The TL,NO/TL,CO ratio in pulmonary function test interpretation

J. Michael B. Hughes; Ivo van der Lee

doi:10.1183/09031936.00082112

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Figure 1–
Effect of voluntary reduction of lung volume from total lung capacity (TLC) in normal subjects on a) transfer factor of the lung for nitric oxide (T_L,NO) and carbon monoxide (T_L,CO) and T_L,NO/T_L,CO ratio, and b) transfer coefficient of the lung (K) for nitric oxide (K_NO; ∼T_L,NO/alveolar volume (V_A)) or carbon monoxide (K_CO; ∼T_L,CO/V_A), and for membrane diffusing capacity per unit volume for CO (D_M,CO)/V_A. Lung expansion expressed as single breath V_A as per cent V_A at maximal inflation (V_A,TLC). Note larger rise in K_CO (versus K_NO) with diminished expansion in (b), which buffers decline of T_L,CO versus T_L,NO in (a), causing a fall in T_L,NO/T_L,CO ratio, as would occur in extrapulmonary restriction. Data taken from a) [13] and b) [14].
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Figure 2–
Ratio of transfer factor of the lung for nitric oxide (T_L,NO) to transfer factor of the lung for carbon monoxide (T_L,CO) in normal subjects at full inflation and with voluntary reduction of lung volume (mimicking “extrapulmonary restriction”) and in different clinical situations. ILD: interstitial lung disease; PVD: pulmonary vascular disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; Hb: haemoglobin. Data are presented with sem±2 error bars. Dashed line represents range. ^#: alveolar volume/alveolar volume total lung capacity 0.7.

Tables

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Table 1– Literature review of values in normal subjects for transfer factor of the lung for nitric oxide (T_L,NO), transfer factor of the lung for carbon monoxide (T_L,CO) and T_L,NO/T_L,CO ratio

First authors [ref.]	Male/female	T_L,NO mmol min⁻¹ kPa⁻¹			T_L,CO mmol·min⁻¹ kPa⁻¹			T_L,NO/T_L,CO ratio
		Total	Male	Female	Total	Male	Female	Total	Male	Female
van der Lee [13]	65/59		54±8.7	39±6.3		12±2.2	9.2±1.6		4.6±0.5	4.3±0.4
Aguilaniu [20]^#	161/142		70	61		14.4	12.8		4.85⁺	4.8⁺
Zavorsky [21]^¶	66/64		56	45		10.8	8.8		5.19⁺	5.13⁺
Guenard [1]	7/7		52±6.7	39±2		10±0.5	7.3±0.37		5.2⁺	5.3⁺
Zavorsky [19]	10	46±8.9			8.5±1.5			5.4±0.3
Glénet [12]	20/7	64±13			13.2±2.8			4.9±0.3
Zavorsky [22]	8/0	70±6.1			15.4±1.5			4.6±0.1
de Bisschop [23]	8/8	57±12			13±2.3			4.4±0.3
van der Lee [24]	35/36	48±11			10.9±2.4			4.36±0.6
Degano [25]	27/8	40±6.7			9.0±1.3			4.34±0.33
Dressel [26]	13/8	35±12			9.1±2.7			3.8±0.4

Data are presented as n or mean±sd . ^#: calculated from regression equations (table 2 [20]) for height 1.75 m and age ≤59 yrs. ^¶: calculated from regression equations (see appendix [19]) for height 1.75 m and age 40 yrs. ⁺: calculated as mean T_L,NO/mean T_L,CO.

Table 2– Methodological aspects of the transfer factor of the lung for nitric oxide (T_L,NO) measurement in five reference studies

	van der Lee [13]	Aguilaniu [20]	Zavorsky [21]	Phansalkar [29]	Dressel [26]
Technique	Single breath	Single breath	Single breath	Rebreathing	Single breath
Commercial system	MasterLab Pro (Erich Jaeger^¶)	HypAir (Medisoft⁺)	HypAir (Medisoft)		Masterscreen PFT (Viasys^§)
NO analyser
Make	Chemiluminescence CLD 77AM (Eco Physics^ƒ)	Electrochemical cell (Medisoft)	Electrochemical cell (Medisoft)	Sievers nitric oxide analyzer 280 (Sievers Instruments, Inc.^##)	Electrochemical cell (Viasys)
Specification	Lower limit 0.02 ppb Upper limit 10 ppm Response time 0.1 s	Lower limit 0.1 ppm Upper limit 450 ppm Response time <10 s	Lower limit 0.1 ppm Upper limit 450 ppm Response time <10 s	Response time <0.5 s	Unknown
NO source	750 ppm in N₂	450 ppm in N₂	450 ppm in N₂		448 ppm in N₂
F_I,NO ppm	8	40	40	c. 40	45
Other gases %
Carbon monoxide	0.25	0.28	0.28	0.3	0.28
Helium	9.17	9.47 or 14	9.47 or 14		9.5
Oxygen		19 or 21	19 or 21	30
Methane				0.3
Acetylene^#				0.4–0.8
Balance gas	Air	N₂	N₂	N₂	Air
Breath hold time s	10	4	5.5	16 (rebreathe)	8
Discard volume mL	750	800	900	NA	750
Sample volume mL	750	600	900	NA	750

F_I,NO: inspiratory nitric oxide fraction; NA: not available; ^#: used for measuring total pulmonary blood flow; ^¶: Erich Jaeger, Friedberg, Germany; ⁺: Medisoft, Dinant, Belgium; ^§: Viasys, Hoechberg, Germany; ^ƒ: Eco Physics, Zurich, Switzerland; ^##: Sievers Instruments, Inc., Boulder, CO, USA.

Table 3– The T_L,NO/T_L,CO ratio in different situations and conditions

T_L,NO/T_L,CO	Situation/diagnosis	Explanation
Increased	High P_O₂ anaemia (uncorrected) [11]	Less binding sites available for CO which lowers T_L,CO but not T_L,NO
Increased	Heavy smokers [27] Diffuse parenchymal disease^# [24] Chronic thromboembolic pulmonary hypertension [24] Hepatopulmonary syndrome [25] Pulmonary artery occlusion in sheep [34]	Greater involvement of microvascular compartment reduces T_L,CO more than T_L,NO
Decreased	Rest to exercise (normals) [22] Voluntary restriction of lung expansion [13] mimicking “extrapulmonary restriction”	Expansion of capillary volume (per unit V_A) increases T_L,CO more than T_L,NO
Decreased	Sarcoidosis^¶ [29] Lifelong altitude exposure⁺ [23] Cystic fibrosis [26] Morbid obesity [19] Chronic heart failure [35] (unconfirmed for T_L,NO/T_L,CO ratio)	Alveolar surface area reduction exceeds microvascular damage, and affects T_L,NO more than T_L,CO

T_L,NO: transfer factor of the lung for nitric oxide; T_L,CO: transfer factor of the lung for carbon monoxide; P_O₂: oxygen tension; CO: carbon monoxide; V_A: alveolar volume. ^#: weighted towards sarcoidosis with end-stage disease; ^¶: sarcoidosis in stages II–III and younger than those in #; ⁺: “highlanders”, corrected for polycythaemia.

Table 4– Calculations of membrane diffusing capacity for nitric oxide (D_M,NO), membrane diffusing capacity for carbon monoxide (D_M,CO) and pulmonary capillary volume (V_c); see Appendix for explanation and commentary

	Data set	D_M,NO mL·min⁻¹·mmHg⁻¹	D_M,CO^# mL·min⁻¹·mmHg⁻¹	1/D_M,CO mL⁻¹·min·mmHg	1/Θ_bl,CO·V_c mL⁻¹·min· mmHg	1/Θ_bl,CO mL⁻¹·min mmHg·mL⁻¹	V_c mL	*1/Θ_bl,CO·V_c/(1/T_L,CO) ∼ T_L,CO red blood cell resistance %*	Comment
NO blood resistance=0 1/Θ_bl,NO = 0
	A	144	73	0.0137	0.0173	1.31	76	55	Most used Θ_bl value but at pH 8.0 [3]
	B	144	73	0.0137	0.0173	1.71	99	55	Θ_bl value at pH 7.4 [15]
	C	144	73	0.0137	0.0173	0.82	47	55	Θ_bl thin film exps [16]
Finite NO blood resistance (1/Θ_bl,NO·V_c)/(1/T_L,NO) = 37%
	D	230	117	0.0086	0.0224	1.31	58	72	D_M,NO from [10]:
	E	230	117	0.0086	0.0224	1.71	76	72	D_M,NO from [10]:
	F	230	117	0.0086	0.0224	0.82	37	72	D_M,NO from [10]:
	G	230			0.0026^¶	0.22⁺	88	36^§	From Roughton–Forster equation and 1/D_M,NO and 1/Θ_bl,NO

The calculations for D_M,CO and V_c were derived from “normal, resting” transfer factor of the lung for NO (T_L,NO; 144 mL·min⁻¹·mmHg⁻¹) and T_L,NO/T_L,CO ratio (4.5) [1, 12, 19, 22–26] (T_L,CO=32 mL min⁻¹ mmHg⁻¹); for situations where NO uptake blood resistance is zero (1/D_M,NO = 1/T_L,NO) or finite (1/D_M,NO<1/T_L,NO). D_M,CO derived from D_M,NO for α = 1.97 (NO/CO diffusivity ratio), and V_c derived via Roughton–Forster equation 1 for different experimental values of the blood resistance to carbon monoxide transfer (1/Θ_bl,CO; at P_O₂ 100 mmHg). Multiply by three to convert to SI units (mmol·min⁻¹·kPa⁻¹1) from mL·min⁻¹·mmHg⁻¹.^#: α = 1.97; ^¶: 1/Θ_bl,NO·V_c was used not 1/Θ_bl,CO·V_c; ⁺: 1/Θ_bl,NO was used not 1/Θ_bl,CO; ^§: ∼NO red blood cell resistance % was used not T_L,CO red blood cell resistance %.