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Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

The adapted patient interface and the flowpast circuit consisted of a mesh type flowmeter (Model 4700A non-heated; flow range 0-160L/min, Hans Rudolph, Kansas, USA), a Intersurgical Clear Guard II bacterial filter (Surgical systems Ireland, Craigavon, N. Ireland ref 1844) and a silicone mouthpiece (Hans Rudolph; Ferraris, UK; size small) fitted over the filter end. Total pre-capillary deadspace (between the gas sampling needle and the patient's mouth) of the adult patient interface was calculated to be 68.2mls from derived component volumes (flowmeter 14.2mls; filter 54mls). Total pre-capillary deadspace of the children's patient interface was calculated to be 48.5mls from derived component volumes (flowmeter 18.5mls; filter 30mls).
A hole was drilled through the small flange side port tube of the flowmeter to house the gas sampling needle (shortened and blunted 21 gauge needle) which was then attached to the gas sampling line. This was positioned distal from the mouthpiece, to avoid the possibility of the gas sampling needle interfering with the functioning of the flowmeter and to reduce reinspired SF 6. The gas sampling line was made from Nafion tubing, allowing dry gas concentrations to be calculated. Post-capillary deadspace (space between the gas sampling needle and end of flowmeter port) was calculated at 5mls equating to less than 1% of the typical minimum tidal volume.
The flowpast circuit consisted of a T-piece connector (22mm-22F-22mm; Intersurgical, Surgical systems Ireland, Craigavon, N. Ireland) which attached to the end of the flowmeter port. The T-piece was attached to disposable plastic anaesthetics tubing (Hudson RCI. Respiratory and anesthesia products Corr-A-flex II 22mm tubing Ref1680) with a reservoir bag (Intersurgical 3 litre 22F neck) in the upstream arm. The reservoir bag was connected to the cylinder of compressed 0.2% SF 6 in air. A fan was in place to disperse any SF 6 expired during the washout phase in order to prevent re-inspiration and subsequent effect on the length of washout and calculation of LCI.
Before each test, the flowmeter was linearised and calibrated. The flow gas delay (FGD) was calculated using inbuilt Innocor TM software (version 6.15). During the test, the Innocor TM software provides visual display of gas concentration, flow and tidal volume allowing identification of the end of wash-in and washout phases and any immediate technical issues.
The modified Innocor TM device meets a number of key recommendations as outlined in the ERS/ATS IGW measurement consensus statement (Robinson et al., 2013). These include:  Accurate flow measurement within 1% across a range of flows.  No volume drift in stable gas concentrations.  Gas analyser accuracy with excellent signal quality.  Data sampling frequency of 100Hz.

Performing the test
The test was performed either before or at least 30 minutes after performing spirometry to avoid any effects from a recent forced expiratory manoeuvre. The patient was seated, wearing a noseclip, and asked to breathe normally. Quiet tidal breathing was encouraged by distraction by watching an age-appropriate DVD. The investigator monitored the Innocor TM online display of flow, breath volume, minute volume and gas concentration to ensure a steady breathing pattern. During the wash-in phase the flowmeter was connected to the flowpast T-piece and the subject breathed a mixture of 0.2% SF 6 in dry air, continuing until the Innocor TM online display indicated that the difference between end-inspiration and endexpiration SF 6 was 0.003% or less for three successive breaths. The flowpast T-piece was disconnected from the flowmeter early in expiration during a subsequent breath and the flowpast shut off, the washout phase beginning with the next inspiration. Washout continued until the maximum expired concentration of SF 6 on the Innocor online display was 0.003% or less for three successive breaths. At least three MBW tests were performed at each visit.

Analysis of MBW data
Innocor TM generates raw flow and gas concentration data. These files were uploaded into the SimpleWashout (SW) programme written in the data analysis package Igor Pro, developed by Dr Nicholas Bell (UKCFGTC) and used with his permission. The SW programme was used to calculate FRC and subsequently LCI. The programme displays the full wash-in and washout, with flow (L/s) and SF 6 concentration (%) signals over time (s), re-aligned according to FGD derived from Innocor software. Breath volume is derived from integration of the flow, and total SF 6 volume is derived from the integration of flow and gas concentration. The programme displays breath by breath data allowing the calculation of FRC and LCI at 1/40 th , 1/30 th , 1/20 th and 1/10 th end points.
Each test was individually assessed for validity using quality criteria as facilitated by the SW programme. Quality criteria were as follows:  Good quality disconnection: Ensuring disconnection during expiration with no leaks, re-breathing or irregular descent of SF 6 .  Complete wash-in: Complete wash-in was defined as a concentration of SF 6 of ≤0.003% for three consecutive breaths. The SW programme calculates a "Cwashin" value (from SF 6 concentration at the end of the last inspiration before disconnection minus the concentration of SF 6 at the end of the last expiration. A "Cwashin" value of ≤ 0.004% was considered ideal; however, values of < 0.008% were considered for inclusion in the calculation of the mean values.

Calculation of FRC mbw & LCI:
 For calculation of LCI 1/40 : the last breath of the washout is defined as the first with an end tidal SF 6 concentration of ≤1/40 th of the starting concentration which is followed by two subsequent breaths meeting the same criterion.  For calculation of LCI 1/30 : the last breath of the washout is defined as the first with an end tidal SF 6 concentration of ≤1/30 th of the starting concentration which is followed by two subsequent breaths meeting the same criterion.  For calculation of LCI 1/20 : the last breath of the washout is defined as the first with an end tidal SF 6 concentration of ≤1/20 th of the starting concentration which is followed by two subsequent breaths meeting the same criterion.
 For calculation of LCI 1/10 : the last breath of the washout is defined as the first with an end tidal SF 6 concentration of ≤1/10 th of the starting concentration which is followed by two subsequent breaths meeting the same criterion.  FRC mbw was calculated by dividing the total expired volume of SF 6 over the course of the washout (with last breath defined as in the previous two paragraphs) by [initial SF 6 concentration before disconnection minus end tidal expired SF 6 concentration at the end of the last breath].  The cumulative expired volume (CEV) is the total expired volume over the course of the washout (with last breath in the washout defined as in the previous two paragraphs).  LCI = CEV / FRC mbw  All tests were then checked for repeatability. FRC values between tests should be within 10% of each other and LCI values between tests should be within 20% of each other. Finally, all mean FRC and LCI value in this study were calculated from a minimum of three valid and repeatable tests.