Thorax 1996;51:126-131

Resting energy expenditure and oxygen cost ofbreathing in patients with cystic fibrosis

S C Bell, M J Saunders, J S Elbom, D J Shale

AbstractBackground - Resting energy expenditure(REE) is often increased and may con-tribute towards energy imbalance inpatients with cystic fibrosis. Severalmechanisms may lead to increased REEincluding the gene defect, the effect ofchronic infection, and abnormal pul-monary mechanics. Increased oxygen costof breathing (OCB) has been dem-onstrated in patients with chronic ob-structive pulmonary disease (COPD), buthas not been the subject of extensive studyin cystic fibrosis.Methods - Ten clinically stable patientswith cystic fibrosis and 10 healthy controlsubjects were studied. OCB was estimatedusing the dead space hyperventilationmethod. Mixed expired gas fractions weremeasured by online gas analysers andventilation by a pneumotachograph. Aftermeasurement of resting ventilation andgas exchange, minute ventilation (VE) wasstimulated by 6-10 I/min by the addition ofa dead space and OCB calculated from theslope of the differences in oxygen uptake(VO2) and VE. REE and the non-res-piratory component of REE were cal-culated from gas exchange data. To assessthe repeatability of OCB all subjects hada further study performed one week later.Results - The patients had lower weight,fat free mass (FFM), forced expiratoryvolume in one second (FEVy), forced vitalcapacity (FVC), and transfer factor forcarbon monoxide (TLCO) than controls.Resting respiratory rate, VE, and oxygenuptake per kilogram ofFFM (Vo2/kg FFM)were higher in patients (20 (7), 10-4 (1.4)1/min and 5 5 (0.8) mllkg FFM/min) than incontrols (13 (4), 7 0 (1-2), and 4*2 (0.5),respectively.) The error standard de-viation for replicate measures ofOCB was0.5 ml O21 VE in controls and 0-8 ml 021VE in patients with coefficients ofvariationof 24% in controls and 28% in patients.The mean OCB in patients was 2-9 (1-4) ml02/ VE and 2-1 (0.7) ml o21 VE in controls.OCB, expressed as mlimin (Vo2resp) was28-5 (11-7) in patients and 14-0 (3.6) incontrols. REE was higher in patients (125 9(14.0)% predicted) than in controls (99.0(9-4)%). The estimated non-respiratorycomponent of REE was 112-1 (14.9)% forpatients and 93-0 (10-0)% for controls.Conclusions - In clinically stable patientswith cystic fibrosis the OCB at rest is in-

creased but is not the sole explanation forincreased metabolic rate. This contrastswith the finding in COPD where the in-crease in REE is largely explained by in-creased OCB. This study also showed poorrepeatability and OCB measurementssimilar to earlier studies, which indicatesthat the technique is not suitable for lon-gitudinal studies.(Thorax 1996;51:126-131)

Keywords: cystic fibrosis, resting energy expenditure,oxygen cost of breathing.

Low body weight is common in cystic fibrosisand is related to inadequate energy intake,nutrient malabsorption, and excessive energyexpenditure. Resting energy expenditure(REE), an estimate of basal metabolic rate, is10-20% greater than in healthy subjects andmay contribute to energy imbalance.' 2At least three mechanisms - the gene defect,

the consequences of chronic pulmonary in-fection, and altered lung mechanics - couldcontribute to increased basal metabolic rate incystic fibrosis. Cultured epithelial and con-nective tissue cell lines with a cystic fibrosisgenotype have greater oxygen demands thannon-cystic fibrosis cells.34 The increased energyexpenditure in infants with cystic fibrosis maybe related to the gene defect, but there isconflicting evidence relating the raised REE togenotype and lung disease.256The cystic fibrosis genotype is unlikely to

account for all the increase of REE in patientswith established lung disease, particularly thatcharacterised by chronic bacterial infection andan intense inflammatory response associatedwith airways and parenchymal damage. Bron-chial sepsis leads to local release ofleukotrienes,free oxygen radicals, and cytokines includingtumour necrosis factor alpha (TNFoc) and theinterleukins IL-1 ,B and IL-8.7`'° CirculatingTNFoc levels in patients with cystic fibrosisand chronic pulmonary infection have beenassociated with an increased REE."

Continuous injury to the lungs leads to pro-gressive parenchymal fibrosis and airway ob-struction resulting in abnormal lung mechanicswith probable increased oxygen cost and workof breathing. This is supported by the inverserelationship between increased REE and theseverity of airways obstruction in cysticfibrosis."2 Increased oxygen consumption byrespiratory muscles occurs in chronic ob-

Section of RespiratoryMedicine, Universityof Wales College ofMedicineS C BellJ S ElbornD J Shale

Respiratory FunctionLaboratoryM J Saunders

Llandough HospitalNHS Trust, Penarth,South GlamorganCF64 2XX, UK

Correspondence to:Dr S C Bell, Heart andLung Transplant Unit,St Vincents Hospital,Victoria Street, Darlinghurst,NSW, Australia 2010.Received 2 March 1995Returned to authors9 May 1995Revised version received30 June 1995Accepted for publication3 October 1995

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Resting energy expenditure and oxygen cost of breathing in cystic fibrosis

structive pulmonary disease (COPD) and thismight account for the increase in REE.'315'6

In view of the limited published data onoxygen cost of breathing (OCB) in cystic fib-rosis, we sought to determine whether the OCBwas increased in clinically stable patients and itscontribution to the increase in REE in patientswith cystic fibrosis. We also examined the re-peatability of the measurement of OCB inpatients and healthy volunteers.

MethodsSUBJECTSTen adult patients with cystic fibrosis diagnosedin childhood (sweat levels of sodium and chlor-ide >70 mmol/l) and 10 age and sex matchedhealthy volunteers were studied. The numberof subjects studied was based on a power cal-culation of data from a study of patients withCOPD using similar methods and experimentalprotocol.16 The difference in OCB betweenpatients and controls was 2 1 ml oxygen/litreof ventilation (ml 02/1 VE) with a standarddeviation of 1-3ml 02/1 VE in patients. Theestimated numbers in each group to detect asignificant difference (p

Bell, Saunders, Elborn, Shale

Height was recorded using a stadiometer andweight using a balance beam scale (accurate to0-1 kg). Body mass index was calculated asweight/height2 (kg/m2). Fat free mass was es-timated by measurement of four skin foldsusing calipers (Holtain, UK) and the equationsof Durnin and Womersley.23

FORMULAE AND CALCULATIONSOxygen cost of breathing (ml 02/1 VE) wascalculated from data collected on each visit by:

[Dead space Vo2 - Resting VO2][Dead space VE - Resting VE].

Mean data from both study days was calculatedfor each individual for Vo2, Vco2, VE, andOCB.

Resting energy expenditure was calculatedusing the equation of Weir24:

REE (ki/day)=[(3-941 x Vo2) + (1-10 x RERx Vo2)] x 6-025

Oxygen consumption of the respiratorymuscles (Vo2resp) was estimated using theequation:

Vo2resp (ml/min) = O2cost (ml/l VE) xresting minute ventilation (VE)

The non-respiratory energy expenditure wasestimated by:

Vo2non-resp = Vo2total - Vo2resp

OCB and forced expiratory volume in onesecond (FEV,), transfer factor for carbon mon-oxide (TLCo) and residual volume to total lungcapacity ratio (RV/TLC). Repeatability ofOCBwas assessed according to the method of Blandand Altman by calculation ofthe error standarddeviation ofrepeatability and coefficient ofvari-ation (CV%).26 A value of p

Resting energy expenditure and oxygen cost of breathing in cystic fibrosis

Table 2 Mean (SD) resting respiratory gas exchange and ventilation

Cystic fibrosis Normal subjects Mean difference (95% CI)

RR (breaths/min) 20 (7) 13 (4) 7 (0 to 12)*VE (1/min) 10-4 (1-4) 7-0 (1.2) 3-8 (2 2 to 4.8)**Vo, (mlmin) 266-1 (30 8) 237-2 (44 3) 35 0 (-5-5 to 73 2)Vo2 (mi/kg FFM/min) 5-5 (0-8) 4-2 (0 5) 1-3 (0 7 to 2 0)**RER 0 77 (0 04) 0-80 (0 05) -0 03 (-0 07 to 0 02)REE (kJ/min) 5-4 (0-6) 4-8 (0 9) 0 7 (-0 1 to 1-5)REE (kJ/kg FFM/min) 0-112 (0-02) 0-085 (0 01) 0-027 (0 01 to 0 04)**

RR =respiratory rate; VE minute ventilation; Vo2= oxygen uptake; RER= respiratory exchange ratio; REE = resting energyexpenditure.* p

Bell, Saunders, Elborn, Shale

OCB compared with control subjects, thoughcomparisons are difficult because of the smallnumbers involved and differences in techniquesused.27 The values for OCB in the healthycontrols in this study are similar to those re-ported by others.1628-30 Many studies have es-timated OCB in patients with COPD. Themean OCB in patients with cystic fibrosis wasless than that reported in COPD using similarmethods, though the range of OCB is greaterin COPD (1 -0-6-1 ml 02/lVE,'6 1.7-18.5,28 and4.7-8.230). Although the pathogenesis differsbetween COPD and cystic fibrosis, there aresimilarities resulting in raised REE and poormaintenance of body mass.The lack of an inverse relationship between

OCB and pulmonary function tests in ourpatients was surprising. In two populations ofpatients with COPD spirometric parameters,resting ventilation, and OCB in the well nour-ished group were similar to the patients withcystic fibrosis in this study with an OCB of2-6 (1 1) ml 02/1 VE. In the undernourishedpatients with more severe pulmonary diseasethe oxygen cost was greater at 4-3 (10) ml02/1 VE.16 In patients with COPD negativecorrelations between FEV1 and oxygen costhave been found in some studies.30 The failureto demonstrate the expected relationship be-tween OCB and pulmonary function tests, asan index of the severity of lung disease, mayrelate to variability ofthe measurement ofOCBin the small population studied here. A furtherfactor may be the wide variation in severityof airways limitation and gas trapping in thispopulation as evidenced by the standard de-viations for FEV, and residual volume.

In many studies OCB has been estimated bystimulating ventilation with an increased deadspace, an increased inspiratory resistance, orby CO2 induced hyperventilation. 3142730 Ir-respective ofthe method, determination of oxy-gen cost assumes a linear relationship betweenVo2 and VE within the range of ventilationstudied. A linear relationship is maintained toat least 30 1/min in healthy subjects to 20 1/minin patients with COPD.'5 We therefore aimedto maintain the increase in ventilation below20 1/min, and the mean increase in our patientswas 8-0 1/min which is similar to the level instudies of patients with COPD in which OCBwas estimated. " 16 30The most important technical issue with the

measurement of the OCB is the repeatabilityof the method which limits the value of thistechnique in longitudinal studies. The errorstandard deviation for repeated measurementof OCB in both control subjects and patientswas a significant proportion of the mean OCB.This is similar to the between day repeatabilityin patients with COPD where an averagedifference of 0-9 ml 02/1 VE was reported.'6Two factors may account for such variability.Augmented ventilation causes a pro-portionately smaller increase in Vo2 than VE.Day to day differences in the AVo2 thereforehad a greater effect on the calculation ofoxygencost than AVE. Relatively small differences inmeasurement ofVo2 at rest and/or during deadspace ventilation may be magnified in the cal-

culation of the OCB. During hyperventilationthe difference between Fio2 and Feo2 is re-duced, which may result in measurement errorofgas concentration within the oxygen analyser.Despite careful preparation of subjects, thecoefficient of variation was in excess of 20%which is similar to values reported previously.Donahoe reported repeatability in patients (butnot controls) for studies performed on con-secutive days. The average day to day differencewas 0-9 ml 02/1 VE of a mean OCB of 3-4,giving an approximate CV of 27%.16 In theonly previous study of OCB in cystic fibrosisthe mean CV for controls (n = 3) was 31% andfor patients (n = 3) was 32%.27

Increased OCB reflects abnormal pulmonarymechanics and structure, and has been sug-gested as a factor in the excessive energy ex-penditure associated with chronic pulmonaryinjury in cystic fibrosis. Accepting the lim-itations imposed by the methodology used inthis study, OCB accounted for less than 50%of the additional REE. This is supported bythe weak relationship between spirometric val-ues and REE, which suggests that additionalfactors to abnormal pulmonary mechanics con-tribute to increased REE.' 12 This is in contrastto the situation in patients with COPD wherethe increase in REE was largely accountedfor by increased OCB.'6 However, we havepreviously shown that one third of the varianceof REE is explained by circulating TNFoc con-centrations and a further one third by FEV1,which suggests that the host inflammatory re-sponse may influence energy expenditure inchronically infected patients with cystic fib-rosis."

Chronic bronchial infection is associatedwith local production of cytokines, includingTNFoc, IL-1i and IL-8.910 Infusion of TNFotin healthy volunteers induces an acute increasein REE with pyrexia, proteolysis, lipolysis, andrelease of acute phase proteins.3' Immuno-reactive circulating TNFot has been detectedin clinically stable patients with cystic fibrosis,though its biological significance remains un-certain.32A further factor may be the effect of the

abnormal cystic fibrosis transmembrane con-ductance regulator (CFTR) protein on REE.In vitro studies suggest that the genetic defectmay increase oxygen consumption, and bothREE and total energy expenditure may be in-creased in infants with cystic fibrosis.45 How-ever, interpretation of these findings iscomplicated by difficulties in estimating se-verity of lung disease and excluding inter-current infection in infants. Additionally,patients homozygous for the AF508 mutationhave higher REE than heterozygotes and non-AF508 patients, but the homozygote group hasmore severe lung disease which may have anindependent influence on increased REE.2 Incontrast, a study of well nourished men withmild bronchiectasis showed that genotype didnot have a major effect on REE in patientswith cystic fibrosis.6

In clinically stable patients with cystic fibrosisthe OCB at rest is increased compared withhealthy volunteers, but the increased OCB was

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Resting energy expenditure and oxygen cost of breathing in cystic fibrosis

not the sole cause of the increased REE ob-served in our patients. The lack of repeatabilityseverely limits the use of OCB, measured bycurrent methods, in longitudinal studies ofchronic progressive lung disorders.

Dr S C Bell was supported by the Cystic Fibrosis Trust ofGreat Britain.The authors would like to thank Dr A P Smith and technical

staff for the use and assistance in the Lung Function Laboratory,and Mrs Pat Davies for typing the manuscript.

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doi: 10.1136/thx.51.2.126 1996 51: 126-131Thorax

S. C. Bell, M. J. Saunders, J. S. Elborn, et al. fibrosis.cost of breathing in patients with cystic Resting energy expenditure and oxygen

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