinical Characteristics
Total
(n=80)
Marasmus
(n=37)
Kwashiorkor (n=43)
Male gender, n (%) 43 (53,8) 22 (59,5) 21 (48,8)
Age at enrolment
in months, median (IQR)
20,0 (13) 19 (6) 22 (7)
HIV reactivity, n (%) 23 (28,7) 15 (40,5) 8 (18,6)
Cerebral palsy, n (%) 7 (8,8) 6 (16,2) 1 (2,3)
Weight-for-Height z-
score, median (IQR)
-2 (1) -3 (0,75) -1 (0,5)
MUAC in cm, mean (SD) 11,35
(1,77)
10,35(1,45) 12,3 (1,46)
Complications at
admission n(%):
Shock
3 (3,8)
1 (2,7)
2(4,7)
Severe
pneumonia Freq (%)
11
(13,8)
5 (13,5) 6 (14,0)
Diarrhea 39 (48,8) 19 (51,4) 20 (46,5)
Malaria 5 (6,3) 2 (5,4) 3 (7,0)
Febrile 37 (46,3) 19 (51,4) 18 (41,7)
Sepsis 33 (41,3) 18 (48,6) 15 (34,9)
Other 17 (21,3) 12 (32,4) 5 (11,6)
Table 2: Characteristics of the study sample at enrolment
3.3. Main results
(A) Is the improvement in nutritional status measured by traditional anthropometry in
agreement with the changes in body composition measured by BIVA?
There is a strong inverse correlation between R/H-ratio and MUAC in both kwashiorkor and
marasmus cases, although the correlation is substantial stronger in the children with
Marasmus (r=0,644), table 3A. A similar agreement is seen in the second measurement of the
R/H-ratio and the MUAC on the day of transition, table 3B.
Traditional
anthropometry
Kwashiorkor
correlation r
P-
value
Marasmus
correlation r
p-value
MUAC 1(cm) -0,440 0,003 -0,644 >0,001
z-score 1weight
for height/length
-0,621 >0,001 0,246 0,142
Table 3A : correlation Bio-electrical impedance parameter R/H-ratio and traditional
anthropometry on day 1 of stabilization phase.
A strong correlation of -0,621 and -0,592 (p>0,001) is seen between the R/H-ratio and the Z-
score weight-for-length/height in children with Kwashiorkor. This also applies to both the
start as well as the end of the stabilization phase. No similar correlation is seen in the children
with Marasmus (Table 3A, 3B).
14
Traditional
anthropometry
Kwashiorkor
correlation r
P-
value
Marasmus
correlation r
p-value
MUAC2 -0,499 0,004 -0,623 >0,001
z-score 2 weight-
for-length/height
-0,592 >0,001 0,248 0,204
Table 3B: correlation Bio-electrical impedance parameter R/H-ratio and traditional
anthropometry at the end of the stabilization phase.
(B) Is the clinical distinction between kwashiorkor and marasmus reflected in differences
in bio-electrical impedance between those groups?
At admission (figure 5A) BIVA measures a significant difference between vector position of
children with kwashiorkor and children with marasmus (p<0,001). At transition (figure 5B)
the difference in vector position between kwashiorkor and marasmus is smaller but still
significant (p<0,001).
Figure 5A: Bio electrical impedance of patients with kwashiorkor (blue vector) and
marasmus (black vector) at admission. Both ellipses show the 95% confidence interval
(n=80.)
Figure 5B: Bio electrical impedance of patients with kwashiorkor (blue vector) and
marasmus (black vector) at the end of stabilization phase. Both ellipse show again the 95%
confidence interval which are slightly bigger due to a smaller group (n=60).
A B
15
(C) Does the bio-electrical impedance within one person change between the start of
treatment and the moment of transition?
The paired one sample Hotellings T test calculates the difference between the BIVA results
from the start and the end of the stabilization treatment phase. The null hypothesis (H0) shows
that no vector trajectory was observed between start and end of the stabilization phase. The
RXc graph will displays the mean difference at the origin (0,0), figure 6. In marasmic children
the R-Xc vector position is seemingly unchanged between baseline and the end of the
stabilization phase (figure 5AB). However, as the 95% confidence interval of the vector
trajectory in figure 6 does not overlap the origin of the graph (point 0,0), it can be concluded
that there is a significant change in vector position (p<0,001 in both as Kwashiorkor and
Marasmus). In children with kwashiorkor the R-Xc vector position moves closer to the
marasmus vector position. Overlap of the two confidence intervals in figure 6 shows that the
change in body composition of children with kwashiorkor during the stabilization phase is not
significant from the change in body composition from children with marasmus.
Figure 6: Vector trajectories shows the change in mean bio-electrical impedance between
start and end of the stabilization treatment phase. The ellipses reflecting mean and 95%
confidence interval of patients with Kwashiorkor (blue vector ) and Marasmus (black vector).
16
4. DISCUSSION
4.1. Key results of research questions
We studied the use of BIVA to assess body composition in children with SAM, and compared
its results with traditional clinical anthropometry. It is found that the resistance-to-height ratio
correlated strongly with the mid upper arm circumference in both marasmus and kwashiorkor
cases. The R/H ratio correlated strongly with the weight-for-length/height z-score in children
with kwashiorkor, though lack of agreement was seen in marasmic children. The reason for
this non-correlation cannot be explained yet.
Secondly, we found that the two phenotypes of SAM (kwashiorkor and marasmus) have
distinct patterns of bio-electrical impedance at baseline, and that these patterns tend to overlap
at the end of the stabilization phase. This means that the loss of edema, that is seen in children
with kwashiorkor during the stabilization phase, can be made visible with the BIVA-method.
Their initially distinct body composition tend to become more similar to the marasmic body
composition at the end of the stabilization phase.
Unlike the R/H ratio, a reliable detection of an absolute change of the Xc/H value in the very
short period of stabilization is questionable. Figure 6 shows an higher increase of Xc/H ratio
in patients with Kwashiorkor comparable with Marasmus during stabilization. This is
probably not due to more growth of lean mass. The density of the cells can also increase due
to the loss of fluids in children with kwashiorkor. This gives a relative increase of the Xc /H-
ratio.
4.2. Methodological limitations
The traditional anthropometric measurements were taken by different staff workers of the
NRU. We frequently observed unrealistic values for which remeasurements were done.
Nevertheless, observer bias is probably not completely prevented.
Although we strictly followed the standard operating procedure for BIVA measurement to
gather reliable results, the resistance (R) value can easily be disturbed by the passage of urine,
sweating or breastfeeding during the test. The magnitude of this potential instrument bias is
unknown as it was not possible to quantify the volume of urine, sweat and breast milk.
4.3. Comparison with other studies
There is a paucity of information on BIVA measurements in malnourished children. In 2003,
reference values of BIVA-parameters from healthy children were published. These reference
values for every age groups were established in two Italian studies in children in the first year
of life (15)and in children between 2 till 15 years old(14). In 2009, a survey in a local health
program also used to reference values to compare 4 to 14 year old Moroccan children (23).
For the current study, it is decided not to follow this example. First of all because reference
values for children between 12 and 24 months do not exist yet. This age group is most
frequently seen in the current study as shown in table 2. Besides that, 41% of Malawian
children is stunted (-2SD height-for-age)(3). The body composition of a 2 year old stunted
child will already be different from the mean value of a reference population from a
developed country, even after normalization for height.
The agreement between anthropometry and BIVA parameters has already been evaluated in
2000. Phase Angle (calculated from Xc and R) did correlate with body weight (r=0,818) and
MUAC (r =0,901) in well-nourished Japanese children (24). This study also predicts that it
should be possible to distinguish between weight gain caused by an increase in body cell mass
and weight gain caused by edema. Severe malnourished children, however, were not included
17
in the study. In 2013, a study on critically ill patients evaluated the effect of hydration status
on the BIVA measurements. BIVA was able to differentiate between mild, moderate and
severe dehydration, but these patients were adults in ICU. In other words, the results cannot
be extrapolated to malnourished children in a low-income setting(25).
An unpublished study gives limited information about the use of BIVA in 350 children with
SAM (Girma (26)). A short summary confirms the presumption of the Japanese study from
2000(24): BIVA parameters should able to distinguish tissue- vs hydration related weight
changes in Ethiopian children during the whole inpatient treatment of SAM. This study also
analyzed the change in R/H ratio and Xc/H ratio during treatment.
There is a notable difference in design: the current Malawian BIVA measured only during the
stabilization period instead of during the whole inpatient treatment. Girma took more time to
measure the difference in Xc/H-ratio. Among marasmic children the R/H ratio decreased and
the Xc/H increased. In other words: both the amount of fluids and lean mass increase.
Therefore, is it very likely that this Ethiopian study detect an absolute change in the Xc/H
value.
4.4. Implications for paediatric practice
Nowadays nutritional status is only assessed by traditional clinical anthropometry (weight-
for-height/length, MUAC, height-for-age). The limitations of these methods were described in
paragraph 1.1.2. There is need for a method that more accurately distinguishes between
nutritional status and hydration status. In this study it is showed that BIVA can be used to
distinguish marasmic from kwashiorkor cases, and that body composition of kwashiorkor
cases changes to the marasmus type at the end of the stabilization phase. This information in
itself is not enough to recommend the use of BIVA in the assessment and management of
children with SAM.
There is a need for a healthy reference population of Malawian children to evaluate whether a
combination of traditional anthropometry and BIVA is more reliable than anthropometry
alone. As described in paragraph 4.1, it was not possible to explain why BIVA parameter R/H
and Z-score weight-for-height/length did not correlate due to lack of reference values. Further
studies should analyze the bio-impedance vector position in well-nourished Malawian
children.
In order to detect both the overestimation of bodyweight due to edema and the
underestimation of bodyweight due to dehydration, there is a need for reference values of the
bio-impedance vector position of well-nourished children with dehydration.
This vector position should be compared with the vector of children with SAM and
dehydration. For this report it was decided not to quantify a hydration status due to limited
variables that could indicate dehydration. Besides the limitations that were described in
paragraph 1.1.2, losses can easily be underreported or overestimated by guardians. It will be
challenging for further studies to analyze the vector position of children with SAM with
confirmed dehydration.
BIVA measurements in dehydrated children, and children with kwashiorkor and marasmus
should take place during the whole inpatient treatment on a daily basis. The quicker change of
the R/H ratio as opposed to the slower change of the Xc/H ratio as described in paragraph 4.1.
justifies a daily record.
Apart from the theoretical validity of BIVA as a suitable to monitor therapy in children with
SAM, it needs to be evaluated whether BIVA is applicable in a daily routine in a low resource
setting.
18
First of all, in many ways the current used NRU is a typical ward in a resource poor setting,
but because of the different research projects that have been going on in this NRU its
resources are far above many other wards. There is a need for both a solid patient file system
and for financial resources. The electrode stickers are priced at €0,80 per test and a set of lead
wires has to be replace once a year (€35,- per set)(27).
Furthermore, the size of the intervariability of BIVA parameters taken by different health care
workers should be analyzed. The execution of the test itself is relatively simple and it asks for
the same precision as using a MUAC- tape. The health care worker only needs to have enough
time and patience to inform the guardian about the procedure and to comfort the child. The
reliability of the results depends on willingness and understanding of the participants to
follow the exact instructions.
5. CONCLUSION
This study concludes that BIVA can distinguish changes in body composition during the
stabilization of children with SAM.
At this moment we cannot recommend the use of BIVA as a useful add-on to the traditional
anthropometry to guide therapy in children with Severe Acute Malnutrition in a low-income
setting.
Further studies that include measurements of bio-electrical impedance in a healthy Malawian
reference population and in patients with confirmed dehydration are essential before a final
recommendation can be made.
6. ACKNOWLEDGEMENT
First of all I want to thank my supervisors. Dr. Patrick van Rheenen was involved from the
very early start until the final report as the supervisor at the UMCG. He introduced me to dr.
Wieger Voskuijl who became my supervisor from the ground on the NRU.
Natasha Lelijveld and Emmanuel Chimwezi also played an important role in my study by
providing me the BIVA device, by answering all my questions during the rest of my study and
providing the BIVA software.
I am grateful to the F75-trial clinicians who allowed me to look over their shoulders and
informed me about new study recruitments.
This also goes for the The NRU staff nurses who enrolled me in the Malawian culture, and
taught me how to deal with the native language, religion, and mournfulness.
7. REFERENCES
(1) Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, De Onis M, et al. Maternal and child
undernutrition and overweight in low-income and middle-income countries. The Lancet
2013;382(9890):427-451.
(2) Danzhen Y., Hug L., Chen Y., et. al. Levels and trends in child mortalitly. 2014.
(3) World Food Program. Malawi, current issues and what the world food program is doing. 2015;
Available at: https://www.wfp.org/countries/malawi. Accessed 07,29, 2015.
19
(4) Trading Economics. World Bank Indicators - malawi - Nutrition. 2010; Available at:
http://www.tradingeconomics.com/malawi/malnutrition-prevalence-weight-for-age-percent-of-
children-under-5-wb-data.html. Accessed July/23, 2015.
(5) Sassi M. Short-term determinants of malnutrition among children in Malawi. Food Security
2012;4(4):593-606.
(6) World Health Organization. Guideline: updates on the management of severe acute malnutrition in
infants and children. 2013;ISBN 978 92 4 150632 8:14-15-20.
(7) World Health Organization. Management of severe malnutrition: a manual for physicians and other
senior health workers. ISBN 9241545119 ed. Geneva: WHO; 1999.
(8) World Health Organization. THE TREATMENT OF DIARRHOEA :A manual for physicians and
other senior health workers 2005;ISBN 92 4 159318 0:22-24.
(9) Heikens GT, Manary M. Wasting disease in African children: the challenges ahead. Malawi Med J
2009 Sep;21(3):101-105.
(10) Kerac M, Bunn J, Chagaluka G, Bahwere P, Tomkins A, Collins S, et al. Follow-up of post-
discharge growth and mortality after treatment for severe acute malnutrition (FuSAM study): a
prospective cohort study. 2014.
(11) Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gomez JM, et al. Bioelectrical
impedance analysis--part I: review of principles and methods. Clin Nutr 2004 Oct;23(5):1226-1243.
(12) Barbosa-Silva MC, Barros AJ. Bioelectrical impedance analysis in clinical practice: a new
perspective on its use beyond body composition equations. Curr Opin Clin Nutr Metab Care 2005
May;8(3):311-317.
(13) Norman K, Smoliner C, Kilbert A, Valentini L, Lochs H, Pirlich M. Disease-related malnutrition
but not underweight by BMI is reflected by disturbed electric tissue properties in the bioelectrical
impedance vector analysis. Br J Nutr 2008;100(03):590-595.
(14) De Palo T T. Normal values of the bioelectrical impedance vector in childhood and puberty.
Nutrition 2000-6;16(6):417-24.
(15) Savino F, Grasso G, Cresi F, Oggero R, Silvestro L. Bioelectrical impedance vector distribution
in the first year of life. Nutrition 2003 Jun;19(6):492-496.
(16) Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A, Sadler K, et al. Probiotics and prebiotics for
severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in
Malawi. Lancet 2009 Jul 11;374(9684):136-144.
(17) Bunn J, Thindwa M, Kerac M. Features associated with underlying HIV infection in severe acute
childhood malnutrition: a cross sectional study. Malawi medical journal 2009;21(3).
(18) Colman S, Stewart RC, MacArthur C, Kennedy N, Tomenson B, Creed F. Psychological distress
in mothers of children admitted to a nutritional rehabilitation unit in Malawi–a comparison with other
paediatric wards. Maternal & child nutrition 2013.
(19) Bioelectrical impedance analysis in body composition measurement: National Institutes of Health
Technology Assessment Conference Statement. Am J Clin Nutr 1996 Sep;64(3 Suppl):524S-532S.
20
(20) Piccoli A, Codognotto M, Piasentin P, Naso A. Combined evaluation of nutrition and hydration in
dialysis patients with bioelectrical impedance vector analysis (BIVA). Clin Nutr 2014 Aug;33(4):673-
677.
(21) World Health Organization. NCHS/WHO normalized reference values for weight-for-
height/length by sex. 2005; Available at: http://helid.digicollection.org/en/d/Js8234e/8.3.html.
Accessed 07-24, 2015.
(22) Piccoli A. PG. Guideline BIVA software 2002. 2002.
(23) Buffa R, Baali A, Lahmam A, Amor H, Zouini M, Floris G, et al. Assessment of nutritional status
in the Amazigh children of Amizmiz (Azgour Valley, High Atlas and Morocco). J Trop Pediatr 2009
Dec;55(6):406-408.
(24) Nagano M, Suita S, Yamanouchi T. The validity of bioelectrical impedance phase angle for
nutritional assessment in children. J Pediatr Surg 2000 Jul;35(7):1035-1039.
(25) Basso F, Berdin G, Virzi GM, Mason G, Piccinni P, Day S, et al. Fluid management in the
intensive care unit: bioelectrical impedance vector analysis as a tool to assess hydration status and
optimal fluid balance in critically ill patients. Blood Purif 2013;36(3-4):192-199.
(26) Girma Nigatu T. Bioimpedance in severely malnourished children : An emerging method for
monitoring hydration of children with severe acute malnutrition. 2014; Available at:
http://nexs.ku.dk/english/calendar/2014/phd_tsinuel-girma-nigatu/. Accessed 07-28, 2015.
(27) Bodystat. Quadscan4000 Specifications, prices on request. 2015; Available at:
http://www.bodystat.com/products/quadscan. Accessed 07-24, 2015.
21
Appendix A. Standard Operating Procedure
1.0 PURPOSE
This SOP describes the Bio impedance analyses (BIVA) procedure.
2.0 SCOPE/RESPONSIBILITY
- This SOP applies to clinicians of the F75 trial
- The principal investigator retains the overall responsibility on implementation of the
SOP
3.0 ABBREVIATIONS
None
4.0 MATERIALS
4.1 BIVA device inclusive all items
4.2 Ruler tape
4.3 Hand gel and cotton wool
4.4 Toys etc: funny movie on phone, music instrument, bubbles, book
4.5 Stickers (reward)
5.0 METHODOLOGY
Start up:
- Start each day with the calibration of the BIVA-device.
- Check the enrolment log (black hardcover) on new admissions to the study. Code: E
- Make a planning for new admission patients regarding their ‘admission time’ that is
written down in the enrolment log. They must be tested preferably after 5 or 6 feedings
after admission.
- For example: Patient X was admitted to the ward at 20.00u. 5 feedings later: (21-24-03-
06-09) you test the patient between 11.00u en 12.00u. Feeding influences the results of the
test! Test in the last hour before the next feed. When a child is still breastfeeding, you can
test the child directly after feeding. Record this exception in CRF.
- Meanwhile: follow the phase 1-study patients during the ward round. Patients ready for
the Transition phase must be tested preferably before they start receiving the actual
Chiponde.
BIVA -test
- Use the plastified demonstration sheet to show the guardian about BIVA and outlight the
safety, non-invasive aspect of the test and emphasize that the help of the mother is very
important. If you need to convince the mother: give a demonstration on your own hands.
Be aware that consenting to the F75 trial, we already have permission to do BIVA. If the
surrounding area is very noisy, you can choose to use the bed behind the last the bay of
the ward. It is better to leave the child on its own bed.
22
- Check before testing:
o Left side is free of clothes or any decorative items. If for some reason the
procedure must be done on the right side, then make a note of this on the CRF.
o All remaining clothes including diaper (!) are dry
- Clean the child ’s hands and feet with some cotton wool and hand gel on the spot where
the stickers will be placed
- Attach the electrodes as follows: (See photograph 1 and 2 for clarification).
1. Hand: Place just behind the knuckles on the fingers. Tab facing away from the body.
2. Put the second electrode minimal 5,5 cm away from the first one. In an older child, it
can be more: measure the distance between the stickers and make a note on the CRF in
order to place the stickers on the same spot during the second reading.
3. Ankle: Place on an imaginary line between the protruding ankle bones straight across
to the lateral of the ankle. Doing so, the tab of the electrode is lateral (facing away
from the body).
4. Foot: Place just behind the toes below the knuckles of the right foot with tab facing
away from the body (lateral position).
5. Attach the leads to the electrodes. (NOTE: The black clip on each lead goes proximal
and red clip goes distal). See photographs
- Wait untill the child feels comfortable with the electrodes and then ask the mother to
put her child in the right position: the child should lie on its back on the bed, with
arms by his/her sides and both arms and both legs must not be touching (Figure 3).
The mother can touch her child if she puts the blanket in-between her hands and the
child. Allow this if it truly necessary to prevent the child from moving.
- Turn the BIVA analyser “on”. When the analyser asks for it, there is no need to enter
the child’s gender, age, height and weight.
- Make sure the subject refrains from movement on the moment that the device says
“measuring”. Movement will influence the BIVA analysis. When you are happy with
the position of the subject, read and record the displayed Impedance at 50kHz, and
Resistance (R), Reactance (Xc) and Phase angle for three times.
- Accept not more difference than a 1% variation in Resistance (R) or a 5% variation in
Reactance (Xc) and Phase Angle. If so, please check the child’s position and electrode
position and repeat until variation is acceptable. Normal range of R: (400 – 1400
ohm), Reactance: (60 – 10 ohm) and Phase Angle: (1,3 -4,0 degrees).
- Remove and dispose of the electrode stickers and offer the child its own sticker.
- Record time of measurement, position of the child, body side of the electrodes,
describe any movement, and earlier physical/feeding activity.
- End of the BIVA assessment.
Tricks to prevent a child from moving:
- Cover the child with their blanket to calm down the child.
- Very upset child under age 2 years: Make sure the child is focused on its mother. If
necessary put a Chitenje between you and the child.
- Very upset child above 2 years old: ask the mother to attach the stickers and
electrodes.
- Count down together with the child.
23
Images from bodystat Photograph 1
24
Appendix B photo report information sheet for guardians
25
26
27
English translation of the information sheet in Chichewa
“No worries, I don’t use injections”
Sticker Test
Thank you for joining the F75 trial!
With this we would like to give you additional information about a potential diagnostic
instrument of malnutrition that is part of the F75 trial.
This instrument can measure the fluids and tissue in the body. A lot of research has been
done already with this instrument. It is considered completely safe and it is not invasive or
hurt your child in any other way.
How does it work?
1. You are very important for this test! You can calm down your child when he or she afraid of
upset.
2. Two stickers will be placed on a hand and two stickers will be placed on a foot.
3. The child needs to lie down as shown on the picture. No rush, we should not force the child.
4. For about 10 sec your child needs to lie very still without touching you.
!! Movement / touch of the child during these 10 seconds will give unreliable results!!
5. Does your child like to watch a movie?
6. Your child can pick its own sticker afterwards.
28
Appendix C BIVA-CRF
CASE RECORD FORM
1. Study Number: F75 | _ | _ | _ | _ |
2. Participant name +
surname:_______________________________________________
3. DATE OF BIRTH |__|__|/|__|__|/| 2 0 |__|__| (dd/mm/yyyy)
4. AGEgroup* |__|
*1 = 0-1 yr, 2 = 2-3 yr, 3 = 4-5 yr, 4 = 6-7 yr, 5 = 8 yr
5. SEX (M/F) |__|
6. DATE OF admission: |__|__|/|__|__|/| 2 | 0 | 1 |__|
7. TIME OF admission: |__|__|:|__|__|
(24 hour clock)
ANTHROPOMETRY 1:
8. Weight: |__|__|.|__|__| kg
9. Height: |__|__|__|.|__| cm
10. MUAC: |__|__|.|__| cm
11. Edema: none / + / ++ / +++ (circle one)1
MEDICAL HYSTORY
1 + = mild, only feet/ankle, ++ moderate: no upper arm or upper leg edema and no facial edema, +++ = severe generalized
bilateral pitting edema including feet, legs, arms and face
29
12. HIV antibody test: Negative Positive
13. Other:
…………………………………………………………………………………………
………………
14. COMPLICATIONS AT ADMISSION:
14.1 SHOCK
(cold hands and capillary refill time longer than 3 seconds and fast
weak pulse)
Yes No
14.2 SEVERE PNEUMONIA (WHO severe or very severe
pneumonia)
Yes No
14.3 DIARRHOEA (3 or more loose stools in 24 hours) Yes No
14.4 MALARIA (confirmed by slide or RDT positive) Yes No
14.5 ANY OTHER FEBRILE ILLNESS Yes No
14.6 OTHER _____________________________________________ Yes No
HYDRATION STATUS 1
15. Number watery stools in last 24 h ___
16. Number vomiting episodes in last 24 h, ___
17. AVPU score ___
18. Cap refill >2: Yes/No ___
19. DATE OF TEST 1: |__|__|/|__|__|/| 2 | 0 | 1 |__|
20. TIME OF TEST 1: |__|__|:|__|__|
21. Number of feedings between admission and testing moment:
30
o 5
o 6
o 7
o Other, because:
BIVA OUTPUT 12:
definitive
22. R(ohm
23. Xc(ohm)
24. PhA
(degrees)
25. Notes (physical activity, (breast) feeding, urine output, body side)
26. Breastfeeding: Yes/No
27. DATE OF TEST 22: |__|__|/|__|__|/| 2 | 0 | 1 |__|
28. TIME OF TEST 2 |__|__|:|__|__|
ANTHROPOMETRY 2:
29. Weight: |__|__|.|__|__| kg
30. MUAC: |__|__|.|__| cm
31. Edema: none / + / ++ / +++ (circle one)3
2 1= onset of stabilisation phase
2= onset of transtition phase 3 + = mild, only feet/ankle, ++ moderate: no upper arm or upper leg edema and no facial edema, +++
= severe generalized bilateral pitting edema including feet, legs, arms and face
31
HYDRATION STATUS 2
32. Number watery stools in last 24 h ___
33. Number vomiting episodes in last 24 h ___
34. AVPU score ___
35. Cap refill >2: Yes/no ___
BIVA OUTPUT 2
definitive
36. R(ohm
37. Xc(ohm)
38. PhA
(degrees)
39. Notes (physical activity, (breast) feeding, urine output, body side)
40. SEVERE ADVERSE EVENT
Name of Event Date of onset End date
40.1 Profuse Watery Diarrhoea
40.2 Vomits everything
40.3 hypothermia
40.4 shock
40.5 Metabolic asidosis
40.6 Hypoxia
40.7 Impaired consciousness (BCS<4)
40.8 WHO severe or very severe pneumonia
40.9 Severe anaemia (Hb<5g/dl)
40.10 Other:
32
HYDRATION SUMMARY: Number of days during stabilisation phase: ___
41. diarrhea (>3 Watery stools) ___
42. requiring ReSoMal ___
43. requiring IV-fluids ___
44. study conlusion date: |__|__|/|__|__|/| 2 | 0 | 1 |__|
45. OUTCOME
o Absconded
o in hospital death
o refused further participation
o full participation