Nitric oxide and carbon monoxide diffusing capacity of the lung Diffusiecapaciteit van de long voor stikstofmonoxide en koolmonoxide (met een samenvatting in het Nederlands) PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op dinsdag 20 juni 2006 des middags te 16.15 uur door Ivo van der Lee geboren op 3 augustus 1967 te Herten Promotores: prof. dr. J.M.M. van den Bosch prof. dr. J-W. J. Lammers Co-promotor: dr. P. Zanen Printing of this thesis was supported by grants from Boehringer Ingelheim, GlaxoSmithKline, Bayer Healthcare, Roche Nederland, Altana Pharma, Merck Sharp & Dohme. II Nitric oxide and carbon monoxide diffusing capacity of the lung Voor mijn ouders III ISBN xxx.xxxx.xxxx Copyright © 2006 by I. van der Lee Printed by: Drukkerij Gravé Cover design: R. Smink IV Contents Chapter 1: General Introduction............................................................1 History...............................................................................................1 The carbon monoxide diffusing capacity of the lung (DLCO)...........3 Clinical use of the DLCO ...................................................................5 The dependency of the DLCO on the alveolar volume (VA ).............6 The value of the measurement of Dm/Vcap.....................................8 The carbon monoxide diffusing capacity of the lung (DLNO).........10 Interpretation of diffusion impairment............................................13 Conclusion.......................................................................................14 Outline of this thesis........................................................................16 References.......................................................................................17 Part 1: The carbon monoxide diffusion capacity of the lung Chapter 2: Pattern of diffusion disturbance related to clinical diagnosis: the KCO has no diagnostic value next to the DLCO ..............................23 Abstract...........................................................................................24 Introduction.....................................................................................25 Methods...........................................................................................26 Results.............................................................................................30 Discussion.......................................................................................32 References.......................................................................................39 Chapter 3: Alveolar volume determined by single-breath helium dilution correlates with the high-resolution computed tomography- derived nonemphysematous lung volume...........................................43 Abstract...........................................................................................44 Introduction.....................................................................................45 Methods...........................................................................................46 Results.............................................................................................47 Discussion.......................................................................................50 References.......................................................................................53 Chapter 4: Early diagnosis of emphysema: computed tomography versus pulmonary function testing......................................................55 Abstract...........................................................................................56 Introduction.....................................................................................57 Methods...........................................................................................58 Results.............................................................................................60 Discussion.......................................................................................65 References.......................................................................................68 V Part 2: The nitric oxide diffusion capacity of the lung Chapter 5: Diffusing capacity for nitric oxide: reference values and dependence on alveolar volume..........................................................73 Abstract...........................................................................................74 Introduction.....................................................................................75 Methods...........................................................................................76 Results.............................................................................................78 Discussion.......................................................................................82 References.......................................................................................85 Chapter 6: The effect of red cell transfusion on nitric oxide diffusing capacity...............................................................................................87 Abstract...........................................................................................88 Introduction.....................................................................................89 Methods...........................................................................................90 Results.............................................................................................93 Discussion.......................................................................................95 References.......................................................................................97 Chapter 7: Diffusing capacity for nitric oxide and carbon monoxide in patients with diffuse parenchymal lung disease and pulmonary arterial hypertension........................................................................................99 Abstract.........................................................................................100 Introduction...................................................................................101 Methods.........................................................................................102 Results...........................................................................................104 Discussion.....................................................................................107 References.....................................................................................111 Chapter 8: The nitric oxide transfer factor as a tool for the early diagnosis of emphysema...................................................................115 Abstract.........................................................................................116 Introduction...................................................................................117 Methods.........................................................................................118 Results...........................................................................................119 Discussion.....................................................................................122 References.....................................................................................126 Chapter 9: Summary, conclusions and view.....................................129 Samenvatting.....................................................................................137 Dankwoord........................................................................................149 Curriculum vitae................................................................................152 VI General Introduction Chapter 1 General Introduction 1 Chapter 1 History Simple measurements of vital capacity were first performed in the middle of the 17th century by Borelli (1679). Hutchinson (1846) designed a spirometer to assess vital capacity and performed some studies. In that second half of the 19th century, rapid progression was noted in the field of lung mechanics and from the beginning of the 20th century pulmonary gas exchange became a research topic in physiology. Great differences in views were present: J.S. Haldane (1860-1936) and Christian Bohr (1855-1911) supported the concept of “oxygen secretion” as the major function of the lung. In this concept the oxygen uptake by the lung was seen as an active process. August Krogh (1874-1949) on the contrary supported the concept of a passive diffusion of oxygen from the alveolar air to the pulmonary capillaries. Marie Krogh (1874-1943), August’s wife, was the first to develop the basis underlying the measurement of the diffusing capacity of the lung 1. She used carbon monoxide in a single breath inspiration method and up to now this method has not changed very much. After the development of the fast infrared carbon monoxide meter in the Second World War the measurement of the diffusing capacity of the lung was standardized and it became a routine method in many lung function laboratories 2. Roughton and Forster 3 revitalized the diffusing capacity measurement by distinguishing two major components: the passage of the (test)gas through the alveolocapillary/red blood cell membrane and the uptake of gas by hemoglobin in the red blood cell. They developed a method which could be used in a lung function