Lung Clearance Index (LCI) - ARIR Associazione riabilitatori della
1 Rassegna della letteratura con commento dell’esperto Lung Clearance Index (LCI) Le prove di funzionalita’ respiratoria rivestono un ruolo fondamentale nella diagnosi e nella gestione delle malattie respiratorie. Per questo la ricerca ha sempre cercato di indirizzarsi verso il loro sviluppo e il loro perfezionamento. Il Lung Clearance Index (LCI) è un indice della disomogeneità ventilatoria che si ottiene attraverso l’esecuzione di Multiple Breath Washout Test (MBW). Questo indice apparve per la prima volta nel 1952 (Becklake, Thorax 1952) a seguito dello sviluppo di analizzatori di gas a rapida risposta, come ad esempio lo spettrometro di massa. Il MBW consiste nel far respirare un gas tracciante inerte a volume corrente attraverso un circuito chiuso. A seconda del tipo di dispositivo i gas utilizzati possono essere l’esafluoruro di zolfo (non permesso in Italia) e l’azoto. Attraverso i sensori di O2 e CO2 si osserva la progressiva discesa della concentrazione del gas tracciante espirato che deve arrivare ad 1/40 esimo della sua concentrazione iniziale. L’analisi della curva dell’espirogramma del gas tracciante permette di calcolare il Lung Clearance Index, definito come il numero di capacità funzionali residue (FRC) necessarie ad ottenere una concentrazione finale di gas tracciante pari ad 1/40esimo di quella iniziale. Esso è stato per diverso tempo accantonato per poi tornare in auge grazie alle teorie di modellizzazione della respirazione nei polmoni umani condotte principalmente a partire dalla fine degli anni ‘80 da ricercatori Manuel Paiva e Sylvia Verbanck. Ciò che emerge dai loro lavori è che il danno provocato dalle malattie respiratorie non è uniforme ma si sviluppa in maniera eterogenea a livello del parenchima. La differente ventilazione specifica tra regioni polmonari, il diverso svuotamento e riempimento sequenziale di unità polmonari, e l'asimmetria strutturale presente a livello acinare sono fenomeni fisiologici che sussistono in minima parte nei polmoni sani ma che vengono accentuati dai processi patologici come l’infiammazione delle vie aeree, il ristagno di secrezioni, la presenza di atelettasie e bronchiectasie. Poichè sappiamo, grazie a numerosi studi, che le piccole vie aeree hanno un ruolo fondamentale nelle patofisiologia di alcune importanti malattie respiratorie come Asma, BPCO e Fibrosi Cistica, MBW e LCI offrono importanti vantaggi e spunti. Nell’ambito della Fibrosi Cistica vari autori hanno dimostrato la capacità di LCI di vedere il danno polmonare più precocemente rispetto ai soliti sospetti delle prove di funzionalità respiratoria (FEV1, FEV0.5, FEF25-75). Sempre in quest’ambito sono state dimostrate: la forte correlazione tra LCI e indice di danno all’esame TAC (HRCT score e Brody II) e l’ indipendenza del valore di LCI rispetto all’età. E’ possibile poi derivare dal MBW alcuni indici che permettono di suddividere la disomogenità ventilatoria in una componente conduttiva (Scond) e acinaria (Sacin). Se da un lato LCI è più sensibile del FEV1 nel captare delle alterazioni strutturali parenchimali, dall’altro però esso è meno specifico. Questa scarsa specificità, associata alla difficile valutabilità delle modificazioni indotte a livello della periferia polmonare da vari trattamenti (inclusi teraSegreteria: [email protected] Sito: www.arirassociazione.org ARIR ti tiene aggiornato 2 pia antibiotica, terapia broncodilatatoria e fisioterapia respiratoria), rendono l’LCI un outcome di dubbia rilevanza soprattutto per i trattamenti a breve termine - inclusa la fisioterapia. A sostegno di queste affermazioni sono stati inseriti alcuni interessanti lavori fra cui la più recente revisione riguardante le proprietà cliniche di LCI con tabelle riassuntive chiare degli studi finora prodotti (J Cyst Fibros. 2014), uno studio di correlazione fra LCI, valori spirometrici e TAC (Thorax. 2008), uno studio riguardante l’utilizzo di LCI come misura di outcome nel trattamento di pazienti FC con soluzione ipertonica (Am J Respir Crit Care Med. 2013) e un recentissimo report riguardante le criticità di standardizzazione delle misurazioni (Ann Am Thorac Soc. 2015). Negli ultimi anni hanno iniziato a comparire lavori d’indagine sulla disomogeneità della ventilazione anche in altre malattie respiratorie. Per questo sono stati inseriti in questa newsletter anche dei recentissimi studi inerenti la Distrofia Muscolare di Duchenne (Respir Care. 2015), le malformazioni toraciche congenite (BMC Pulmonary Medicine 2015), e le bronchiectasie non correlate con Fibrosi Cistica (Respir Res. 2014). Nonostante questo indice sia stato inventato parecchi decenni fa, è ancora di attuale importanza riuscire ad approfondire la conoscenza dei meccanismi fisiologici e patofisiologici della ventilazione a livello della periferia polmonare. LCI e gli altri indici derivati (S cond e Sacin) hanno le potenzialità per divenire dei partner nella pratica del fisioterapista respiratorio non prima però di averne ulteriormente indagato con modalità di ricerca appropriate la rilevanza clinica. Buona Lettura! Riccardo Guarise 3 J Appl Physiol. 2012. RELATIONSHIPS BETWEEN THE LUNG CLEARANCE INDEX AND CONDUCTIVE AND ACINAR VENTILATION HETEROGENEITY Verbanck S, Paiva M, Schuermans D, Hanon S, Vincken W, Van Muylem A. BACKGROUND: The lung clearance index (LCI) derived from a multiple breath washout test has regained considerable popularity in recent years, alternatively being promoted as an early detection tool or a marker of small airways function. METHODS: In this study, we systematically investigated the link between LCI and indexes of acinar and conductive airways ventilation heterogeneity (Sacin, Scond) to assess potential contributions from both lung zones. RESULTS: Relationships were examined in 55 normal subjects after provocation, where only Scond is known to be markedly increased, and in 55 asthma patients after bronchodilation, in whom both Scond and Sacin ranged between normal and abnormal. LCI was correlated to Scond in both groups (R _ 0.37– 0.43; P _ 0.01 for both); in the asthma group, LCI was also tightly correlated to Sacin (R _ 0.70; P _ 0.001). Potential mechanisms operational at various levels of the bronchial tree were identified by considering washout curvilinearity in addition to LCI to distinguish specific ventilation and dead space effects (also illustrated by simple 2-compartment model simulations). Although the asthma data clearly demonstrate that LCI can reflect very peripheral ventilation heterogeneities, the normal provocation data also convincingly show that LCI increases may be the exclusive result of far more proximal ventilation heterogeneities. CONCLUSIONS: Because LCI potentially includes heterogeneities at all length scales, it is suggested that ventilation imaging in combination with LCI measurement at the mouth could identify the scale of relevant ventilation heterogeneities. In the meantime, interpretations of LCI results in the clinic based on washout curves collected at the mouth should be handled with caution Respir Care. 2015 DECLINE IN LUNG VOLUME WITH DUCHENNE MUSCULAR DYSTROPHY IS ASSOCIATED WITH VENTILATION INHOMOGENEITY. Stehling F, Dohna-Schwake C, Mellies U, Große-Onnebrink J. BACKGROUND: Advanced stages of Duchenne muscular dystrophy (DMD) result in severe lung volume decline and are associated with high respiratory morbidity and mortality. The aim of this study was to investigate whether lung volume decline in subjects with DMD is associated with ventilation inhomogeneity measured with the multiple-breath washout technique. METHODS: This cross-sectional study of lung function included 45 subjects with DMD and 16 healthy controls using multiple-breath washout, spirometry, and cough peak flow. RESULTS: Subjects with DMD exhibited an elevated lung clearance index (>7.0) defined as the cumulative exhaled volume divided by the functional residual capacity to lower the sulfur hexafluoride concentration below 2.5% compared with controls (8.16 ± 2.55 vs 6.23 ± 0.46, P < .001). Lung clearance index elevation was negatively correlated with vital capacity (% predicted: r = -0.79, P < .001) and cough peak flow (L/min: r = -0.41, P = .005). Furthermore, dead-space ventilation (dead-space-to-tidal-volume ratio) and functional residual capacity showed a positive correlation with lung clearance index elevation (r = 0.81 and 0.48, P < .001). An FVC of < 24% predicted lung clearance index elevation with a sensitivity of 96% and a specificity of 80%. CONCLUSIONS: Moderate-to-severe lung volume decline in subjects with DMD is associated with ventilation inhomogeneity. Lung clearance index elevation may be the result of altered ventilation geometry or retention of airway secretions in the infection-free DMD subject. 4 Ann Am Thorac Soc. 2015 MULTIPLE-BREATH WASHOUT AS A LUNG FUNCTION TEST IN CYSTIC FIBROSIS. A CYSTIC FIBROSIS FOUNDATION WORKSHOP REPORT. Subbarao P, Milla C, Aurora P, Davies JC, Davis SD, Hall GL, Heltshe S, Latzin P, Lindblad A, Pittman JE, Robinson PD, Rosenfeld M, Singer F, Starner TD, Ratjen F, Morgan W. Abstract The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF. KEYWORDS : cystic fibrosis; lung clearance index; multiple-breath washout; pulmonary function tests Respir Res. 2014 LUNG CLEARANCE INDEX IN ADULTS WITH NON-CYSTIC FIBROSIS BRONCHIECTASIS. Gonem S, Scadding A, Soares M, Singapuri A, Gustafsson P, Ohri C, Range S, Brightling CE, Pavord I, Horsley A, Siddiqui S. BACKGROUND: Lung clearance index (LCI) is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout (MBW) technique. We aimed to determine the clinical utility of LCI in non-CF bronchiectasis, and to assess two novel MBW parameters that distinguish between increases in LCI due to specific ventilation inequality (LCIvent) and increased respiratory dead space (LCIds). METHODS: Forty-three patients with non-CF bronchiectasis and 18 healthy control subjects underwent MBW using the sulphur hexafluoride wash-in technique, and data from 40 adults with CF were re-analysed. LCIvent and LCIds were calculated using a theoretical two-compartment lung model, and represent the proportional increase in LCI above its ideal value due to specific ventilation inequality and increased respiratory dead space, respectively. RESULTS: LCI was significantly raised in patients with non-CF bronchiectasis compared to healthy controls (9.99 versus 7.28, p < 0.01), and discriminated well between these two groups (area under receiver operating curve = 0.90, versus 0.83 for forced expiratory volume in one second [% predicted]). LCI, LCIvent and LCIds were repeatable (intraclass correlation coefficient > 0.75), and correlated significantly with measures of spirometric airflow obstruction. CONCLUSION: LCI is repeatable, discriminatory, and is associated with spirometric airflow obstruction in patients with non-CF bronchiectasis. LCIvent and LCIds are a practical and repeatable alternative to phase III slope analysis and may allow a further level of mechanistic information to be extracted from the MBW test in patients with severe ventilation heterogeneity. 5 J Cyst Fibros. 2014 LUNG CLEARANCE INDEX: EVIDENCE FOR USE IN CLINICAL TRIALS IN CYSTIC FIBROSIS. Kent L, Reix P, Innes JA, Zielen S, Le Bourgeois M, Braggion C, Lever S, Arets HG, Brownlee K, Bradley JM, Bayfield K, O'Neill K, Savi D, Bilton D, Lindblad A, Davies JC, Sermet I, De Boeck K; European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee. Abstract The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. KEYWORDS: Clinimetric properties; Lung clearance index; Multiple breath washout; Outcome measures; Surrogate endpoints Thorax. 2008 MULTIPLE-BREATH INERT GAS WASHOUT AND SPIROMETRY VERSUS STRUCTURAL LUNG DISEASE IN CYSTIC FIBROSIS Gustafsson P, De Jong P, Tiddens H, Lindblad A. BACKGROUND: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. A study was undertaken to determine the agreements between LCI and spirometry, respectively, with structural lung disease as measured by high resolution computed tomography (HRCT) in children and teenagers with CF. METHODS: A retrospective study was performed in 44 consecutive patients with CF aged 5–19 years (mean 12 years). At an annual check-up inspiratory and expiratory HRCT scans, LCI and spirometric parameters (forced expiratory volume in 1 s (FEV1) and maximal expiratory flow when 75% of forced vital capacity was expired (FEF75)) were recorded. Abnormal structure was defined as a composite HRCT score of .5%, the presence of bronchiectasis or air trapping .30%. Abnormal lung function was defined as LCI above the predicted mean +1.96 residual standard deviations (RSD), for FEV1 or FEF75 below the predicted mean 21.96 RSD. Sensitivity/specificity assessments and correlation analyses were done. RESULTS: The sensitivity to detect abnormal lung structure was 85–94% for LCI, 19–26% for FEV1 and 62–75% for FEF75. Specificity was 43–65% for LCI, 89–100% for FEV1 and 75–88% for FEF75. LCI correlated better with HRCT scores (Rs +0.85) than FEV1 (20.62) or FEF75 (20.66). CONCLUSIONS: LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF. CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies. 6 Am J Respir Crit Care Med. 2013 LUNG CLEARANCE INDEX AS AN OUTCOME MEASURE FOR CLINICAL TRIALS IN YOUNG CHILDREN WITH CYSTIC FIBROSIS. A PILOT STUDY USING INHALED HYPERTONIC SALINE Subbarao P, Stanojevic S, Brown M, Jensen R, Rosenfeld M, Davis S, Brumback L, Gustafsson P, Ratjen F. RATIONALE: Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF). OBJECTIVES: To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. METHODS: The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a singlecenter pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to accountfor height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect. RESULTS: A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34– 4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n . 12) by 1.19 z-scores units (95% confidence interval [CI].22.46 to 0.06), and remained stable in the isotonic saline group (n . 13) at 0.81 (95% CI . 20.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI . 0.26 to 3.76; P . 0.025). CONCLUSIONS: MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies. BMC Pulmonary Medicine 2015 VENTILATION INHOMOGENEITIES IN CHILDREN WITH CONGENITAL THORACIC MALFORMATIONS Mandaliya P, Morten M, Kumar R, James A, Deshpande A, Murphy V, Gibson P, Whitehead B, Robinson P, Mattes J. BACKGROUND: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with surgical resection or active surveillance. The objective of this study was to comprehensively assess large and small airway function in children with CTM who underwent lobectomy in early life. We hypothesise that sensitive measures of lung function will demonstrate residual impairments in CTM compared to healthy children. METHODS: Nitrogen lung clearance index (LCI), reactance and resistance (X5Hz and R5Hz), forced expiratory volume in 1 s and forced vital capacity (FEV1 and FVC) were prospectively measured in 10 children with CTM (mean age/SD: 7.6/1.3) who had undergone surgical resection in early life and in 17 healthy children (mean age/SD: 4.8/0.4). Total lung capacity (TLC) was also conducted in children older than 7 years of age with CTM (n = 8). RESULTS: Mean LCI was 8.0 (95% CI 7.5 to 8.5) in the CTM group and 7.3 (95% CI 7.0 to 7.6) in healthy children (p = 0.016). Mean X5Hz was −0.44kPa/l/s (95% CI −0.58 to −0.31) in the CTM group and −0.31kPa/l/s (95% CI −0.35 to −0.27) in healthy children (p = 0.02). Mean Z score for X5Hz was −2.11 (95% CI −3.59 to −0.63) in the CTM group and −0.11 (95% CI −0.55 to 0.33) in healthy children (p = 0.0008). Mean FEV1 was 1.21 L (95% CI 0.97 to 1.45) in the CTM group and 1.02 L (95% CI 0.90 to 1.15) in healthy children (p = 0.22). Mean % predicted FEV1 was 83% (95% CI 74 to 92) in the CTM group and 97% (95% CI 87 to 107) in healthy children (p < 0.05). Mean % predicted TLC in CTM children was 121.3% (95% CI 88.45 to 154.1). Mean LCI was inversely correlated with height z-scores in the CTM group (rs = −0.88, p = 0.002) but not in healthy children (rs = 0.22, p = 0.4).