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Pediatric Pulmonology 45:1057–1063 (2010) Lung Function in Children With Repaired Tracheo-Oesophageal Fistula Using the Forced Oscillation Technique Joanne Harrison, MBChB, 1,2,3 * Jessica Martin, BEng, 1,4 Joe Crameri, MD, 5 Colin F. Robertson, MD, 1,2,3 and Sarath C. Ranganathan, PhD 1,2,3,6 Summary. Background: Tracheo-oesophageal fistula (TOF) and oesophageal atresia (OA) are congenital anomalies commonly associated with pulmonary complications during early childhood. This study investigated the role of the forced oscillation technique (FOT) in assessing lung function in young children with repaired TOF/OA. Methods: Forty children with repaired TOF/OA of median (range) age 8.0 (3.3–10.6) years, and 20 healthy children without TOF aged 6.1 (3.1– 10.8) years were studied. FOT measurements were attempted in all subjects and spirometry only in those 6 years and above. Resistance and reactance (both hPasL 1 ) at 6 Hz (Rrs6 and Xrs6, respectively) and 8Hz (Rrs8 and Xrs8) measured using FOT, and forced expired volume in 1sec (FEV 1 ), forcedvital capacity, functional residual capacity, total lung capacity, and residual volume (all L) obtained from spirometry or plethysmography were compared with reference values and expressed as z-scores. Results: Technically acceptable measurements of Rrs6, Rrs8, Xrs6, Xrs8, Fdep, and Fres were obtained in 37 children with TOF and 20 healthy children without TOF, respectively. Those with TOF had significantly higher mean (SD) z-scores for Rrs6 [0.99 (0.75)] versus healthy children without TOF [0.31 (0.69)] and lower mean (SD) z-scores for Xrs6 [1.04 (1.07)] versus healthy children without TOF [0.34 (0.83)]. Spirometry was successful in 24 of the 29 with TOF in whom it was attempted and all healthy children without TOF. Mean (SD) z-score for FEV 1 was significantly lower in those with TOF [0.86 (1.13)] versus healthy children without TOF [0.67 (0.54)]. z-Scores for Rrs6 and FEV 1 were significantly correlated (r ¼0.49; P ¼ 0.003). Conclusions: Children with repaired TOF have diminished lung function compared with healthy children. FOT is sensitive and correlates well with standard spirometry. It can be used to measure lung function in younger children when spirometry is difficult to perform and should be considered as an objective method for monitoring clinical progress in young children with TOF. Pediatr Pulmonol. 2010; 45:1057–1063. ß 2010 Wiley-Liss, Inc. Key words: child; respiratory impedance; respiratory function tests; tracheo-esophageal fistula. Funding source: Oesophageal Atresia Research Auxiliary of the Royal Children’s Hospital, Melbourne. INTRODUCTION Tracheo-oesophageal fistula (TOF) and oesophageal atresia (OA) are congenital anomalies which affect between 1:2,400 and 1:4,500 individuals. 1 Respiratory symptoms such as cough and wheeze, recurrent pneu- monia and cyanotic episodes are common in patients with repaired TOF/OA occurring in up to 46% of patients. 2 Additional Supporting Information may be found in the online version of this article. 1 Department of Respiratory Medicine, Royal Children’s Hospital, Mel- bourne, Victoria, Australia. 2 Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia. 3 Infection, Immunity & Environment Theme, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia. 4 Swinburne University, Melbourne, Victoria, Australia. 5 Department of Surgery, Royal Children’s Hospital, Melbourne, Mel- bourne, Victoria, Australia. 6 Brighton and Sussex Medical School, Brighton, UK. This work was presented as a poster at: The American Thoracic Society Meeting 2007, San Francisco, USA. *Correspondence to: Joanne Harrison, MBChB, Department of Respiratory Medicine, Royal Children’s Hospital Melbourne, Flemington Road, Parkville, VIC 3052, Australia. E-mail: [email protected] Received 26 November 2008; Revised 18 May 2010; Accepted 18 May 2010. DOI 10.1002/ppul.21282 Published online 1 September 2010 in Wiley Online Library (wileyonlinelibrary.com). ß 2010 Wiley-Liss, Inc.

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Page 1: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

Pediatric Pulmonology 45:1057–1063 (2010)

Lung Function in Children With RepairedTracheo-Oesophageal Fistula Using the Forced

Oscillation Technique

Joanne Harrison, MBChB,1,2,3* Jessica Martin, BEng,1,4 Joe Crameri, MD,5

Colin F. Robertson, MD,1,2,3 and Sarath C. Ranganathan, PhD1,2,3,6

Summary. Background: Tracheo-oesophageal fistula (TOF) and oesophageal atresia (OA) are

congenital anomalies commonly associated with pulmonary complications during early childhood.

This study investigated the role of the forced oscillation technique (FOT) in assessing lung function

in young children with repaired TOF/OA. Methods: Forty children with repaired TOF/OA of median

(range) age 8.0 (3.3–10.6) years, and 20 healthy children without TOF aged 6.1 (3.1–10.8) years

were studied. FOT measurements were attempted in all subjects and spirometry only in those

6 years and above. Resistance and reactance (both hPasL�1) at 6 Hz (Rrs6 and Xrs6, respectively)

and 8 Hz (Rrs8 and Xrs8) measured using FOT, and forced expired volume in 1 sec (FEV1),

forced vital capacity, functional residual capacity, total lung capacity, and residual volume (all L)

obtained from spirometry or plethysmography were compared with reference values and

expressed as z-scores. Results: Technically acceptable measurements of Rrs6, Rrs8, Xrs6,

Xrs8, Fdep, and Fres were obtained in 37 children with TOF and 20 healthy children

without TOF, respectively. Those with TOF had significantly higher mean (SD) z-scores for Rrs6

[0.99 (0.75)] versus healthy children without TOF [0.31 (0.69)] and lower mean (SD) z-scores for

Xrs6 [�1.04 (1.07)] versus healthychildren without TOF [�0.34 (0.83)]. Spirometry was successful

in 24 of the 29 with TOF in whom it was attempted and all healthy children without TOF. Mean (SD)

z-score for FEV1 was significantly lower in those with TOF [�0.86 (1.13)] versus healthy children

without TOF [0.67 (0.54)]. z-Scores for Rrs6 and FEV1 were significantly correlated (r¼�0.49;

P¼0.003). Conclusions: Children with repaired TOF have diminished lung function compared with

healthy children. FOT is sensitive and correlates well with standard spirometry. It can be used to

measure lung function in younger children when spirometry is difficult to perform and should be

considered as an objective method for monitoring clinical progress in young children with TOF.

Pediatr Pulmonol. 2010; 45:1057–1063. � 2010 Wiley-Liss, Inc.

Key words: child; respiratory impedance; respiratory function tests; tracheo-esophageal

fistula.

Funding source: Oesophageal Atresia Research Auxiliary of the Royal Children’s

Hospital, Melbourne.

INTRODUCTION

Tracheo-oesophageal fistula (TOF) and oesophagealatresia (OA) are congenital anomalies which affect

between 1:2,400 and 1:4,500 individuals.1 Respiratorysymptoms such as cough and wheeze, recurrent pneu-monia and cyanotic episodes are common in patients withrepaired TOF/OA occurring in up to 46% of patients.2

Additional Supporting Information may be found in the online version of

this article.

1Department of Respiratory Medicine, Royal Children’s Hospital, Mel-

bourne, Victoria, Australia.

2Department of Paediatrics, University of Melbourne, Melbourne, Victoria,

Australia.

3Infection, Immunity & Environment Theme, Murdoch Children’s

Research Institute, Melbourne, Victoria, Australia.

4Swinburne University, Melbourne, Victoria, Australia.

5Department of Surgery, Royal Children’s Hospital, Melbourne, Mel-

bourne, Victoria, Australia.

6Brighton and Sussex Medical School, Brighton, UK.

This work was presented as a poster at: The American Thoracic Society

Meeting 2007, San Francisco, USA.

*Correspondence to: Joanne Harrison, MBChB, Department of Respiratory

Medicine, Royal Children’s Hospital Melbourne, Flemington Road,

Parkville, VIC 3052, Australia. E-mail: [email protected]

Received 26 November 2008; Revised 18 May 2010; Accepted 18 May

2010.

DOI 10.1002/ppul.21282

Published online 1 September 2010 in Wiley Online Library

(wileyonlinelibrary.com).

� 2010 Wiley-Liss, Inc.

Page 2: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

Such symptoms occur most commonly in the first 3 yearsof life and improve with time. However, a significantproportion of older children and adults continue to reportrespiratory symptoms3–5 and have variable abnormalitieson pulmonary function tests.6,7

Most studies of lung function in children with TOF/OAhave demonstrated mean forced expired volume in 1 sec(FEV1) and forced vital capacity (FVC) within the normalpopulation range8 although some studies suggest that theyare at the lower end of the normal range.9–11 Infant lungfunction studies have been performed in children withTOF/OA, but lung function at this age correlates poorlywith subsequent conventional lung function performed inthe same children when they reach school age.9 Moreover,infant lung function usually requires sedation of thesubject which may add extra risk in children with trachealairway obstruction due to tracheomalacia. Althoughrespiratory function measurements are considered impor-tant in the diagnosis and monitoring of respiratory disease,no studies have been published to date in pre-schoolchildren with repaired TOF/OA in whom symptoms andcomplications are more likely to be encountered than inolder subjects. Reliable and reproducible spirometry maybe difficult to obtain in pre-school children. In contrast,the forced oscillation technique (FOT) requires minimalpatient cooperation and is ideally suited to subjects unableto perform voluntary forced expirations. The FOT hasbeen used in research studies for several decades. Morerecently its use in clinical practice has been advocated12

and guidelines and recommendations published.13 Thetechnique allows measurement of the respiratory inputimpedance (Zrs) under tidal breathing conditions. Fromthis, resistance (Rrs) and reactance (Xrs) of the respiratorysystem can be obtained.

The aims of this study were to assess lung function inyoung children with repaired TOF/OA using the FOT andto determine the association between measurements madeby FOT, spirometry, and clinical features frequentlyencountered in this patient population including need forfundoplication. We hypothesized that younger children,children with more frequent respiratory symptoms, andthose with evidence of more severe gastro-oesophagealreflux disease (necessitating fundoplication) would bemore likely to demonstrate abnormalities of lung function.

METHODS

TOF/OA Subjects

Children aged between 3 and 10 years, with previouslyrepaired TOF were identified from a hospital database.Families were contacted by letter and invited to participate inthe study. A questionnaire was completed for eachchild seeking details about respiratory symptoms suchas cough, wheeze, dyspnea; gastrointestinal symptoms suchas dysphagia, choking, and symptoms of gastro-oesophageal

reflux; drug treatment and details of surgical proceduresincluding oesophageal dilatations and fundoplication. Eachchild’s case notes were reviewed to confirm details ofsurgical procedures and investigations undertaken.

Healthy Children Without TOF

Advertisements were placed within public areas of thehospital and in the staff bulletin seeking healthy childrenwithout TOF from the community aged 3–10 years toparticipate in order to provide a comparison populationwhen using previously published reference data.14

Respiratory health was assessed using an administeredquestionnaire and children were excluded if they had ahistory of doctor diagnosed or parent-reported respiratorydisease, including asthma, recurrent croup, pneumonia,recurrent bronchitis, or if they had ever had an abnormalchest X-ray. Children were also excluded if they were bornweighing <2.5 kg, required oxygen for more than 24 hr asa newborn, or were admitted to hospital for bronchiolitis inthe first year of life. Other reasons for exclusion includedheight and weight >97th, or <3rd percentile; if they hada systemic illness known to influence the respiratorysystem, or congenital abnormalities of the respiratorysystem or chest wall abnormalities.

Height and weight were measured in all children anda clinical examination of the respiratory system wasperformed. The FOT was then attempted in each child.Children from 6 to 10 years were then asked to attemptspirometry and plethysmography. One healthy childwithout TOF aged 5 years also attempted spirometry andplethysmography.

Measurements of Respiratory Function

Children were studied when they were well and free ofrecent respiratory tract infections.

Impedance

Methods have been described previously.14 Briefly,children were tested sitting in an upright position withtheir head in a neutral position. They were connected tothe oscillation device via a mouthpiece incorporating abacterial filter (SureGard: Bird Healthcare, Melbourne,Australia) and instructed to breath normally while wearinga nose-clip. The child’s cheeks and lower jaw were firmlysupported by a staff member during all measurements.

Measurements of Zrs were obtained using a commer-cially available device (I2M, Chess Medical, Ghent,Belgium) and performed according to American ThoracicSociety/European Respiratory Society guidelines.13 Theequipment was calibrated daily using a known resistance.A minimum of 5 and maximum of 12 technicallyacceptable measurements were obtained. The child wasallowed to disconnect from the equipment betweenmeasurements if they wished. Individual measurements

Pediatric Pulmonology

1058 Harrison et al.

Page 3: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

were excluded if there was a leak due to incompleteseal around the mouthpiece, if the child moved theirmouth (chewing), swallowed, closed their glottis ortalked. Individual Zrs measurements were examined posthoc for evidence of inadequate measurement quality. Acoherence function �0.95 was considered acceptable andmeasurements were excluded if three or more individualfrequencies had a coherence of <0.95.15,16 The followingZrs variables were reported: resistance and reactance at6 and 8 Hz (Rrs6, Rrs8, Xrs6, and Xrs8, respectively). Theaverage Rrs (Rrs4–24), and its frequency dependence(Fdep) were calculated as previously described.14

Resonant frequency (Fres) was defined as the frequencyat which reactance crossed zero.

Spirometry and Lung Volumes

FEV1 and FVC were measured (MasterScreen BodyJaeger, Hoechberg, Germany). Children were studiedwhile sitting upright, wearing a nose-clip. A minimum ofthree technically satisfactory recordings were madeand analyzed according to American Thoracic Society/European Respiratory Society criteria.17

Measurements of total lung capacity (TLC), functionalresidual capacity (FRC), and residual volume (RV)were made with the child seated within a whole bodyplethysmograph (MasterScreen Body Jaeger).

All measurements were compared to predictive valuesbased on height and sex and expressed as z-scores.18,19

Statistical Analysis

Data were expressed as mean (standard deviation) ormedian (25–75th centiles) for normal and non-normaldistributions, respectively.

Lung function variables obtained using FOT wereconverted to z-scores using prediction equations incorpo-rating a co-efficient for height.13 Values above 1.64 z-scores(95th percentile) or below �1.64 z-scores (5th percentile)were considered to be unusually high/low. As predictionequations are not available for the variable Fres, a multiplelinear regression model was fitted for this variableincorporating co-variates for height, age, gender, clinical

status, and exposure to parental smoking. Thevariable Fdepis not related to height or other anthropometric data, butupper and lower limits of normal have been published forhealthy children up to a height of 128 cm.13 Fisher’s exacttest was performed to analyze the proportions of children(of this height) in each group with abnormal results for thevariable Fdep.

T-tests were used to compare groups where results werenormally distributed. Where results were not normallydistributed (e.g., Fdep) the Mann–Whitney rank sumtest was used. Pearson’s correlation was used to compareFEV1 and FOT results. Multiple linear regression modelswere fitted for the z-scores of the FOT variables incorporat-ing co-variates for age and disease group to assess theassociation of these variables with age. The Sigma Stat(Systat Software Inc. San Jose, CA) statistical package wasused. Significance was accepted at the 0.05 level.

The study received ethical approval from the RoyalChildren’s Hospital, Melbourne Ethics in HumanResearch Committee. Parents gave written consent fortheir children to participate in this study.

RESULTS

In total, the parents of 57 children with repaired TOF/OAwere approached of whom 40 were recruited. Reasonsfor failure to recruit included incorrect address (n¼ 9),parental refusal (n¼ 4), or too far from lung functionlaboratory (n¼ 2). Twenty-two healthy children withoutTOF were recruited of whom two were excluded; onebecause of admission to hospital for bronchiolitis as ababy, and the other because of a history of recurrent croup.

Thirty-seven children had TOF type 3B by Vogtclassification (distal TOF with proximal OA),20 onehad type 3C (proximal TOF and distal TOF) and twohad type 4 (H-type TOF). Of the children with repairedTOF 23 (58%) had required at least one oesophagealdilatation procedure, and for these children the median(range) number of dilatations was 2.1–11 Fifteen (38%)children had undergone fundoplication. The backgrounddetails of the study children with TOF/OA and healthychildren without TOF are shown in Table 1.

Pediatric Pulmonology

TABLE 1— Demographics

TOF/OA Healthy children without TOF

Difference TOF�healthy children

without TOF (95% CI)

N 40 20

Male, n (%) 25 (62.5) 6 (30) 32.5% (5.7, 59)*

Mean age, years (SD) 7.6 (2.2) 6.4 (2.3) 1.2 (�0.03, 2.22)

Mean height, cm (SD) 124.6 (13.7) 118.3 (13.2) 6.3 (�1.2,13.8)

Mean weight, kg (SD) 26.1 (7.6) 23.0 (6.6) 3.1 (�0.9, 7.1)

Family history atopy, n (%) 24 (60) 11 (55) 5 (�21.5, 31)

Smoker at home, n (%) 9 (22.5) 1 (5) 17.5 (�2.5, 37.5)

SD, standard deviation; n, number; CI, confidence interval.

*P< 0.05.

Lung Function in Children With Tracheo-Oesophageal Fistula 1059

Page 4: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

Of the children with repaired TOF/OA, 5 (12.5%) hadongoing stridor and 12 (30%) ongoing wheeze. Cough wasreported in 33 (82.5%) children with TOF/OA of whom24 (60%) had a ‘‘TOF-cough.’’ Fifteen (37.5%) childrenwith TOF/OA were reported to be short of breath (SOB)and in 14 (35%) of these the breathlessness was limited toexertion. Eleven (27.5%) children with TOF/OA reportedrecurrent chest infections in the first 2 years of life, whilst14 (35%) children with TOF/OA had been re-admitted tohospital with lower respiratory tract infections.

Lung function was measured at a median (range)age 8.0 (3.3–10.6) years in the TOF group and 6.1 (3.1–10.8) years in the group of healthy children without TOF.

Technically acceptable measurements of impedancemeasured by FOT were obtained in 37 children with TOFand 20 healthy children without TOF, respectively. Of the40 children with TOF, 29 were aged 6 years and above andspirometry was successful in 24. Eleven healthy childrenwithout TOF were old enough to attempt spirometry andall completed it successfully.

Table 2 shows the results for all parameters of lungfunction. Average resistance and resistance at 6 and 8 Hzwere significantly increased in those with repaired TOF/OA compared with healthy children without TOF.Reactance at 6 Hz was significantly lower than healthychildren without TOF (�1.04 vs. �0.34; P¼ 0.015).

Although reactance at 8 Hz and Fdep were lower in thosewith TOF/OA, these differences were not statisticallysignificant. Fres was higher in the TOF/OA group butagain this was not statistically significant (Table 2). Thevariable Fres was examined using a multiple linearregression model. A history of repaired TOF was notassociated with a difference in Fres (b coefficient¼ 14.96,P¼ 0.68). Of the 37 children with repaired TOF/OA, only1 had a value for Fdep that was outside the normal rangeand none of the 20 healthy children without TOF had anabnormal Fdep (P¼ 1.0).

Of the children with TOF/OA, 6 (16.2%) had a z-scorefor Rrs6 above 1.64 (i.e., >95th percentile) and in 4(10.8%) children with TOF/OA it was above 1.96 (i.e.,>97.5th percentile). In contrast, none of the healthychildren without TOF had z-scores above 1.64. A similarresult was seen for Rrs8 with 6 (16.2%) TOF/OA childrenhaving a z-score above 1.64 and 3 (8.1%) having a z-scoreabove 1.96. Again no healthy children without TOF hadz-scores above 1.64.

Similar differences in FOT results between thosewith TOF/OA (n¼ 23) and healthy children withoutTOF (n¼ 15) were identified when the analysis wasrestricted only to younger children (median age 5.6 years,range 3.1–8.8 years) with a height of 128 cm or less(Table 3).

Pediatric Pulmonology

TABLE 2— Lung Function in Those With TOF/OA and Healthy Children Without TOF

TOF Healthy children without TOF Difference1

Mean value (SD)

Mean

z-score (SD) Mean value (SD)

Mean

z-score (SD)

Mean z-score TOF–healthy

children without TOF (95% CI)

FOT

n 37 37 20 20

Rrs4–24 6.78 (1.70) 1.29 (0.82) 6.62 (1.6) 0.45 (0.67) 0.84 (0.41, 1.27)***

Rrs6 7.42 (2.22) 0.99 (0.75) 7.36 (2.04) 0.31 (0.69) 0.68 (0.27, 1.09)**

Rrs8 7.28 (2.09) 0.93 (0.76) 7.03 (1.97) 0.14 (0.66) 0.79 (0.39, 1.20)***

Xrs6 �2.67 (1.42) �1.04 (1.07) �2.64 (1.17) �0.34 (0.83) �0.69 (�1.24, �0.14)*

Xrs8 �1.95 (1.25) �0.33 (1.04) �1.98 (1.17) 0.09 (0.92) �0.42 (�0.98, 0.13)

Fdep median

(25%; 75%)

�0.05 (�0.08; �0.02) �0.04 (�0.08; �0.02) �0.055 (�0.41, 0.4)

Fres (Hz) 26.98 (8.02) 23.53(6.29) 3.5 (�0.9, 7.8)

PFT

n 24 24 11 11

FEV1 (L) 1.47 (0.33) �0.86 (1.13) 1.64 (0.37) 0.67 (0.54) �1.53 (�2.54, �0.89)***

FVC (L) 1.60 (0.37) �1.61 (1.33) 1.79 (0.45) 0.29 (0.58) �1.90 (�2.75, �1.06)***

TLC (L) 2.49 (0.53) �0.55 (1.39) 2.55 (0.47) 0.28 (0.95) �0.83 (�1.81, 0.15)

FRC (L) 1.34 (0.31) �0.26 (1.08) 1.34 (0.33) 0.11 (1.16) �0.37 (�1.19, 0.45)

RV (L) 0.83 (0.27) 0.24 (1.27) 0.70 (0.12) �0.28 (0.61) 0.52 (�0.35, 1.38)

TOF, tracheo-oesophageal fistula; FOT, forced oscillation technique; Rrs 4–24, average Rrs between 4 and 24 Hz; Rrs6, Rrs8 respiratory resistance at

6 and 8 Hz; Xrs6, Xrs8 respiratory reactance at 6 and 8 Hz; Fdep, frequency dependence of Rrs4–24; Fres, resonant frequency; PFT, standard

pulmonary function tests; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; TLC, total lung capacity; FRC, functional residual

capacity; RV, residual volume.

Respiratory impedance data expressed in hPa/s/L and lung volumes and flows in L.1Reported differences are in mean values for the variables Fdep and Fres, and differences in mean z-scores for the other variables.

*P< 0.05.

**P< 0.01.

***P< 0.001.

1060 Harrison et al.

Page 5: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

Figure 1 shows the association between FEV1 obtainedby spirometry and resistance at 6 Hz obtained by the FOT.Parameters were significantly correlated (r¼�0.49;P¼ 0.003) indicating that increased Rrs was associatedwith lower FEV1.

In those with TOF/OA, z-scores for resistance tended toincrease with age and z-scores for FEV1 to decrease withage. This is shown graphically in Figure 2 for resistance at6 Hz and in Figure 3 for FEV1. Multiple linear regressionwas used to further analyze the relationship betweenresistance at 6 Hz and age. The resulting regressionequation which expresses the change in z-score for Rrs6with age and disease status (TOF¼ 1 if subject hadrepaired TOF and TOF¼ 0 if subject was healthy control)is

z-Score Rrs6 ¼ �0:48 þ ð0:12 � ageÞ þ ð0:5 � TOFsÞ

Children with repaired TOF/OA who had undergonefundoplication had worse lung function than the groupwho did not require fundoplication (E-Table 1 in OLS).Reactance at 6 and 8 Hz was significantly lower inthe group requiring fundoplication (�1.44 vs. �0.62;P¼ 0.01 and �0.56 vs. 0.00; P¼ 0.048, respectively).Resistance at 6 and 8 Hz was also higher in the grouprequiring fundoplication, but this did not reach statisticalsignificance (P¼ 0.23 and 0.27, respectively).

No association was identified between the presence ofany individual symptom such as cough, wheeze, or stridorand any FOT variable or with FEV1 z-score. There was nosignificant difference between mean z-scores for any FOTvariable between children who required oesophagealdilatation and those who did not.

Pediatric Pulmonology

TABLE 3— Lung Function in Children With TOF/OA and Healthy Children Without TOF of Height 128 cm or Less

TOF Control Difference1

Mean value (SD) Mean z-score (SD) Mean value (SD) Mean z-score (SD)

Mean z-score TOF–healthy

children without TOF (95% CI)

FOT n 20 20 15 15

Rrs4–24 7.80 (1.27) 0.98 (0.80) 7.19 (1.43) 0.27 (0.67) 0.71 (0.19, 1.23)**

Rrs6 8.69 (2.00) 0.78 (0.80) 8.03 (1.90) 0.16 (0.72) 0.62 (0.09, 1.15)*

Rrs8 8.55 (1.73) 0.78 (0.81) 7.68 (1.82) 0.00 (0.70) 0.78 (0.25, 1.31)**

Xrs6 �3.18 (1.67) �0.60 (1.24) �2.97 (1.16) �0.14 (0.84) �0.46 (�1.22, 0.29)

Xrs8 �2.43 (1.48) �0.21 (1.32) �2.27 (1.21) 0.17 (1.02) �0.38 (�1.22, 0.46)

Fdep �0.08 (0.09) �0.07 (0.08) �0.01 (�0.06, 0.05)

Fres 31.02 (5.18) 25.78 (5.53) 5.24 (1.23, 9.24)*

1Reported differences are in mean values for the variables Fdep and Fres, and differences in mean z-scores for the other variables.

*P< 0.05.

**P< 0.01.

Fig. 1. Association of z-scores of resistance at 6 Hz measured by

FOT and FEV1 measured by spirometry (r¼�0.49; P¼ 0.003).

Fig. 2. Relationship between age and Rrs6 plotted as individual

mean z-scores (r¼ 0.3, P¼ 0.06 for cases). Predicted, upper and

lower limits of normal (�1.96 z-scores) derived from a healthy

reference population are plotted as horizontal lines.

Lung Function in Children With Tracheo-Oesophageal Fistula 1061

Page 6: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

DISCUSSION

Children with repaired TOF/OA frequently haverespiratory complications and this is confirmed by ourstudy which identified a variety of respiratory symptoms,particularly cough, in a large percentage of these patients.Several mechanisms may contribute to the respiratorycomplications including tracheobronchomalacia andrecurrent aspiration of refluxed gastric or oesophagealcontents.

Previous studies of lung function in subjects withrepaired TOF have involved adults or small numbers ofchildren. To our knowledge, this is one of the largeststudies of lung function in children with TOF/OA and thefirst using the FOT. One of the benefits of this technique isthat it allows children to be tested from as young as 3 years.This was confirmed in our study in which 5 out of 6 (83%)3-year olds, and 7 out of 8 (88%) 4-year olds successfullyperformed FOT. Our data show that the FOT correlateswell with spirometry in school age children with repairedTOF. However, FOT and spirometry measure differentaspects of respiratory function so this correlation maysimply reflect that those patients with reduction in onemeasure of lung function have more significant respiratorydisease which results in abnormalities in all aspects ofrespiratory function. Similar to other studies of lungfunction in children, our data show that the majority ofyoung children with TOF/OA have resistance values at theupper end of the normal range, with 10% being above the97.5th percentile. Although symptoms are most prevalentin the pre-school years and become less commonwith time, no studies have assessed lung function in pre-school children with repaired TOF/OA. Thus, FOT mayprovide an objective method of monitoring and assessing

respiratory complications in this group of patients duringtheir pre-school years.

Children with repaired TOF/OAwho have also requiredfundoplication have diminished lung function comparedto those who did not require fundoplication. There is aclear link between severity of gastro-oesophageal refluxand the persistence of respiratory symptoms,4 so it isunsurprising that those children with the most significantgastro-oesophageal reflux, that is, those that requirefundoplication, should have the worst lung function, butfundoplication itself may impact further on lung function.Closer monitoring of the lung function outcomes of suchsurgery in children with TOF is indicated and may bepossible using techniques such as FOT.

No clear relationship existed between any particularsymptom and lung function variables measured by theFOT. Diminished lung function may reflect developmen-tal changes to the respiratory system as a consequence ofearly pulmonary insults due to impaired mucociliaryclearance and early surgical repair, rather than currentmorbidity. However, z-scores for resistance and FEV1

were worse in older children. This tendency for lungfunction to be lower in older children during the firstdecade of life suggest that the abnormalities in lungfunction result from the cumulative effects of multipleinsults to the developing lungs. As these insults aremultifactorial, including recurrent lower respiratory tractinfections, aspiration of foodstuffs, and abnormalities ofthe airways, it is not surprising that no one symptom can beclearly shown to be associated with abnormalities of lungfunction as measured by FOT.

Our study included children up to the age of 10 years asthis allowed us to enrol sufficient numbers of children toallow comparison between measurements obtained usingFOT and spirometry. The reference data chosen tocalculate z-scores for the FOT results only includeschildren up to 128 cm in height.13 Although the extra-polation of reference data has the potential to lead toerroneous results we feel that this is not true of our data asthe differences in FOT results persisted when analysis wasrestricted to a subgroup of children <129 cm in height(Table 3). In addition, we included healthy childrenwithout TOF >128 cm and found z-scores for all FOTvariables to be within the normal ranges based onextrapolation of the reference data. One could also arguethat the reference equations chosen to calculate z-scoresfor the spirometry and plethysmography data are not themost appropriate for our population given that the meanz-scores for the healthy children without TOF were notzero for each variable. However, these reference equationswere chosen because they include children as young as6 years of age and because they are taken from a Caucasianpopulation similar to ours. Any differences betweenour population of healthy children without TOF and thepopulations used to produce reference equations for the

Pediatric Pulmonology

Fig. 3. Relationship between age and FEV1 (r¼�0.42; P¼0.04

for cases). Predicted, upper, and lower limits of normal (�1.96

z-scores) derived from a healthy reference population are plotted

as horizontal lines.

1062 Harrison et al.

Page 7: Lung function in children with repaired tracheo-oesophageal fistula using the forced oscillation technique

different lung function variables would apply equally toour patients as they are drawn from a similar population asthe healthy children without TOF. Children with TOFwere more likely to be female than the TOF group andalthough they were slightly younger, lighter, and smallerto those with TOF this was not statistically different. Weonly recruited a small number of children without TOFwhich could be considered a limitation but we do notbelieve this significantly alters our findings as lungfunction in those with TOF was significantly worse thanboth the reference populations and the healthy childrenwithout TOF.

Whilst it may have been of interest to assessbronchodilator response in the children with TOF incomparison to the healthy children without TOF, wedecided against this assessment. Children with TOF have ahigh incidence of tracheomalacia which can causewheezing. Bronchodilators, however, may relax trachealsmooth-muscle tone with resultant worsening of airwayobstruction in such patients.

Further prospective longitudinal studies are indicated inthis group of children. These would allow progress to bemonitored from the time of surgical repair, for example,using infant lung function studies, through the so-called‘‘silent’’ pre-school years in order to assess whether theFOT alters in association with development of respiratorycomplications.

Our results show that children with repaired TOF/OAhave significant ongoing respiratory morbidity anddiminished lung function compared with healthy childrenwithout TOF identifying a need for continued andobjective assessment of respiratory status. They alsoconfirm that FOT is sensitive and feasible in this group,and correlates well with standard methods of measuringlung function. Thus, FOT could be used routinely tomonitor progress in young children unable to performspirometry. Further studies are therefore indicated toassess the ability of the FOT to monitor lung functionover time in those with repaired TOF/OA, its relationshipto respiratory complications and its role in the clinicalmanagement of young children with this condition.

ACKNOWLEDGMENTS

The authors wish to thank the children and families whoparticipated in this study and the thoracic surgeonsinvolved in their care. We would also like to thank MsAlisa Hawley for providing information and help withthe TOF/OA database. We also wish to acknowledge theOesophageal Atresia Research Auxiliary of the RoyalChildren’s Hospital, Melbourne, who provided fundingin part towards this study. This funding body had noinvolvement in the design; collection, analysis, andinterpretation of data; in the writing of the report, orsubmission of the paper for publication.

REFERENCES

1. Harmon CM, Coran AG. Congenital anomalies of the

esophagus. In: O’Neill JA, Jr., Rowe MI, Grosfeld JL, editors.

Pediatric surgery. St. Louis, MO: Mosby; 1998. pp. 941–

967.

2. Delius RE, Wheatley MJ, Coran AG. Etiology and manage-

ment of respiratory complications after repair of esophageal

atresia and tracheoesophageal fistula. Surgery 1992;112:527–

532.

3. Dudley NE, Phelan PD. Respiratory complications in long-term

survivors of oesophageal atresia. Arch Dis Child 1976;51:279–

282.

4. Chetcuti P, Phelan PD. Respiratory morbidity after repair of

oesophageal atresia and tracheo-oesophageal fistula. Arch Dis

Child 1993;68:167–170.

5. Malmstrom K, Lohi J, Lindahl H, et al. Longitudinal follow-

up of bronchial inflammation, respiratory symptoms and

pulmonary function in adolescents after repair of esophageal

atresia with tracheoesophageal fistula. J Pediatr 2008;153:396–

401.

6. Chetcuti P, Myers NA, Phelan PD, et al. Adults who survived

repair of congenital oesophageal atresia and tracheo-oesophageal

fistula. BMJ 1988;297:344–346.

7. Biller JA, Allen JL, Schuster SR, et al. Long-term evaluation of

esophageal and pulmonary function in patients with repaired

esophageal atresia and tracheoesophageal fistula. Dig Dis Sci

1987;32:985–990.

8. Robertson DF, Mobaireek K, Davis GM, et al. Late pulmonary

function following repair of tracheoesophageal fistula or

esophageal atresia. Pediatr Pulmonol 1995;20:21–26.

9. Agrawal L, Beardsmore CS, MacFadyen UM. Respiratory

function in childhood following repair of oesophageal atresia

and tracheoesophageal fistula. Arch Dis Child 1999;81:404–408.

10. Van Gysel D, De Boeck K, Lerut T, et al. Pulmonary status during

childhood after corrected esophageal atresia. Eur Respir J

1992;15:103s.

11. Couriel JM, Hibbert M, Olinsky A, et al. Long term pulmonary

consequences of oesophageal atresia with tracheo-oesophageal

fistula. Acta Paediatr Scand 1982;71:973–978.

12. Oostveen E, MacLeod D, Lorino H, et al. The forced oscillation

technique in clinical practice: methodology, recommenda-

tions and future developments. Eur Respir J 2003;22:1026–

1041.

13. Beydon N, Davis SD, Lombardi E, et al. American Thoracic

Society/European Respiratory Society Working Group on infant

and young children pulmonary function testing. Am J Respir Crit

Care Med 2007;175:1304–1345.

14. Hall GL, Sly PD, Fukushima T, et al. Respiratory function in

healthy young children using forced oscillations. Thorax 2007;62:

521–526.

15. Landser FJ, Nagles J, Demeedts M, et al. A new method to

determine frequency characteristics of the respiratory system.

J Appl Physiol 1976;41:101–106.

16. Frey U. Forced oscillation technique in infants and young

children. Paediatr Respir Rev 2005;6:246–254.

17. Miller MR, Hankinson J, Brusaco V, et al. Standardisation of

spirometry. Eur Respir J 2005;26:319–338.

18. Rosenthal M, Bain SH, Cramer D, et al. Lung function in white

children aged 4 to 19 years: I—spirometry. Thorax 1993;48:794–

802.

19. Rosenthal M, Cramer D, Bain SH, et al. Lung function in white

children aged 4 to 19 years: II—single breath analysis and

plethysmography. Thorax 1993;48:803–808.

20. Vogt EC. Congenital atresia of the esophagus. Am J Roentgenol

1929;22:463–465.

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