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Abstract
Background The influence of lobectomy on pulmonary function in children was still controversial. A systematic review and meta-analysis were essential to explore whether pulmonary function was impaired after lobectomy in children.
Methods PubMed, Embase and Web of Science were searched from 1 January 1946 to 1 July 2022. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and total lung capacity were extracted from the studies as the primary analysis indicators. Subgroup analyses were performed between the congenital lung malformation (CLM) group and other diseases group, early surgery and late surgery group (1 year old as the dividing line).
Results A total of 5302 articles were identified through the search strategy; finally, 10 studies met the inclusion criteria. Through the meta-analysis, we found a mild obstructive ventilatory disorder in children who underwent lobectomy. However, a normal pulmonary function could be found in young children with CLM who underwent lobectomy, and the time of operation had no significant influence on their pulmonary function.
Conclusions The overall result of pulmonary function after lobectomy in children was good. Surgeons may not need to be excessively concerned about the possibility of lung surgery affecting pulmonary function in children, particularly in patients with CLM.
PROSPERO registration number CRD42022342243.
- Adolescent Health
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Impaired pulmonary function is the greatest concern when performing lung surgery in children. Currently, clinical studies on this topic have small sample sizes and inconsistent viewpoints.
WHAT THIS STUDY ADDS
Postoperative lung function in children appears to be good following lobectomy. There have however been few studies.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Prospective studies assessing pulmonary function following lobectomy are needed.
Introduction
For children just beginning their lives, the choice of any operation should be very cautious. The main causes of performing lung surgery on children or infants included severe pneumonia, lung abscess, malignant tumour, non-cystic fibrosis bronchiectasis and congenital lung malformation (CLM).1 Among them, the proportion of CLM increased gradually, while the proportion of infections decreased by year.2 At present, the obstacle preventing paediatric surgeons from performing lung surgery on young children was no longer solely attributed to the risks and difficulties inherent in the procedure, rather the primary concern now centres on whether the operation will have long-term side effects on pulmonary function in children, especially for children diagnosed with benign diseases.
Pulmonary function tests (PFTs) were simple, non-invasive, widely used methods for examining pulmonary function. Early intervention could achieve better therapeutic results if abnormal lung function can be detected. Fortunately, some scholars have reported the results of pulmonary function after lung surgery in children. Some studies showed perfect results of postoperative pulmonary function in children,3 4 while some scholars have voiced different opinions.5 6 These studies generally have the problem of small sample sizes, inconsistent results and cannot be generalised to all ethnic groups; thus, current evidence was insufficient to guide surgeons in making correct decisions. Therefore, a meta-analysis that summarised the current clinical research findings and provided compelling evidence is crucial.
In this study, we conducted a meta-analysis on postoperative pulmonary function in children who underwent lobectomy, and performed several subgroup analyses, which could help doctors make better medical advice.
Methods
This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement 2020.7 This review was registered in the International Prospective Register of Systematic Reviews (CRD42022342243). The technical standard on interpretive strategies for PFTs was based on the European Respiratory Society (ERS)/American Thoracic Society (ATS) 2021.8
Inclusion criteria
The population of the included studies should be children who underwent lung surgery at the age below 14 years old and at least one PFT was performed on the patients 1 year post-surgery. The research population included in the articles must not be duplicated. The data on PFTs should be provided in the form of mean (SD) and the type of the included studies should be original research.
Exclusion criteria
Studies involving patients over 14 years old who had lung surgery or underwent multiple lung surgeries, as well as patients who received chemotherapy or treatment that affects lung function before the surgery, were excluded. Studies that did not perform PFTs on patients at least 1 year after surgery, as well as PFTs that did not use spirometry but whole-body plethysmograph, were excluded. Studies with a sample size of less than 10 were considered too small and were excluded. Review and case reports were also excluded.
Search strategy
Comprehensive searches of databases including PubMed, Embase and Web of Science were performed for all relevant studies published from 1 January 1946 to 1 July 2022, and all languages were included. The search strategy was designed and conducted by an experienced scholar. The major search terms in the title/abstract field were ‘Pulmonary function test’ AND ‘child’ AND ‘lung surgery’. The detailed search strategy for this article was demonstrated in online supplemental figure 1.
Supplemental material
Study selection
After searching the articles, online reference management software (EndNote, Clarivate Analytics, V.X9) was used to automatically remove articles with the same title and author first. Then, two experienced reviewers (CL and JL) independently screened the titles and abstracts for potential eligibility. Full-text versions of the included abstracts were retrieved and screened. Disagreements were harmonised by a consensus, and a third reviewer (MY) would participate if not possible.
Data extraction
If the article contained multiple pulmonary function data, only the one with the longest time from the operation was included. The following information for each study was extracted by a reviewer (CL): article characteristics (authors, publication year, country of origin, sample size and study design); participant characteristics (baseline disease, surgical method, surgical age and follow-up time); characteristics of pulmonary function (forced expiratory volume in 1 s (FEV1) (percentage predicted, abbreviated as %), forced vital capacity (FVC%), FEV1/FVC, total lung capacity (TLC%), functional residual capacity %, residual volume %, diffusion capacity of the lungs for carbon monoxide (DLCO%) and forced expiratory flow 25–75% (FEF25–75). Another reviewer (DL) re-examined the data, ensuring the data’s correctness.
Quality score, risk of bias assessment and certainty of evidence
Quality assessment of the included studies was performed using the Newcastle‒Ottawa Scale (NOS).9 The NOS was used to assess the quality of non-randomised studies, which ranged between 0 and 9, with 9 being the highest quality. This tool contains eight items in three sections: selection, comparability and outcome. Publication bias was assessed using funnel plots and the Egger’s test of bias when there were more than 10 included studies.10 The certainty of evidence was evaluated with GRADE (Grade of Racommedations Assessment, Development and Evaluation) framework.11
Data synthesis and analysis
Meta-analyses were performed in R programming language (V.4.1.2) with the R package ‘meta’.12 Statistical heterogeneity was assessed using the I2 statistic, Cochran’s Q-test and restricted maximum likelihood estimator (τ2). I2>50% or p<0.05 represented high heterogeneity, and a random-effects model was used for pooling data. The raw means were used as the effect sizes in the meta-analysis. Knapp-Hartung adjustments were used to calculate the CI around the pooled effect.13 A sensitivity analysis using the leave-one-out method was carried out to examine the robustness of the conclusions, and subgroup analysis was used to explore the high heterogeneity. In terms of whether the patients of the articles had CLM or not, the included articles were divided into the CLM group and the other diseases group. The alveolarisation stage occurs from birth to 2 years of age, and the older the age is, the slower the alveolar growth14 15; therefore, some studies suggested that surgery should be performed between 6 months and 1 year old to obtain more lung function compensation.16 17 Therefore, we defined the early surgery group with an average operative age of less than 1 year and the late surgery group with an average operative age of more than 1 year and performed the second subgroup analysis. The Cochran’s Q-test was used to find the difference between subgroups, and a p value of <0.05 was considered statistically significant.
Interpretation strategies
As the average age of patients at follow-up was approximately 15 years old, the fifth percentile values lower limit of normal (fifth LLN) pulmonary function indices of 15-year-old girls were used in our study to classify the physiological impairments, that is, FEV1%: 80.5, FVC%: 80.4, FEV1/FVC: 87.8%, TLC%: 79.8, DLCO%: 75.4 (in fact, there was very little difference in lung function indicators between 10 and 25 years old, and the standard for females was slightly lower than that for males). ERS/ATS 2021 recommended using the Z-score to evaluate the severity of lung function impairment. However, few included studies reported the data in this form, and we can only use the old evaluation criteria in ERS/ATS 2005.18 The specific interpretation strategies used in our research were shown in online supplemental table 2.
Results
A total of 5302 articles were identified through the search strategy: 1960 from PubMed, 1111 from Embase and 2231 from Web of Science. After removing 1517 duplicated articles, 3785 articles underwent initial review, then 140 of them have been identified as potential targets for the second round of review through reviewing the titles and abstracts. Full texts of these 140 articles were obtained and read. Out of these, 130 articles were excluded as they did not meet our inclusion criteria, leaving a total of 10 articles for the meta-analysis (online supplemental figure 1). The quality of the included studies was poor according to the NOS quality score, with an average score of 6.2 (online supplemental table 3). The GRADE assessment showed the certainty of the evidence was low because of serious concerns about risk of bias, imprecision and non-control study.
The characteristics of the 10 included studies were shown in online supplemental table 4. Only three of them were comparative studies.6 19 20 Seven articles focused on CLM,3–6 20–22 and three focused on other diseases, including non-cystic fibrosis bronchiectasis, and mixed diseases.23–25
A total of 164 children undergoing lung surgery were included, including 127 patients with CLM and 37 patients with other diseases or mixed diseases. The age range for lung surgery was from 10 days to 14 years old. The average time for PFTs was more than 5 years after the operation, and the average follow-up age was approximately 15 years old. All the studies reported at least the FEV1% and FVC%. Four studies reported FEV1/FVC.4–6 20 22 The most important indicator of lung volume test, TLC%, was reported in eight studies.3 4 6 20–22 24 25 In addition, the symbol of gas transfer, DLCO%, was reported in two studies.20 25 Additionally, four studies reported FEF25–75.5 22 23 25 The results of the summary data were shown in table 1.
Characteristics of included studies
Main findings
FEV1 test
Pooling all the results of 10 studies showed that the mean value of FEV1% was 80.09 (95% CI: 75.03 to 85.16, I2=83%, p<0.01) (figure 1), indicating a mild obstructive ventilatory defect. Sensitivity analysis indicated that the mean value of FEV1% would increase to 82.32 (95% CI: 78.82 to 85.82) if the study of Emiralioglu et al was omitted23 or 81.00 (95% CI: 78.82 to 85.82) if the study of McBride et al4 was excluded (online supplemental figure 2). The funnel plot and Egger’s test showed no obvious publication bias (online supplemental figure 4).
Forest plot of postoperative FEV1%. FEV1, forced expiratory volume in 1 s; MRAW, Raw Mean.
Two subgroup analyses were performed as mentioned above. The first subgroup analysis showed that the mean value of FEV1% was 81.95 (95% CI: 77.46 to 86.44) in the CLM group and 75.90 (95% CI: 61.69 to 90.11) in the other diseases group. The Q-test for subgroup differences showed no significant difference (p=0.43>0.05) (figure 2). The second subgroup analysis showed that the mean value of FEV1% was 77.35 (95% CI: 67.89 to 86.81) in the early surgery group and 83.35 (95% CI: 81.10 to 85.61) in the late surgery group (figure 3). The Q-test for subgroup differences also showed no significant difference (p=0.23) between the two groups.
Subgroup analysis on diseases. CLM, congenital lung malformation; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity.
Subgroup analysis on surgical age. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity.
FVC test
The pooled value of 11 studies for FVC% was 87.66 (95% CI: 83.14 to 92.18, I2=72%, p<0.01) (figure 4). A sensitivity analysis showed stable results (online supplemental figure 5). The funnel plot and Egger’s test demonstrated no obvious publication bias (online supplemental figure 6).
Forest plot of postoperative FVC%. FVC, forced vital capacity; MRAW, Raw Mean.
Subgroup analysis showed that the mean value of FVC% was 90.96 (95% CI: 88.82 to 93.10) in the CLM group and 82.53 (95% CI: 70.16 to 94.90) in the other diseases group. The Q-test for subgroup differences also showed no significant difference (p=0.19) between the two groups (figure 2). The second subgroup analysis pointed out that the mean value of FVC% was 88.13 (95% CI: 84.49 to 91.77) in the early surgery group and 88.09 (95% CI: 79.37 to 96.82) in the late surgery group. The test for subgroup differences did not show a significant difference between the two groups (p=0.99) (figure 3).
FEV1/FVC test
Pooling the results of four studies established a normal FEV1/FVC.5 6 20 22 The overall value of FEV1/FVC was 93.73% (95% CI: 89.15% to 98.31%, I2=82%, p<0.01) (figure 5). A sensitivity analysis revealed that this result was robust. Because few articles were included, a publication bias test was not conducted. Only one study reported FEV1/FVC in the early surgery group, which was 88.4% (95% CI: 86.24% to 90.56%),6 and the pooled value of FEV1/FVC in the late surgery group was 94.79% (95% CI: 89.85% to 99.73%).5 20 22 The test for subgroup differences showed no statistical significance between the two groups (p=0.28) (figure 3).
Forest plot of postoperative FEV1/FVC. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MRAW, Raw Mean.
TLC test
The pooled value of nine studies for TLC% was 91.17 (95% CI: 86.71 to 95.63, I2=80%, p<0.01) (figure 6). A sensitivity analysis showed stable results (online supplemental figure 7). Publication bias was not performed due to an insufficient number of included studies.
Forest plot of postoperative TLC%. TLC, total lung capacity; MRAW, Raw Mean.
Subgroup analysis was also performed. The pooled value of TLC% was 92.31 (95% CI: 90.83 to 93.78) in the CLM group and 85.35 (95% CI: 73.99 to 96.71) in the other diseases group. Test for subgroup differences yielded a p value of 0.23 (figure 2). The second subgroup analysis showed that the mean value of TLC% was 92.92 (95% CI: 90.03 to 95.81) in the early surgery and 88.55 (95% CI: 81.16 to 95.94) in the late surgery. The test for subgroup differences showed no significant difference between early and late surgery for CLM on the value of TLC% (p=0.28) (figure 3).
DLCO test
The overall value of DLCO was 99.94% (95% CI: 96.64% to 103.23%, I2=56%, p=0.13) (online supplemental figure 8). Publication bias test, sensitivity analysis and subgroup analysis were not performed because only two studies were included. No postoperative diffusion function impairment was found through the limited number of studies.
Interpretation
As a whole, after lung surgery in children, medium-term follow-up of PFTs indicated a mild obstructive ventilation disorder. Subgroup analysis also showed a mild obstructive ventilatory disorder in the other diseases group. Compared with other diseases, children with CLM presented better and normal pulmonary function after lung surgery, and there was no significant difference between the early and late surgery groups.
Discussion
PFTs are a simple and convenient examination that can detect abnormal pulmonary function after pulmonary surgery by early examination and can be followed up continuously.26 The results of 10 PFT studies were pooled through meta-analysis. A total of 164 children, including 127 patients with CLM, were included. The results showed that lung surgery had little side effects on pulmonary function because of the good lung conditions and strong pulmonary compensation ability of children. Only mild obstructive ventilatory disorder was caused. Compared with other diseases, CLM showed normal post-surgery pulmonary function. There was no significant difference in pulmonary function level between early and late surgery in a medium-term follow-up.
FEV1% can be used to evaluate the severity of lung function impairment, and a cut-off of 70 was widely used in the Global Initiative for Chronic Obstructive Lung Disease standard.27 This was often confusing because chronic obstructive pulmonary disease mainly involves people over 65 years of age, and its FEV1% standard was very different from that of children. We found that, in general, children underwent lung resection with a slightly damaged FEV1% value, especially in the other diseases group. Although the CLM group has a normal FEV1% value, it is very close to the fifth LLN value, which suggested that even patients with CLM should continuously monitor lung function after the operation. The Lung Clearance Index (LCI) is a powerful parameter to quantify ventilation inhomogeneity using the multiple breath washout technique, and it is more sensitive for detecting early airway changes than routine PFTs.28 Mandaliya et al and Dincel et al reported the same conclusion: children with CLM have normal lung function after lung surgery but have an abnormal LCI, which may represent ventilation inhomogeneity during compensatory growth of the surrounding airway.5 6
Human lungs have compensatory lung growth capacity, even in adults,29 30 and children were considered to have the stronger compensatory ability. Several studies also reported normal PFTs on infants with CLM who underwent surgery.31–33 However, a restrictive ventilatory disorder in infants with CLM without surgery was described by Barikbin et al.34 This finding can be interpreted to indicate that after removing a dysfunctional lesion, compensatory lung growth may even improve previously impaired lung function to the normal level. With the development of thoracoscopic surgery in children, the risk and trauma of lung surgery can be well controlled. Considering the risk of infection and malignant transformation, surgery may be a better choice for asymptomatic children with CLM.
CLM is the most common congenital lung disease in children and the most common cause of lung surgery in children, of which congenital pulmonary airway malformation accounts for the highest proportion.35 36 It may not be accurate for the statement of early operation for better compensatory lung growth through our research (at least 1 year old was not the best dividing line), and the optimal age for surgery may need more research. For patients with cancer or severe pneumonia who require surgery, their lung function was already impaired prior to the surgery, so it was difficult to obtain normal lung function during postoperative follow-up. However, considering the slight impact of surgery on pulmonary function, our research supported more positive surgical interventions in lung diseases on children without CLM if necessary.
Exercise intolerance is a more intuitive method to evaluate postoperative pulmonary function. Single PFTs may overestimate pulmonary function impairment, and PFTs combined with exercise tolerance tests may be a better choice.37 Dunn et al reported a normal postoperative exercise capacity of asymptomatic patients with CLM by using healthy age-matched children control.38 However, Sritippayawan et al found that 23% of children with CLM under surgery had a lower exercise capacity than normal children.39 Some researchers believed that regardless of undergoing surgery or not, patients with CLM may experience a decline in exercise tolerance.40 Based on existing studies, it was currently difficult to draw a convincing conclusion, and more rigorous experiments on exercise tolerance in children after lung surgery are needed.
Limitations
The main limitations of this paper were that the quality of the included articles was not high, the sample sizes were small even after pooling and our study could not represent long-term post-surgery pulmonary function in children either. Few studies have conducted preoperative and postoperative comparisons or have a normal control, and few studies have a systematic follow-up. In addition, most studies reported the results of the PFTs in terms of percentage predicted but not Z-score, which was a more impartial index. Moreover, as the deadline for the search was 1 July 2022, this paper could not represent the findings of the latter studies.
Implications for future research
We call on future research to conduct research and report results in accordance with the latest ERS/ATS 2021 standard. A more extensive, multicentre, prospective clinical study on children’s long-term postoperative pulmonary function should be conducted, which could make a more reasonable surgical decision for children.
In summary, in this systematic review and meta-analysis, we found a mild obstructive disorder in children who underwent lung surgery. However, a normal pulmonary function could be found in young children with CLM who underwent lung surgery, and the time of operation had no significant influence on their pulmonary function. The risk of impairment of pulmonary function may not be an obstacle for performing lung surgery on children, particularly in patients with CLM.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
Ethics statements
Patient consent for publication
Ethics approval
The data of the study were sourced from published articles and did not involve identifiable patient privacy content; thus, this study obtained an exemption from the Ethics Committee of West China Hospital of Sichuan University.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
CL and JL contributed equally.
Contributors Design of the work—CL, JL and CX. Article retrieval and data collection—CL, JL and MY. Article selection—CL, JL and MY. Data analysis, code writing and mapping—CL, KC, DL and LZ. Supervision, conduted and responsibility for the entire study—CX. Drafting the manuscript and revising it—all authors.
Funding This study was funded by the Key Research and Development Program of Sichuan Province (no. 2021YFS0244).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.