Citation for published version (APA): Haverkort, E. B. (2014). The value of nutritional assessment in major abdominal surgery

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1 UvA-DARE (Digital Academic Repository) The value of nutritional assessment in major abdominal surgery Haverkort, E.B. Link to publication Citation for published version (APA): Haverkort, E. B. (2014). The value of nutritional assessment in major abdominal surgery General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 01 May 2018

2 Chapter 5 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review E.B. Haverkort P.L.M. Reijven J.M. Binnekade M.A.E. van Bokhorst de van der Schueren C.P. Earthman D.J. Gouma R.J. de Haan Submitted

3 Abstract 68 Bioelectrical impedance analysis (BIA) is a commonly used method for the evaluation of body composition. However, BIA estimations are subject to uncertainties. The aim of this systematic review was to explore the variability of regression equations used in the BIA estimations and to evaluate the validity of BIA estimations in adult surgical and oncological patients. Included were studies developing new equations and studies evaluating the validity of BIA estimations compared with a reference method. Only studies using BIA devices measuring the entire body were included. Excluded were studies including patients with and altered body composition or a disturbed fluid balance, and studies written in languages other than English. To illustrate variability between equations, fixed normal reference values were entered into the equations and the results plotted in figures. The validity was expressed by the difference in means between the BIA estimates and reference method, and relative difference in %. Substantial variability between equations was found for both total body water (newly developed equations up to 5 litres, existing equations up to 20 litres or kilograms), and fat free mass (over 25 kg). BIA mainly underestimated total body water (range relative difference -18.8% to +7.2%) and fat free mass (range relative differences -15.2% to +3.8%). Estimates of the fat mass demonstrated a large variability (range relative difference % to +43.1%). The absence of measurement precision precludes a valid estimate of a body compartment. We suggest that BIA estimations can only be useful when performed longitudinally and under strict conditions. Key words Surgery; Oncology; Bioelectrical impedance analysis; Variability; Validity; Systematic review.

4 Introduction In clinical practice bioelectrical impedance analysis (BIA) is routinely used in The Netherlands to surgical and oncological patients where quick measurement of body compartments are needed, in terms of total body water, fat free mass, fat mass or other body compartments. BIA is considered to be an easy, non-invasive, less expensive and less time consuming method compared to other methods such as deuterium dilution; tritiated water dilution; bromide dilution; and dual energy X-ray absorptiometry (Appendix 1 at page 70-71) Reaching an estimate of a certain body compartment based on BIA estimation is achieved in two steps. In the first step a single or multiple frequencies BIA device measures the value of resistance and reactance of the body at a certain frequency (Appendix 1). In the second step the measured resistance and/or reactance is incorporated into a statistically-derived regression equation considered most suitable to estimate the body compartments of interest. The equation usually consists of a set of population-related variables such as height, body weight, age and gender and was originally derived from reference data obtained in a specific population (e.g. specific disease state, ethnicity). Although BIA is a commonly used method, 19 BIA estimations are subject to uncertainties. Firstly, a large number of equations with a variety of included variables are used to estimate a certain body compartment; secondly, different types of devices are based on different mathematical methods and techniques, and finally, the validity of the BIA estimation itself has not been unequivocally demonstrated. The purpose of this systematic review was therefore to explore the variability of the equations used, and to investigate the validity of BIA estimations compared to a sound reference method in surgical and oncological patients. Subjects and methods For systematic reporting, the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement were followed. 20 Search strategy A systematic literature search was conducted in several electronic databases up to August 2012: Medline; the Cochrane Central Register of Controlled Trials (CENTRAL); EMBASE; the meta-search engine Sumsearch and CINAHL/Ebsco. The following terms were used: electric impedance; body composition; surgery; operation; oncology; and cancer. Details of the search strategy are described in Appendix 2 (page 72). Chapter 5 69 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

5 Appendix 2 Literature search - search terms and number of studies Data base: PubMed Impedance and surgery AND. reference (136) - body composition (215) - reference AND body composition (20) Impedance AND operation AND. reference (105) - body composition (141) - reference AND body composition (12) Impedance AND oncology AND. reference (9) - body composition (23) - reference AND body composition (3) Impedance AND cancer AND.. reference (50) - body composition (149) - reference AND body composition (10) ( electric impedance [Mesh] OR electrical impedance OR *impedance) AND ( reproducibility of results [MeSH] OR reference values [MeSH] OR reference standards [MeSH]). NOT (adipose OR fat) (723) AND body (441). Limits: Humans, English, All Adult: 19+ years 70 Data base: Cochrane Impedance AND surgery AND. reference (6) - body composition (6) - reference AND body composition (0) Impedance AND operation AND. reference (1) - body composition (0) - reference AND body composition (0) Impedance AND oncology AND. reference (0) - body composition (0) - reference AND body composition (0) Impedance AND cancer AND.. reference (0) - body composition (7) - reference AND body composition (0) (electric Impedance OR electrical impedance OR *impedance) AND (reproducibility of results OR reference values OR reference standards) AND (body) NOT (child OR infant OR adolescent) (30) Data base: Embase Ovid Impendance AND surgery AND. reference (58) - body composition (96) - reference AND body composition (17) Impendance AND operation AND.. reference (19) - body composition (13) - reference AND body composition (1) Impendance AND oncology AND. reference (4) - body composition (7) - reference AND body composition (1) Impendance AND cancer AND. reference (26) - body composition (113) - reference AND body composition (6) (electric impedance OR electrical impedance OR *impedance) NOT (child OR infant OR adolescent) (397). AND (reproducibility of results OR reference values OR reference standards AND (body) (11). Limits: Human, English language Data base: SUMsearch Impedance AND surgery AND. reference (124) - body composition (195) - reference AND body composition (18) Impedance AND operation AND. reference (82) - body composition (97) - reference AND body composition (11) Impedance AND oncology AND. reference (9) - body composition (20) - reference AND body composition (3) Impedance AND cancer AND. reference (48) - body composition (139) reference AND body composition (9) (electric impedance OR electrical impedance OR *impedance) AND (reproducibility of results OR reference values OR reference standards ) AND (body) (511). Limits: Humans only, English only Age adult. Data base: CINAHL ( Electric Impedance MH) AND surgery AND. reference (5) - body composition (25) - reference AND body composition (2) ( Electric Impedance MH) AND operation AND. reference (1) - body composition (1) - reference AND body composition (1) ( Electric Impedance MH) AND oncology AND. reference (0) - body composition (0) - reference AND body composition (0) ( Electric Impedance MH) AND cancer AND. reference (5) - body composition (28) - reference AND body composition (1) ( MH body composition ) AND ( MH electric impedance ) AND adult NOT child NOT adolescent NOT infant (445)

6 Study eligibility criteria Types of studies Included were two different types of studies: (1) studies focusing on the development of new equations suitable for a specific target population, (2) studies describing the validity of BIA estimations compared to a reference method. All study designs were allowed, with the exception of case reports, case series, meeting abstracts and editorial letters. Excluded were studies written in languages other than English. Types of participants Included were studies in adult human surgical and oncological patients. The term surgical was defined as the period before the surgical procedure up to one year postoperatively. Studies with regard to oncological patients were included up to one year after finishing therapy (e.g. chemotherapy or radiotherapy). Excluded were studies in patients with altered body composition and/or a disturbed fluid balance as it can result in overestimation and underestimation of body compartments measured by BIA, i.e. patients with a BMI 35 (extreme obesity); patients with endocrine diseases that influence body composition (e.g. Cushing syndrome); patients treated with (growth) hormone; acutely ill intensive care patients; patients with clinical 1, 5, 13 signs of oedema ; and patients before or after organ transplantation. Types of BIA devices Included were studies using bioimpedance devices measuring the entire body: singlefrequency bioelectrical impedance analysis (SF-BIA); multiple-frequency bioelectrical 1-3, 7, 12, 13 impedance analysis (MF-BIA); and bioimpedance spectroscopy (BIS). Excluded were studies using foot-to-foot SF-BIA devices and segmental impedance techniques as these methods do not measure the entire body. Study selection and data extraction One review author (EBH) collected the potential studies from the various databases and screened the articles on title and abstracts. From the full texts of the selected studies, three review authors (EBH, PLMR, MAEvB) independently included the studies into this review. Disagreement about inclusion was resolved by consensus. Data were extracted by one review author (EBH) with the use of an extraction form containing: aim of study (development of equation; measurement validity); body compartment of study (total body water (TBW); body cell mass (BCM); extra cellular water (ECW); intra cellular water (ICW); fat free mass (FFM); fat mass (FM); and lean body mass (LBM) which is also referred to as lean tissue mass (LTM); target population (surgery; oncology); number of patients studied; reference method; type and manufacturer of BIA device; and characteristics of the equations (new; existing; set of variables included in equation). Chapter 5 71 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

7 Types of reference methods used in the validity studies For the measurement of TBW deuterium dilution and tritiated water dilution are used. BCM can be estimated by radioactive total body potassium (TBK) by whole body counting and total body nitrogen (TBN) by neutron activation. ECW is measured by bromide dilution and ICW can be measured by radioactive TBK. FFM, FM and LTM can be measured by hydrostatic weighing (hydro densitometry or underwater weighing), air-displacement plethysmography and dual energy X-ray absorptiometry (DXA). Magnetic resonance imaging (MRI) and computed tomography (CT) can both be used for the measurement of 3, 7, 12, 17, 18, 21, 22 FM, muscle, skin, viscera and bone tissue. 72 Risk of Bias Altered body composition and/or fluid disturbances can result in overestimation and underestimation of body compartments measured by BIA. Therefore, patients suffering from oedema; significant fluid disturbances; extreme obesity; illnesses and treatments that could influence body composition and/or fluid balance should be excluded from analyses. In order to evaluate whether the included studies are well designed, performed and described general information with regard to the reference method and the target population (compartment of study; main characteristics of the study population; surgical or oncological patients; number of participants; inclusion and exclusion criteria of the study population; recruitment procedures) should be clearly described. In studies that focus on the development of new equations, besides a detailed description of the used device (manufacturer; model), the variables included in the new equation (resistance, gender, height, weight, age, others) must clearly be recorded. In addition, studies on the validity of BIA estimations must give detailed information on the type of device, existing equation(s), and reference methods. Best-evidence synthesis This systematic review is a qualitative synthesis of the available evidence. In view of the heterogeneity of the target population, the variability of study objectives and differences in methodological quality, a meta-analysis could not be performed. Statistical Analysis Study characteristics were summarized using descriptive statistics. To explore the variations of newly developed and existing equations, we used the frequently used normal reference values published by Kyle as input for the equations to simulate measures of body compartments (TBW and FFM). 23 Kyle s reference values are available for eight different age groups, each with a bandwidth of 9 years ranging from 15 to over 85 years. Hence, the clinical measures normally obtained from patients (gender, height, weight and age) and the direct estimations of the BIA device (resistance and reactance) at 50 khz were replaced by these reference values. So, in our simulation approach each body compartment measure was the result of a series of fixed reference values for patient and BIA, but calculated

8 with different equations. Consequently, variability found in body compartments is the reflection of the differences between equations. Estimation results were grouped by body compartment and plotted per age group. With regard to the validity of BIA estimations, we assessed the discrepancy between BIA estimations and reference methods, using the difference in means and the relative difference in %. The relative difference in % was calculated by: [(compartment estimated by BIA compartment measured by reference method) / compartment measured by reference method] x 100%. Statistical uncertainty was expressed in 95% confidence intervals (CI). Chapter 5 Results 73 Literature search and study selection The literature search revealed a total of 4369 studies. After exclusion of the duplicates (n = 838), and screening of titles and abstracts, the full text of 63 studies were independently examined by three reviewers. Fifty-two studies were excluded based on disease (e.g. obesity; nephrology; intensive care); uncertainty about the actual absence of fluid disturbances; age (adolescent; child); performed surgical procedure (e.g. gastric bypass due to obesity; organ transplantation); time point (more than one year postoperative); or lack of an actual reference method (e.g. comparison of two different BIA devices). A total of 11 studies (six studies with surgical patients and five studies with oncological patients) met the inclusion criteria, and were considered suitable for the systematic review (Figure 1). Study characteristics Table 1 shows detailed information about the aim of the study (development of equations 24-29, 31 and/or the validity of the BIA estimations 25, 29, 30, ) and the measured body compartments (TBW; BCM; ECW; FFM; and (%)FM). The main characteristics of the study population were well described in all studies except for one. 31 Surgery was the field of study in six of the included studies. 24, 26, 28, 30, 31, 34 Four of these studies consisted of a heterogeneous group of surgical patients, including cancer patients, 24, 26, 28, 31 one study reported on patients after major abdominal surgery 30 and one described patients undergoing elective heart surgery. 34 Five studies focused on oncological patients: three studies consisted of untreated ambulatory (incurable) patients with a malignancy in the gastro-intestinal tract or lung, 25,29,33 one study described patients suffering from esophageal or gastric cancer with various extents of weight loss, 27 and one studied had included men suffering from prostate cancer. 32 All studies provided information about the used reference method (tritiated water dilution; deuterium dilution; bromide dilution; TBK; and DXA), the four manufacturers of the BIA devices, and their types: SF-BIA; BIS; and MF-BIA + BIS. In all but two studies 24, 26 the specific models of the devices were also described. Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

9 Figure 1 Flow of information through the different phases of the systematic review Pubmed -Medline 2021 studies Cochrane 50 studies Embase Ovid 372 studies Sum Search 1189 studies Cinahl 472 studies Other sources 3 studies Total 4639 studies duplicates removed 3801 studies screened on title 2596 studies excluded based on title 1205 studies screened on abstract 1142 studies excluded based on abstract 63 studies screened on full text 52 studies excluded based on full text 11 studies included in qualitative synthesis Surgery n= 6 Oncology n = 5 In seven studies (four surgical; three oncological) statistical regression equations were developed to estimate TBW, BCM, and ECW (see also Appendix 3) , 31 Resistance at 50 khz, height, and body weight were variables often included in these newly developed regression equations. The six studies evaluating the validity of BIA estimations (two surgical; four oncological) 25, 29 30, 32, 33, 34 used existing general equations to estimate TBW, FFM, and (%)FM (Appendix 4). 3, The majority of the existing equations also included the resistance value at 50 khz; height; and body weight in their set of variables. In addition, three studies (also) made use 29, 33, 34 of an equation incorporated into the instrument s software itself.

10 Table 1 Characteristics of the included studies (N= 11) General information Reference Bioelectrical impedance (BIA) estimation method e Device Equation (O) c N d Type f Manufac- Model Equation Variables in equation R khz k Gender Height Weight Age Others Unknown l Compartment b Population Surgery (S) study a of or oncology Author Aim of study new 50 x S 120 TD SF-BIA RJL unknown TBW heterogeneous surgical group Schroeder 24 Development equation O 33 DD SF-BIA RJL 101 new 50 x existing 35 (G) 50 x TBW new cancer patients no treatment 50 x x existing 36 (G,M,F) Fredrix 25 Development equation and Measurement validity 50 x x x (x) existing 37 (G,M,F) new TBW 50 x x S 43 TD SF-BIA RJL unknown TBK heterogeneous surgical group Fearon 26 TBW Development equation BCM new TBK 50 x x x O 21 BD SF-BIA RJL 103 new - x x ECW cancer patients with weight loss Miholic 27 Development equation x (x) (x) S 43 TD MF-BIA Xitron 4000B new (4) TBW 50 BD and 500 heterogeneous surgical group TBW ECW Hannan 28 Development equation x new (2) ECW 5 and 50 O 41 DD SF-BIA RJL 101 new (2) 50 x 50 (x) x x (x) existing incorpated 37 (G, M,F) TBW ambulatory incurable cancer patients existing 38 (G) 50 x x x x Simons 29 Development equation and Measurement validity 50 (x) x x (x) existing 39 (G,M,F) existing 40 (G) 50 x x existing 42 (G) 50 x Chapter 5 75 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

11 76 General information Reference Bioelectrical impedance (BIA) estimation method e Device Equation 50 x x x existing 43 (M, F) 50 x x existing 44 (M, F) existing 45 (G) 50 x x existing 46 (G) 50 x x x x 50 (x) x x (x) S 28 DXA SF-BIA HTS Animeter existing 39 (G,M,F) postop. abdominal surgery FFM FM Jensen 30 Measurement validity Xitron 4000B new TBW 200 x x x S 29 TD MF-BIA BD approach+ BIS approach heterogeneous surgical group TBW ECW Hannan 31 Development equation new ECW 5 x x 50 x x x O 38 DXA SF-BIA RJL 101A existing 43 (M,F) % FM ambulatory prostate cancer Smith 32 Measurement validity existing 45 (G) 50 x x x existing incorporated O 132 DXA BIS Xitron Hydra 4200 incurable and untreated cancer gi-tract TBW FFM Ellegård 33 Measurement validity existing 3 (G) x x x x existing incorporated S 26 DXA BIS Fresenius Body Scout elective heart surgery FFM FM existing 41 (G) zero and infinity Measurement validity van Venrooij 34 a Compartment of study: TBW = total body water; BCM = body cell mass; ECW = extra cellular water; FFM = fat free mass; FM= fat mass; % FM = percentage fat mass. b Population: heterogeneous surgical group = heterogeneous group of surgical patients (cancer, ibd, pancreatitis); new cancer patients no treatment = ambulatory, patients with malignancy of gi-tract or lung no chemotherapy or radiation therapy; cancer patients with weight loss = patients with esophageal or gastric cancer with various extents of weight loss; ambulatory incurable cancer patients = group of ambulatory patients with incurable and untreated cancer of the gi-tract; postop. abdominal surgery = patients 2-4 months after major abdominal surgery; ambulatory prostate cancer = group of ambulatory locally advanced, lymph-node positive, or recurrent men with prostate cancer no hormone therapy; incurable and untreated cancer = group of patients with incurable and untreated cancer of the gi-tract; elective heart surgery = patients undergoing elective open heart surgery (CABG, heart valve). c Surgery (S) or oncology (O): S = surgical patients; O = oncological patients. d N: number of participants in the study. e Reference method: TD = tritium dilution for TBW; DD = deuterium dilution for TBW; TBK = radioactive 40K (= TBK) for BCM; BD = bromide dilution for ECW; DXA = dual energy x-ray absorptiometry for FFM and FM. f Type of BIA device: SF = single frequency bioelectrical impedance analysis (SF-BIA); MF = multiple frequency bioelectrical impedance analysis (MF-BIA); BIS = bioimpedance spectroscopy. g Manufacturer of BIA device : RJL systems, Detroit, USA; Xitron technologies, San Diego, USA; HTS-engineering, Odense, Denmark; Fresenius Kabi Medical Care, Bad Homburg, Germany. h Equation, ref and (G,F,M): new = drafting new equation ; existing + number + (G,M,F) = use of existing equation + reference number and an equation for entire the group (G), equation for the male subgroup (M), equation for the female subgroup (F); existing incorporated = use of equation incorporated in the instrument s software. k R khz: Resistance in khz included in equation. l unknown: no documentation available with regard to the used equation.

12 Appendix 3 Newly drafted equations used in 7 studies Author ref Reference method a BIA b Equation Equations for the estimation of total body water (TBW) in litres Schroeder 24 TD SF-BIA TBW (L) = 1.04 (TBW estimated by SF-BIA) Fredrix 25 DD SF-BIA TBW (L) = (height 2 ) / resistance 50 Fearon 26 TD SF-BIA TBW (L) = (weight) (height) (resistance 50 ) Hannan 28 TD MF-BIA TBW (L) = (height) 2 / resistance (antero-posterior thickness) TBW (L) = 0.45 (height) 2 / resistance (antero-posterior thickness) (height) / reactance (height)2 / reactance 500 TBW (L) = (height) 2 / resistance (weight) TBW (L) = (height) 2 / resistance (weight) Simons 29 DD SF-BIA TBW (L) normal weight = (height 2 / resistance 50 ) TBW (L) underweight = (height 2 / resistance 50 ) Hannan 31 TD MF-BIA TBW (L) = (height) 2 / resistance (weight) (gender:1 = male, 0 = female) BIS not described Equations for the estimation of extra cellular water (ECW) in litres Miholic 27 BD SF-BIA ECW (L) = (height 2 / reactance ) (weight) (phase angle 50 ) Hannan 28 BD MF-BIA ECW (L) = (height) 2 / resistance (height)2 / resistance ECW (L) = 0.01 (height) 2 / resistance (height)2 / resistance Hannan 31 BD MF-BIA ECW (L) = (height) 2 / resistance (weight) BIS not described Equations for the estimation of body cell mass (BCM) by total body count potassium (TBK) in grams Fearon 26 TBK SF-BIA TBK (g) = (height) (weight) (resistance 50 ) (reactance 50 ) (total body potassium ) (age) a Reference method : TD = tritiated water dilution; DD = deuterium dilution; BD = bromide dilution; TBK = total body count potassium b estimation: SF-BIA = single frequency bioelectrical impedance analysis; MF-BIA = multi frequency bioelectrical impedance analysis; BIS = bioimpedance spectroscopy Chapter 5 77 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

13 78 Bias in the individual studies Risk of bias with regard to design and performance may have occurred in the majority of the included studies. In only one study the inclusion and exclusion criteria, the time period in which patients were included and the recruitment methods were clearly described. 34 In addition, the conditions under which the BIA estimations were used to obtain body composition estimates were not completely described in all studies. One study included 120 subjects in total, with eight being healthy volunteers. Data from these healthy subjects was included in the presented results. 24 In another study the information of the entire study population, including the postoperative subgroup, was used in order to develop a new statistical regression equation for the estimation of ECW. 27 In two studies the equations to estimate FFM were used from the indirect estimations of 29, 32 TBW and %FM. 28, 31 Two studies both explicitly described the presence of oedema in a subpopulation. To reduce the risk of bias, the patients described to have oedema were excluded from the results. Variability of newly developed and existing general equations The included studies describe 15 newly developed equations (10 for the estimation of TBW, four for ECW and one for BCM, Appendix 3), 25 general existing equations (14 for TBW, and 11 for FFM, Appendix 4) and three equations incorporated in the instrument s software. Just to illustrate the variation between the equations, the normal reference values of Kyle were included in the newly developed and existing general equations. 23 This was not possible for five of the 10 newly developed equations for TBW 24, 28, 31 and three of 25 general existing equations for TBW and FFM 3, 41 because these equations include variables for which normal reference values are unknown (e.g. resistance at 200 khz or reactance at 500 khz). Based on the variables included in the equations, a graphical representation was possible for five newly developed equations with regard to TBW as described in Appendix 3 and depicted in Figure 2. 25, 26, 28, 29 The newly developed equations show a variation up to 5 litres for the TBW estimations. Figures could also be constructed for twelve out of fourteen of the (gender specific) existing equations for TBW and ten out of eleven for FFM (see Appendix 4) , 31 A wide variation between the various existing general equations was observed for TBW (up to 20 litres or kilograms) and for FFM (over 25 kg) (Figures 3 and 4). The validity of BIA estimations Table 2 shows that in four of the six studies evaluating the validity of BIA estimations the difference in means and the relative difference in % (point estimate) could be described and/or calculated completely. 25, 32, 33, 34 In the remaining two studies these results could only partially be described or calculated as the necessary data were incomplete or missing. 29, 30 Compared to the reference methods deuterium dilution and DXA, the TBW compartment was mainly underestimated by the various BIA estimations. The calculated relative

14 Figure 2 Presentation of the variability between newly developed equations using normal reference values - total body water (TBW) in litres Legend: 1. Fredrix 25 ; 2. Fearon 26 ; 3. Hannan 28 - nr 3; 4. Simons 29 - nr 1; 5. Simons 29 nr 2. Application of the normal reference values of Kyle for resistance, body weight, height, gender and age determined at 50 khz in the newly developed equations to estimate total body water (TBW) as described in Appendix x-axis describing various age-groups defined by Kyle. y-axis describing the estimated number of litres of TBW. Figure 3 Presentation of the variability between general existing equations using normal reference values - total body water (TBW) in litres or kilograms Application of the normal reference values of Kyle for resistance, body weight, height, gender and age determined at 50 khz in existing general equations to estimate total body water (TBW) as described in Appendix x-axis describing various age-groups defined by Kyle. y-axis describing the estimated number of litres or kilograms of TBW. Legend: 1.Lukaski 35 group equation; 2. Kushner 36-1 group equation; 3. Kushner 36-2 male equation; 4. Kushner 36-3 female equation; 5. van Loan 37-1 group equation; 6. van Loan 37-2 male equation; 7. van Loan 37-3 female equation; 8. Lukaski 38 group equation; 9. Heitmann 39 1 group equation; 10. Heitmann 39-2 male equation; 11. Heitmann 39-3 female equation; 12. Kushner 40 - group equation. Chapter 5 79 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

15 Figure 4 Presentation of the variability between general existing equations using normal reference values - fat free mass (FFM) in kilograms 80 Application of the normal reference values of Kyle for resistance, body weight, height, gender and age determined at 50 khz in existing general equations to estimate fat free mass (FFM) as described in Appendix x-axis describing various age-groups defined by Kyle. y-axis describing the estimated number of kilograms of FFM. Legend: 1. Heitmann group equation; 2. Heitmann male equation; 3. Heitmann female equation; 4. Lukaski 42 group equation; 5. Segal male equation; 6. Segal female equation; 7. Graves male equation; 8. Graves female equation; 9. Deurenberg 45 group equation; 10. Deurenberg 46 group equation. difference ranged from -18.8% to + 7.2% (total range 26%). The smallest relative difference (0.9%) was demonstrated in a group of incurable, underweight cancer patients 29 by means of a SF-BIA device and the Heitmann equation. 39 The largest underestimated BIA measurement (relative difference -18.8%) was demonstrated by using a SF-BIA device and the Deurenberg equation (45) in the same study among a normal weight subgroup. 29 FFM also tended to be underestimated by BIA. Relative differences ranged from -15.2% to + 3.8% (total range 19%). The smallest relative difference (3.7%) was demonstrated in a group of patients after elective cardiac surgery using a BIS device in combination with an equation incorporated into the instrument s software. 34 The largest underestimated BIA measurements (relative difference -15.2%) was shown in patients suffering from incurable and untreated cancer of the gastro-intestinal tract. The BIA estimation was performed with a BIS device and an equation incorporated into the instrument s software. 33 The FM estimations in the included studies were described in both %FM and kilograms of FM and this should be taken into account with regard to the interpretation of the results. A large variability in discrepancies between BIA and reference methods could be observed. Relative differences ranged from % to 43.1% (total range 58.8%). The smallest relative difference (1.2%) was demonstrated in a group of patients undergoing elective cardiac surgery measured by means of a BIS device and an equation incorporated into the instrument s software. 34 The largest overestimated BIA measurement (relative

16 Appendix 4 Existing general equations used in 13 studies Reference Group M / F a Equations for the estimation of total body water (TBW) in litres Ellis 3 G TBW (L) = fat free mass (kg) x Lukaski 35 G TBW (L) = (height cm 2 /resistance 50 ) Kushner 36 G TBW (L) = (height cm 2 / resistance 50 ) (weight kg) Van Loan 37 M TBW (L) = (height cm 2 / resistance 50 ) (weight kg) F TBW (L) = (height cm 2 / resistance 50 ) (weight kg) G M F TBW (L) = (height cm 2 ) (weight kg) (resistance 50 ) (gender; male = 0, female = 1) (age years) TBW (L) = (height cm 2 /resistance 50 ) (weight kg) TBW (L) = (height cm 2 /resistance 50 ) (weight kg) Lukaski 38 G TBW (L) = (height cm 2 /resistance 50 ) (weight kg) (age years) (gender; male = 1, female = 0) Moissl 41 G TBW (L) = ρ ICW (ρ ICW ρ ECW) x (R infinity / R 0 ) (2/3) Heitmann 39 G Equations for the estimation of total body water (TBW) in kilograms TBW (Kg) = (height cm 2 /resistance 50 ) (weight kg) (gender; male = 1, female = 0) (age years) M TBW (Kg) = (height cm 2 /resistance 50 ) ( weight kg) F TBW (Kg) = (height cm 2 /resistance 50 ) (weight kg) Kushner 40 G TBW (Kg) = 0.59 (height cm 2 /resistance 50 ) (weight kg) Heitmannn 39 G M F Equations for the estimation of fat free mass (FFM) in kilograms FFM (Kg) = (height cm 2 /resistance 50 ) (weight kg) (gender; male = 1, female = 0) (age years) (height in cm) FFM (Kg) = (height cm 2 /resistance 50 ) (weight kg) (height in cm) FFM (Kg) = (height cm 2 /resistance 50 ) (weight kg) (height in cm) Moissl 41 G FFM (Kg) = (δ ECW x ECW bis ) + (δ ICW x ICW bis ) Lukaski 42 G FFM (Kg) = (height cm 2 /resistance 50 ) Segal 43 M F FFM (Kg) = (height cm 2 ) (resistance 50 ) (weight kg) (age years) FFM (Kg) = (height cm 2 ) (resistance 50 ) (weight kg) (age years) Graves 44 M FFM (Kg) = 0.485(height cm 2 /resistance 50 ) (weight kg) Deurenberg 45 Deurenberg 46 F FFM (Kg) = 0.475(height cm 2 /resistance 50 ) (weight kg) G G a Group, Male or Female specific equation FFM (Kg) = (0.671 x height m 2 /resistance 50 ) (gender; male =1, female = 0) FFM (Kg) = (height cm 2 /resistance 50 ) (height in cm) (weight kg) (age years) (gender; male = 1, female = 0) Chapter 5 81 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

17 Table 2 Difference between BIA estimations and reference methods expressed in difference in means and relative difference in 6 studies Author ref Reference method a Type of device b Fredrix 25 reference method: DD Device: SF-BIA Reference equation c BIA estimation mean (95% CI) Reference method mean (95% CI) Field of study: total body water (TBW) L (33.5 to 37.7) L (35.9 to 40.1) 36.0 L (33.9 to 38.1 ) 36.0 L (33.9 to 38.1 ) Difference in means (95% CI) -0.4 L (-3.2 to 2.4) 2.0 L (-0.8 to 4.8) Relative difference in % (point estimate): d Simons 29 normal weight e Reference method: DD Device: SF-BIA L (30.5 to 34.7) 36.0 L (33.9 to 38.1 ) L 38.2 L (35.9 to 40.5) L 38.2 L (35.9 to 40.5) -3.4 L (-6.2 to -0.6) -9.4 not available f not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f L 38.2 L (35.9 to 40.5) not available f Simons 29 underweight g Reference method: DD Device: SF-BIA L 33.2 L (30.1 to 36.3) L 33.2 L (30.1 to 36.3) not available f 7.2 not available f L 33.2 L (30.1 to 36.3) not available f L 33.2 L (30.1 to 36.3) not available f L 33.2 L (30.1 to 36.3) not available f L 33.2 L (30.1 to 36.3) not available f L 33.2 L (30.1 to 36.3) not available f -10.8

18 Author ref Reference method a Type of device b Ellegård 33 Reference method: DXA Device: BIS Jensen 30 Reference method: DXA Device: SF-BIA Ellegård 33 Reference method: DXA Device: BIS van Venrooij 34 Reference method: DXA Device: BIS Smith 32 Reference method: DXA Device: SF-BIA van Venrooij 34 Reference method: DXA Device: BIS a Reference equation c BIA estimation mean (95% CI) Reference method mean (95% CI) L 33.2 L (30.1 to 36.3) L 33.2 L (30.1 to 36.3) L 33.2 L (30.1 to 36.3) in 32.9 kg (31.6 to 34.2) kg (33.4 to 35.8) 36.9 kg (35.6 to 38.2) 36.9 kg (35.6 to 38.2) Difference in means (95% CI) Relative difference in % (point estimate): d not available f 4.2 not available f not available f kg (-5.8 to -2.2) -2.3 kg (-4.1 to -.0.6) 39 not available f not available f Difference ± SD: 1.4 kg ± 2.5 in Field of study: fat free mass (FFM) 42.9 kg (41.2 to 44.6) kg (43.0 to 46.6) kg (44.2 to 47.2) in-pre h in-post i 63.0 kg (58.6 to 67.4) 62.1 kg (57.5 to 66.7) 50.6 kg (48.8 to 52.4) 50.6 kg (48.8 to 52.4) 50.6 kg (48.8 to 52.4) 60.7 kg (56.5 to 64.9) 59.9 kg (55.8 to 64.0) -7.7 kg (-10.2 to -5.2) -5.8 kg (-8.3 to -3.3) -4.9 kg (-7.3 to -2.5) 2.3 kg (-3.6 to 8.2) 2.2 kg (-3.8 to 8.2) Field of study: percentage fat mass (%FM) and fat mass (FM) % (20.7 to 24.3) % (35.9 to 40.5) age related in-pre h in-post i 35.4% (32.2 to 38.6) 25.2 kg (20.3 to 30.1) 24.9 kg (20.7 to 29.1) 26.7% (25.0 to 28.4) 26.7% (25.0 to 28.4) 26.7% (25.0 to 28.4) 24.9 kg (20.8 to 29.0) 24.6 kg (20.9 to 28.3) -4.2% (-6.7 to -1.7) 11.5% (-8.7 to.14.3) 8.7% (5.2 to 12.2) 0.3 kg (-6.0 to 6.61) 0.3 kg (-5.2 to 5.8) a Reference method: DD = deuterium dilution; DXA = dual energy x-ray absorptiometry b Type of device: SF-BIA = single frequency bioelectrical impedance analysis; BIS = bioimpedance spectroscopy c Reference equation = reference number of the existing equation; in = use of equation incorporated in the instrument s software d Relative difference in %: [(compartment estimated by BIA compartment measured by reference method) / compartment measured by reference method] x 100% e Normal weight: Simons et al. (1995) defined normal weight as body weight > 95% of ideal body weight f Not available = necessary data to describe and/or calculate the difference in means, the 95% CI for the difference in means, and relative difference in % (point estimate) between the BIA estimation and reference method were insufficient or not available g Underweight weight: Simons et al. (1995) defined underweight as: body weight < 95% of ideal body weight. h pre = measurement in preoperative patients i post = measurement in postoperative patients Chapter 5 83 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

19 difference 43.1%) was demonstrated in men suffering from prostate cancer 32 by using a SF-BIA device and the Deurenberg equation. 45 Disscusion 84 Eleven studies (six surgery and five oncology) were consistent with the predetermined inclusion criteria and were included in this systematic review exploring the variability of the equations and investigating the validity of the BIA estimations. In answer to our research questions, the following results, conclusions and recommendations can be elaborated from this systematic review. Variability of equations This systematic review demonstrates the development and the application of a large number of BIA equations. The 11 included studies describe 15 newly developed equations, 25 general existing equations and three equations incorporated in the instrument s software. In seven of the eleven studies new equations were developed , 31 In our opinion the continuous development of new equations seems redundant, unnecessary and undesirable without determining whether existing general equations are useful or can be improved. Thirteen studies used existing general (gender specific) equations for the estimation of TBW, FFM and %FM, none specifically developed for oncological or surgical patients. 3, The European Society for Clinical Nutrition and Metabolism (ESPEN) advises the application of the Geneva equation based on bioimpedance data measured at 50 khz. 47 However, we cannot assess the usefulness of the Geneva equation with regard to oncological or surgical patients as none of the studies included in this systematic review used this equation or were published before the Geneva equation in In three of the included studies 29, 33, 34 an equation was incorporated into the instrument s software. These included equations contribute to the black box phenomenon as most manufacturers are not transparent about the variables included and/or the incorporation of an existing general equation. This uncertainty makes it difficult to determine whether these types of equations are the most appropriate. A BIA estimation is derived from the combination of a device and an populationspecific equation considered suitable for the patient being measured. As described by Kyle et al., an adequate equation is therefore of great importance for a valid estimation of a patient s body composition. 5 When using Kyle s fixed reference values in the newly developed and existing general equations, we found a substantial amount of variability between the equations with regard to TBW and FFM, which is not surprising in view of the diversity of variables and regression weights included into the equations. In addition, study population, research team, laboratory, and the modified analysis techniques and correction factors with regard to the reference methods are also of influence to variability. So, one can wonder if valid BIA estimates of body compartments are per definition possible in light of the absence of measurement precision.

20 The validity of the BIA estimations The review findings demonstrate both overestimation and underestimation of the different body compartments with all the used existing general equations combined with all devices compared to the reference methods. The review findings demonstrate a tendency towards underestimation of both the TBW and the FFM compartment irrespective the BIA devices and the used existing general equations. Underestimation of the TBW may wrongly assume dehydration and could result in the adverse clinical decision to hydrate the patient. Underestimation of the FFM has major consequences as well; it may result in the postponement of a surgical procedure (given that a low preoperative FFM is a potential risk factor for postoperative complications) It may also result in a delay in the beginning of (neo) adjuvant treatment given that a low FFM contributes to more severe side effects, and unnecessary physical therapy and/or dietary therapy may be started. The FM compartment demonstrated a large variability; overestimation, underestimation, and adequate estimation were observed in the two studies evaluating this body compartment. An incorrect estimate of the FM is undesirable as it also estimates the FFM incorrectly. Overestimation of the FM implies underestimation of FFM and may result in adverse clinical decisions. Unfortunately, the absence of data made it impossible to calculate the difference in means in the studies of Simons 29 and Jensen 30 evaluating TBW. In addition, the relative difference could not be calculated in the study of Jensen. This systematic review demonstrates that, although not ideal, the Heitmann SF-BIA equation 39 leads to the best estimate of TBW. With regard to FM and FFM, the most preferable equation cannot specifically be identified as it was an equation incorporated into the Bodyscout instrument s software and details about the variables included are not described. 34 It is remarkable that the Deurenberg SF-BIA equation produced 45 the poorest estimations of TBW and %FM (largest relative difference). These results raise the question whether the used equation or the used device (both studies used a SF-BIA) primarily contributed to the large differences. In contrast to the claims, that MF-BIA and BIS devices estimate more accurately than SF-BIA, this review does not confirm the superiority of MF-BIA or BIS over SF-BIA in surgical and oncological patients. 1-3, 5, Our included studies demonstrated the smallest and the largest relative difference for TBW by means of SF-BIA. For FFM the smallest and the largest relative difference were calculated when using a BIS device. For FM, the smallest relative difference was calculated with a BIS device and the largest difference when a SF-BIA was used. According to our knowledge, among oncological and surgical patients no studies have been performed measuring a certain body compartment using different BIA devices in combination with a reference method at the same point in time. Chapter 5 85 Bioelectrical impedance analysis to estimate body composition in surgical and oncological patients: a systematic review

21 86 Other aspects of influence to BIA estimations Although device and equations have the most prominent impact on the outcome of the BIA estimation, other aspects and conditions may also play a role. Exercise and food intake before the measurement probably also influence the results. 18 None of the included studies described whether activity before the measurement was (not) allowed, five studies reported (briefly) about fasting before the measurement. 25, 27, 29, 33, 34 The literature also recommends to take into account that the position of the body during the measurement, movements during the measurement, the degree of degreasing of the skin for securing the electrodes, the type of electrodes and the skin temperature and condition are all, to a certain extent, influence on BIA outcome. 18 Seven out of the 11 studies provided information about the position of electrodes and/or the (supine) position of patient during the measurement; and only one also described the room temperature , 30, 32 The phase of the menstrual cycle and the use of contraceptives may also influence the results; however, these details were typically not provided. 18 Limitations of the review To estimate the validity of BIA, we used strict inclusion criteria and this resulted in exclusion of a large number of studies. Clinical practice is considerably more stubborn and patients often present with oedema, overweight or serious underweight. This systematic review shows that there are considerable differences between BIA and reference methods in a population selected to have a normal body composition. What can be expected from BIA estimations within the total population of surgical and oncologic patients, including those with a (suspected) altered body composition, disturbed fluid balance, severe malnutrition or extreme obesity? Moreover, oncological patients undergoing surgery consist of a very large and diverse group of patients incomparable in terms of disease, prognosis and treatment. Neither surgical nor oncological patients can be seen as one group of patients, but include a wide palette of patients with a variety of diseases. Therefore, conclusions cannot simply be drawn for the entire subpopulations. Only a part of the new and existing equations could be shown in figures to illustrate varia tion between the equations. However, given the content of the regression variables and their regression weight an entirely different picture and result is not in line with the expectations. As only English articles were included in this review, this may have influenced the completeness of the total available studies with regard to the estimation of body composition by BIA in surgical and oncological patients. Implications for practice In our hospital, we routinely perform BIA estimations in oncological surgical patients visiting the outpatient clinic preceding and following therapeutic interventions. The large variability and the weak validity of BIA estimations, as described in this systematic review, raise the question whether it makes sense to continue BIA estimations in individual patients.