2017 Changes in DLCO Technical Standards Rick Ballard, RRT, RPFT Senior Applications Specialist MGC Diagnostics Corporation

2017 Changes in DLCO Technical Standards Background Methods System Specifications Calibration System Quality Control Testing Reference Equations

2017 DLCO Technical Standards Background Primary updates revolve around RGA analyzers(Rapid Gas Analysis) Did take into consideration “classical” systems will be in use for some time Provide new calculations standards for analysis of the entire exhaled gas sample Recommendations revolve around the single breath technique as this is the most common methodology used globally

Methods Task force was formed Included Physicians & Scientists experienced in international guidelines, experience in lung function testing and specialist knowledge in gas transfer Pubmed search was conducted reviewing data from 2000-2015 Polled all manufactures 8 of 13 manufacturers responded 5 members from the 2005 task force Pubmed search yielded 3637 citations. 113 documents were found to be relevant and 99 were potentially relevant Reviewed the manufacturers websites: reviewed company stated specifications

System Specifications Flow & Volume Analyzers Accuracy over range from ± 10 L/sec must be within ±2% Calibration volume must be within ±2.5% (≤75 ml) (3 liter syringe accuracy: ±0.5% 2.985-3.015L) Measurement accuracy must be maintained over the range of gas composition and concentrations encountered during DLCO tests

Gas analyzers RGA Analyzer response time (rise time) required to be ≤150 milliseconds Discussed sample transit time, no specific recommendations were implemented Suggested manufacturers minimize these effects but no specific recommendations were implemented Analyzer linearity ≤ 0.5% full scale Output of analyzer accuracy within ± 1% full scale Every increase of 100ms in rise time equals 0.7% error. % error due to nonlinearity depends on lung size and rate of CO uptake. Nonlinearity of 0.5% can causes errors ranging from 0.5-1.7% (0.5% error in pt. with DL of 40, 1.7% error in pt with a 10 ml DLCO

Gas analyzers CO accuracy (RGA/Discrete systems) ≤10 ppm (±0.3% of 0.3% CO) Interference from CO2 and H20 vapor for both types of analyzers ≤10 ppm error in CO (CO2 & H2O vapor ≤5%) 2005 statement did not include error limits

Gas analyzers Analyzer drift: ≤ 10ppm for CO and ≤0.5% of full scale for the tracer gas over 30 seconds Recommended manufactures include a test mode to test system drift 2017 statement now specifies barometric drift to be within ± 2.5% (not specified previously)

Gas analyzers Manufacturers are required to determine lowest exhaled flow that will not entrain gas other than exhaled gas Must be reported in system specifications In measurements of exhaled gas concentrations the system must not sample from below the specified flow that could influence measurement of exhaled tracer gas from previous maneuver or calculation of absolute end-expiratory lung volume

Gas Analyzers Digital sampling rate: minimum of ≥100 hz Recommend 1000 hz sampling rate A/D resolution must be ≥14 bits Was not discussed in the 2005 recommendations Allows for proper signal processing and data alignment

Manufacturer specific recommendations RGA systems must include the following features: Monitor and report end-expiratory CO and tracer gas concentrations to alert technologist if previous test washout was incomplete Compensate for end-expiratory gas concentrations prior to gas inhalation for calculation of VA and DLCO Ensure proper alignment of gas concentrations and flow signal (no specifications addressed)

Manufacturer specific recommendations Measure anatomic dead-space utilizing the Fowler technique Display graph of exhaled gas concentrations versus volume (not time). Confirms the point of dead-space washout. Also report amount of manual adjustment if technologist manipulates this point Measure VA using all the tracer gas from the entire maneuver using the mass balance equation

Fowler dead-space calculation

Manufacturer specific recommendations Report DLCO adjusted for change in PAO2 due to barometric pressure Circuit resistance must be < 1.5 cmH2O up to 6L·s flow Demand valve inspiratory pressure to ˂ 9 cmH2O (2005 < 10 cmH2O) (circuit & valve) Machine deadspace ˂200 ml (2005-350ml), recommended smaller for children and subjects with a VC ˂ 2.0 liters (no specific requirements) Demand valve specs in relation to generating 6 l/sec flow Machine deadspace includes breathing circuit proximal to analyzer sampling port, filter and mouthpiece

Manufacturer specific recommendations Recommended but not required RGA options Input simulated digital test data and compute DLCO, VA and TLC within ±2% accuracy Report DLCO adjusted for Δ PAO2 due to PACO2

Calibration Daily volume calibration - At least 3 strokes, flow variation between 0.5 and 12 L/sec - Accuracy must be ˂ 2.5% error - No timer specifications in new recommendations Required to zero flow sensor and gas analyzers prior to each maneuver Monthly calibration syringe leak test required

System Quality control Biologic and syringe QC are now required weekly Previously it was either or bio or syringe Syringe volume accuracy for VA ± 300 ml and DLCO measured ˂ 0.5 ml·min mmHg Biologic standards: if there is > 12% or > 3 ml·min mmHg from the mean of 6 previous tests, further system evaluation necessary before testing patients Gas analyzer linearity check monthly (Q 3 2005) Both cal and QC logs can now be stored digitally Previously the change was > 10%. The standard was relaxed

Patient Testing Maneuver begins with an unforced exhalation to residual volume. Exhalation time to RV has increased from 6 to 12 seconds At RV patient inhales maximally to TLC Target VI has increased to ≥90%. However a VI ≥85% of the patients largest VC is acceptable if the VA is within 200 ml or 5% (whichever is largest) of the patient’s highest VA from acceptable DLCO maneuvers Patient off O2 for 10 minutes or more, No cigarettes on day of test. Note time of last cigarette. Adjust for COHB Data collected from a large study verified 90% of VC is obtainable.

Patient Testing Inspiration must be rapid, 85% of VI must be inspired in ≤4 sec. Note if inspiratory time >4 sec During breath-hold, the patient should not exhibit a Valsalva or Müller maneuver. Breath-hold time must be 10±2 sec Exhalation is smooth, unforced without hesitation or interruption Discrete systems collection time should not exceed 4 sec Valsava decreases, Muller increases DLCO due to change in thoracic blood volume.

Patient Testing RGA systems: exhalation continues to RV with a maximum exhalation time of 12 sec Improves measurement of VA Washout volume with a discrete system is 0.75-1.0 L If the VC is < 2.0 L washout volume may be reduced to 0.5L. If VC < 1L, sample collected < 0.5 L if dead- space clearance is verified

Patient Testing DLCO test gas is required to contain 21% oxygen Required time interval between maneuvers: 4 minutes, 10 minutes if severely obstructed. Complete washout tracer gas at end exhalation (prior to gas inhalation) ˂ 2% of inspired concentration End exhalation CO concentration (prior to gas inhalation) is used to adjust DLCO for CO back pressure, to calculate COHb and compensate for the effects H2O vapor and CO2 on gas analyzers 21% O2 requirement: Majority of new reference sets used 21% O2. If reduced FIo2 is intended to simulate tidal volume conditions, it may not do so for all subjects (PAO2 of 100 mmhg)

Patient Testing In RGA systems plotting exhaled gas versus volume allows a better approach to determine dead-space clearance Observing exhaled gas versus time can be deceptive due to high flows during at the start of exhalation DLCO sample is calculated from flow and gas concentration data. 200 ml sample analyzed using Jones/Meade technique was found to be robust RGA systems samples of 85 ml are adequate. Jones/Meade used an 85 ml sample in development of their method.

Patient Testing Graphs A & C show computer selected 500 ml sample. Graphs B & D show manual adjustment by user. Operators tend to be conservative and may over shift sample collection.

Patient Testing Repeatability criteria 2.0ml/min/mmHg compared to 3.0 ml/min/mmHg in previous recommendation. -Study of 4797 sessions found 95.5% of cases met this criteria Mean of acceptable tests are reported Not recommended to perform more than 5 maneuvers (Increase of ~3.5% COHb from baseline which will decrease DLCO by ~3-3.5%) Recommend Interim grading scale

Recommended grading Still needs validated.

Grading Scale Grade A meets all acceptability criteria If after repeat testing 2 repeatable grade A tests are not obtainable the following values are reported and with a note of caution to the interpreter that the testing session was suboptimal If 2 or more grade A maneuvers that are not repeatable are obtained, then the average DLCO value from the acceptable maneuvers are reported

Grading Scale If only 1 grade A maneuver is obtained that is the only value reported If no acceptable maneuvers are obtained, the average DLCO value of maneuvers with grade B, C or D is reported If only F grade maneuvers are obtained, no DLCO values are reported

Patient testing Miscellaneous factors: Possible diurnal variation in DLCO testing Reported change of 13% during menstrual cycle has been reported Ethanol has been reported to decrease DLCO No recommendation against bronchodilator delivery prior to DLCO testing Recommended to perform DLCO prior to N2 washout maneuver 1 study showed dl dropped 1.2- 2.2% per hour throughout the day Highest DL obtained prior to menses and Lowest DLCO on third day of menses 400 ug dose of salbutamol showed no significant change in DLCO Another study in COPD pts showed no significant change in DLCO with doses of salbutamol < 1000mg

DLCO Reporting requirements

DLCO Reporting requirements Although systems are required to report the variables listed, it is not the intent of the recommendations to specify which variables laboratories choose to report Nor is it intended address interpretation of the results There are “standardized” reporting forms released

DLCO Reporting KCO (Transfer coefficient of the lung for carbon monoxide) Logarithmic change in CO during breath hold divided by breath hold and PB of dry gas Some users prefer KCO as it eliminates the uncertainty in VA measurement from the assessment of CO uptake VA is not a component of KCO

DLCO Reporting KCO can be reported as DLCO/VA BTPS Should not be reported as DLCO/VA as it can inferred DLCO can be normalized for VA KCO can add insight into CO uptake properties in the lung, it cannot be used as a simple technique to normalize DLCO for volume

Reference Values Reference values utilizing the 2005 update (Not recommended)

Reference Values GLI DLCO reference equations were released in September