Objectives After completing this article, readers should be able to:

Article pulmonology Measurement of Forced Expiratory Flows and Lung Volumes Myrza R. Perez, MD,* Daniel J. Weiner, MD* Objectives After completing this article, readers should be able to: 1. Describe the information that measurements of forced expiratory flow can provide in spontaneously breathing and mechanically ventilated infants. 2. Delineate how lung volume can be measured. Introduction The measurements of and lung volumes are important to the evaluation of patients who have respiratory symptoms. Until recently, measurements have been restricted to adults and children old enough to cooperate with testing maneuvers. Newer techniques have enabled such measurements to be made in infants and led to improved understanding of normal lung and airway growth during infancy and early childhood, when dramatic changes occur. The measurements have had important clinical uses in the evaluation and treatment of infants who have respiratory disease, but their use has been limited because they require specialized equipment and expertise as well as sedation of the infant. In this article, we discuss the techniques required for measurement of and lung volumes, their limitations, and applications in clinical practice. Forced Expiratory Flows Detection of airflow obstruction, by physical examination or by quantitative measurement techniques, is facilitated by increasing expiratory flow rates. Measurement of forced expiratory flows is useful because flow rates are inversely proportional to the fourth power of the radius of the airway and, therefore, are indicative of airway size when flow is limited. Disease states affecting the airways, including asthma, bronchopulmonary dysplasia (BPD), or congenital lesions such as pulmonary hypoplasia or vascular airway compression, are expected to decrease expiratory flow. Infants typically are sedated for testing to maintain relaxed breathing with a face mask placed over the mouth and nose. This sedation often is perceived by parents and physicians as one of the barriers to such testing. (1) However, sedation can be achieved safely using oral chloral hydrate at a dose of 80 to 100 mg/kg. The primary risks of such sedation are hypoxemia and paradoxic excitement or dizziness, with occasional infants experiencing nausea or vomiting. Abbreviations BPD: bronchopulmonary dysplasia FRC: functional residual capacity RDS: respiratory distress syndrome RTC: rapid thoracic compression RV-RTC: raised volume rapid thoracic compression V maxfrc: maximal flow at FRC Rapid Thoracic Compression Technique Older children who perform spirometry are coached to inspire to near total lung capacity, then to exhale rapidly and forcefully down to residual volume. Because cooperation generally cannot be obtained from infants and toddlers, other techniques have been used. (2) The rapid thoracic compression (RTC) technique has been used to generate maximal expiratory flow by applying a positive pressure externally to the chest. This involves a plastic jacket that encircles the chest and abdomen of the sedated, supine infant that can be inflated rapidly ( 100 msec) from a pressure reservoir using a valve that can be controlled manually or by *Division of Pulmonary Medicine, The Children s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, PA. e202 NeoReviews Vol.5 No.5 May 2004

Figure 1. Rapid thoracic compression method for measurement of forced flows. A. Configuration of patient and equipment. The thorax is encircled by an inflatable jacket that is attached to a gas reservoir. A face mask is applied over the mouth and nose to measure expiratory flow and volume. B. Expiratory flow-volume curve. Because the volume plotted is exhaled volume, lung volume in the patient is higher at the left of the volume axis. The smaller, oval shaped curve is generated during tidal breathing. The lung volume at the end of tidal exhalation is functional residual capacity (FRC). The larger curve is the partial expiratory curve generated by rapid compression of the thorax. Maximal flow is quantitated by extrapolating a line from FRC volume to the maximal flow line. The normal shape of the curve is convex toward the volume axis, with peak flow occurring relatively early in exhalation and flow sustained well past FRC. Reprinted with permission from Stocks J, Sly PD, Tepper RS, Morgan WJ. Infant Respiratory Function Testing. New York, NY: John Wiley & Sons; 1996:382 384. computer (Fig. 1A). The inflation is timed to occur at end inspiration, (3) when the infant s lung volume is just above functional residual capacity (FRC). Approximately 20% to 50% of the pressure applied to the chest is transmitted to the pleural space. Expiratory flow (and volume, by computer integration of the flow signal) is measured via a face mask and pneumotachograph, and a partial forced expiratory flow-volume curve over the tidal range of breathing can be constructed (Fig. 1B). As in older children or adults, the shape of the flow volume curve can provide important information about the site of obstruction. (3)(4) For example, an expiratory curve that is concave to the volume axis is consistent with intrathoracic obstruction (which may be seen in asthma, BPD, or cystic fibrosis). Truncation of peak flow, with a plateau over the tidal volume, is suggestive of a central airway lesion, such as tracheomalacia or vascular compression. Jacket pressures (via the inflating reservoir) are increased on serial maneuvers until no further increases in expiratory flow occur, which suggests flow limitation. Flow limitation occasionally cannot be achieved in healthy infants over the range of jacket pressures used commonly. Instantaneous flows are measured, the most common being the flow rate at functional residual capacity (V maxfrc). Increasing flow rates above tidal flow values enhances the ability to detect abnormal airway function. The externally applied thoracic pressure is contraindicated in infants who have pneumothorax, active pulmonary bleeding, rib fractures, or an otherwise unstable chest wall, but gastrostomy tubes or central venous catheters should not preclude testing. Infants weighing as little as 2.1 kg have been studied using RTC, although a commercial system approved by the United States Food and Drug Administration is restricted to infants weighing at least 5 kg. There are now several commercially available systems (see http://www.collinsmedical.com/ for information about the Collins Infant Pulmonary Lab or http://www.viasyshealthcare.com/ for information about the Jaeger MasterScreen Baby Body). The RTC has been used serially to assess normal and abnormal airway growth and to gain understanding of airway function in a variety of disease states. Baraldi and associates (5) made serial measurements (from birth to 2 y) of pulmonary mechanics in 24 infants who had BPD and measured V maxfrc using RTC at 2 years of age. In early infancy, respiratory system compliance was reduced severely, and respiratory system resistance was elevated significantly; these measures improved gradually over the first postnatal year and were near normal by age 2 years. However, forced expiratory flow remained low ( 40% predicted) in 70% of the infants. Interestingly, V maxfrc NeoReviews Vol.5 No.5 May 2004 e203

Figure 2. Raised volume rapid thoracic compression (RV-RTC) method for measurement of forced flows. A. Configuration of patient and equipment. The thorax is encircled by an inflatable jacket that is attached to a gas reservoir. A face mask is applied over the mouth and nose to measure expiratory flow and volume. For RV-RTC, airflow from a pump is directed through the mask to inflate the infant s lungs prior to rapid compression by the jacket. B. Three completely superimposable full expiratory flow volume curves. The largest curves represent maximal flow from a raised lung volume and look very much like curves obtained from cooperative children and adults. The smaller triangular-shaped curves represent passive exhalation after inflation to total lung capacity. At the far right (at lower lung volume), a triangular partial expiratory flow volume curve is superimposed over the even smaller oval-shaped tidal breaths. Note the substantial difference between the partial expiratory flow volume curve and the maximal flow volume curve obtained after inflation. Reprinted with permission from Stocks J, Sly PD, Tepper RS, Morgan WJ. Infant Respiratory Function Testing. New York, NY: John Wiley & Sons; 1996:393 400. at 2 years of age correlated strongly with respiratory system compliance at 10 to 20 postnatal days, during the more acute phase of lung disease. These data suggest that airway obstruction persists in older infants who have BPD and that the degree of obstruction might be predicted from measurements earlier in life. One major limitation of the RTC technique is that flows are dependent on the lung volume at which they are measured. (6) End-expiratory lung volume in infants can vary dramatically because maintenance of the FRC is a dynamic process. Infants use expiratory laryngeal braking and postinspiratory activity of the diaphragm to maintain their FRCs above a volume that would be determined passively by elastic recoil. The FRC, thus, can change from breath to breath; instability of the FRC limits the reproducibility of flow measurements and may decrease the sensitivity of the technique to subtle changes in airway mechanics. Interventions that relieve airway obstruction also might decrease air trapping, with resultant flows measured at lower lung volumes. In such situations, improvement in airway function may be masked. Additionally, the flows are measured only over the tidal volume range, a relatively small portion of the infant s lung volume, rather than over the entire range of lung volumes, as they would be in older children and adults. Raised Volume Rapid Thoracic Compression Technique A modification of the RTC technique has been used to overcome the variability in lung volume at which forced flows are measured (Fig. 2). (7)(8) In the raised volume rapid thoracic compression (RV-RTC) technique, the infant s lung is inflated initially to a predetermined pressure (typically, 30 cm H 2 O). This results in an endinspiratory lung volume that is close to total lung capacity (in contrast, the RTC technique begins measurement close to FRC). After several inflations, the Hering- Breuer reflex is elicited, and a brief apnea ensues, relaxing the muscles of the chest wall. Relaxation of the chest wall enhances transmission of the externally applied pressure to the pleural space. From this raised lung volume, the jacket encompassing the chest is inflated rapidly from the pressure reservoir, generating a full expiratory flowvolume curve (Video #1). The resultant curves are highly reproducible, with values being reported as timed volumes (eg, FEV 0.5, FEV 0.75 ) in addition to instantaneous flow rates. This technique also allows for flows to be measured over a larger portion of the vital capacity. Wildhaber and colleagues (9) compared the two forced expiratory flow techniques in infants who were wheezing and suggested that the RV-RTC technique is e204 NeoReviews Vol.5 No.5 May 2004

more sensitive than the RTC maneuver at detecting airway obstruction. The V maxfrc from RTC and FEV 0.5 from RV-RTC were compared with subjective measures (by parents and clinicians) of health in the infants. The infants were studied using both techniques at different times; once when ill and again when well. There was no significant difference in V maxfrc when the infants were ill compared with when they were judged to be well. However, the FEV 0.5 was significantly lower during illness. There also was a significant improvement in FEV 0.5 (but not V maxfrc) as the illness resolved. In addition, there was good correlation between FEV 0.5 and the physician s assessment. In contrast, maternal symptom assessment did not correlate with FEV 0.5. Parental reporting of symptoms has been criticized in the past as an investigative outcome measure for not being entirely accurate. This study confirmed the poor correlation between parental determination of symptom severity and objective measures of lung function. This helps to underscore the importance of having objective measurements of lung function in disease monitoring and management for infants as they are used in older children who have chronic respiratory diseases such as asthma and cystic fibrosis. The RV-RTC technique has offered insight into airway function of healthy infants. (10) The maximal expiratory flows of 41 healthy infants were analyzed using RV-RTC at baseline and following inhalation of albuterol or placebo. There was a statistically significant rise in FEV 0.5, FEF 0.75, and FEF 0.85 in the albuterol-treated infants. This change was greater in infants younger than 1 year of age compared with older infants. The authors concluded that healthy infants have similar degrees of airway tone compared with older children, and younger infants and those exposed to environmental tobacco smoke are more likely to show bronchodilator response. Forced Deflation Technique An alternative method of measuring forced expiratory flow over the vital capacity is the forced deflation technique. (11) This technique uses a negative pressure applied to the airway opening (rather than an externally applied positive pressure) following several inflations to near total lung capacity. This can be accomplished only in intubated and sedated (and frequently paralyzed) infants. The analysis methods are similar to those used with RV-RTC, integrating expiratory flow with respect to time to obtain forced vital capacity. Instantaneous flows generally are referenced to a volume above residual volume (eg, MEF 25 is maximal flow at 25% of vital capacity above residual volume). This technique, while applicable to intubated infants, requires the elimination of leaks with a cuffed endotracheal or tracheostomy tube. The forced deflation technique was used to study longitudinal changes in pulmonary function in 11 infants who had moderate-to-severe BPD and tracheostomies. (12) Infants were grouped according to duration of ventilation ( 5 mo versus 10 mo) and studied at 6 months, 12 to 15 months, 24 months, and 36 months of age. MEF 25 was low in both groups at 6 months and gradually increased in infants ventilated for a shorter course. They remained severely decreased, however, in infants ventilated for a longer course. Similarly, vital capacity remained low in the infants ventilated longer but improved in infants ventilated for a shorter period. Most infants also demonstrated significant bronchodilator responsiveness. These data demonstrated that airway hyperreactivity can be detected early in infants who have BPD and that it persists. Additionally, lower airway obstruction gradually improves but persists to some extent even at 3 years of age. Lung Volumes As in older children and adults, lung volumes in infants can be measured by dilutional techniques or by body plethysmography. (13)(14) Theoretically, both techniques can be used to measure any lung volume from residual volume to total lung capacity. In practice, however, the lung volume measured is from the endexpiratory lung volume (FRC). Once the FRC has been determined, other lung volumes can be calculated using other values from spirometry. Helium dilution employs the principle of conservation of mass to calculate FRC. (15) The infant breathes a gas mixture through a face mask from a closed circuit that has a known volume (V 1 ) and contains a known concentration (C 1 ) of helium, an inert gas not taken up across the alveolar-capillary membrane. After an equilibration period, the final concentration of helium is measured in the breathing circuit. The conservation of mass principle (C 1 V 1 C 2 V 2 ) is used to calculate the volume that was added to the circuit, which is the volume in the lung of the infant (V 2 V 1 V lung ). Leaks in the circuit result in overestimation of the lung volume (because the final concentration of helium is artifactually low). Because of this, dilutional techniques are not suitable for intubated infants unless they have cuffed endotracheal tubes. Also, noncommunicating portions of the lung volume (eg, due to airway obstruction) are not measured, and dilutional techniques underestimate the true lung volume in these cases. Another dilutional technique involves the washout NeoReviews Vol.5 No.5 May 2004 e205

of nitrogen from the infant s lung. (13) While the infant breathes 100% oxygen, nitrogen is exhaled from the lung and collected in a reservoir until the exhaled concentration of nitrogen is nearly zero. After this equilibration, and knowing the initial concentration of nitrogen in the lung (approximately 80% of the gas if the infant was breathing room air) and the volume of the reservoir, the FRC can be calculated. The time needed to reach equilibration by either dilutional technique depends on the homogeneity of ventilation in the lung and may be as long as 5 to 7 minutes in the presence of significant lung disease. Gerhardt and associates (16) measured lung volumes serially (1, 3, 6, 12, 18, 24, and 36 mo) in 39 preterm infants who had chronic lung disease using nitrogen washout. FRC was decreased in the first 6 months of life, but normalized thereafter. Furthermore, it increased proportionately to somatic growth and at the same rate as in healthy infants. This was speculated to reflect rapid postnatal alveolar growth in these infants. Lung volumes measured using plethysmography involve application of Boyle s Law: (P 1 V 1 ) (P 1 P) (V 1 V) where P 1 is mouth pressure, V 1 is the infant s resting lung volume, and P and V are the pressure and volume changes during breathing efforts against an occluded airway. For these measurements, the infant is placed within a rigid, closed container (Video #2). The infant breathes through a face mask connected to an airway pressure gauge and a pneumotach to measure flow and volume. A shutter within the face mask can occlude the infant s airway briefly; continued respiratory efforts alternately compress and rarify the gas within the lung. Because airflow is absent when the shutter occludes the airway, there is no pressure loss from airflow resistance, and the pressure measurements made at the mask (airway opening) are reflective of alveolar pressure. By relating alveolar pressure changes to the volume changes in the plethysmograph (which are equal and opposite to those in the infant s lung), the volume of gas within the lung can be calculated. Plethysmographic measurements include any gas in the thorax, including that in lung units subtended by obstructed airways. The two techniques used to measure lung volumes were compared in infants who did and did not have BPD by Wauer and associates. (17) FRC measured by nitrogen washout (FRC N2 ) was compared with that volume measured by plethysmography (FRC pleth ) in healthy infants, infants who had respiratory distress syndrome (RDS), and infants who had BPD. The dilutional measurement was lower in the infants who had RDS or BPD compared with controls. The difference between the two measurements reflected the volume of gas in obstructed portions of the lung and was significantly greater in the infants who had BPD compared with infants who had RDS or controls. There has been some interest in using bedside measurements of lung volumes in mechanically ventilated infants to guide adjustments in end-expiratory pressure, hoping to target a normal FRC and avoid overdistension of the lung. Infants receiving mechanical ventilation cannot be studied within the plethysmograph, but they can undergo dilutional measurements with helium or nitrogen as long as their FiO 2 s are less than 0.65 mm Hg and there are no leaks in the system (requiring a cuffed endotracheal tube). One major limitation to the measurement of fractional lung volumes in the plethysmograph in combination with RV-RTC is that total lung capacity is determined passively by external active inflation to a predetermined pressure. This is in contrast to older children and adults where volitional effort and respiratory muscle strength are required to reach this volume. Therefore, infants who have inspiratory muscle weakness may have a normal-appearing total lung capacity, and their weakness may not be apparent without direct measurement of muscle pressures (see article on tests of respiratory muscle strength in this issue). Summary Measurement of and lung volumes can provide important insights into the normal growth and development of the infant lung as well as information about developmental abnormalities or changes due to disease states. They can offer vital information to guide the management of infants who have known lung disease or to aid in the evaluation of symptoms for which the diagnosis is not clear. Serial measurements may help to prognosticate the course of chronic lung diseases such as BPD or cystic fibrosis. These measurements also continue to be important for research involving new therapies or ventilator strategies for infants. With recently improved equipment and measurement techniques, these measurements should be more readily available to physicians caring for infants who have lung disease. References 1. Hayden MJ, Wildhaber JH, LeSouef PN. Parental attitudes toward infant pulmonary function testing. Pediatr Pulmonol. 1998; 25:309 313 e206 NeoReviews Vol.5 No.5 May 2004

2. Morgan WJ, Geller DE, Tepper RS, Taussig LM. Partial expiratory flow-volume curves in infants and young children. Pediatr Pulmonol. 1988;5:232 243 3. Miller RD, Hyatt RE. Evaluation of obstructing lesions of the trachea and larynx by flow-volume loops. Am Rev Respir Dis. 1973;108:475 481 4. Fillipone M, Narne S, Pettenazzo A, Zacchello F, Baraldi E. Functional approach to infants and young children with noisy breathing: validation of pneumotachography by blinded comparison with bronchoscopy. Am J Respir Crit Care Med. 2000;162: 1795 1800 5. Baraldi E, Filippone M, Trevisanuto D, Zanardo V, Zacchello F. Pulmonary function until two years of life in infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med. 1997;155: 149 155 6. Davis S, Jones M, Kisling J, Angelicchio C, Tepper RS. Effect of continuous positive airway pressure on in infants with tracheomalacia. Am J Respir Crit Care Med. 1998;158: 148 152 7. The raised volume rapid thoracoabdominal compression technique. The Joint American Thoracic Society/European Respiratory Society Working Group on Infant Lung Function. Am J Respir Crit Care Med. 2000;161:1760 1762 8. Castile R, Filbrun D, Flucke R, Franklin W, McCoy K. Adulttype pulmonary function tests in infants without respiratory disease. Pediatr Pulmonol. 2000;30:215 227 9. Wildhaber JH, Dore ND, Devadason SG, et al. Comparison of subjective and objective measures in recurrently wheezy infants. Respiration. 2002;69:397 405 10. Goldstein AB, Castile RG, Davis SD, et al. Bronchodilator responsiveness in normal infants and young children. Am J Respir Crit Care Med. 2001;164:447 454 11. Mallory GB Jr, Motoyama EK, Koumbourlis AC, Mutich RL, Nakayama D. Bronchial reactivity in infants in acute respiratory failure with viral bronchiolitis. Pediatr Pulmonol. 1989;6:253 259 12. Mallory GB Jr, Chaney H, Mutich RL, Motoyama EK. Longitudinal changes in lung function during the first three years of premature infants with moderate to severe bronchopulmonary dysplasia. Pediatr Pulmonol. 1991;11:8 14 13. Morris MG, Gustafsson P, Tepper R, Gappa M, Stocks J. The bias flow nitrogen washout technique for measuring the functional residual capacity in infants. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J. 2001;17: 529 536 14. Stocks J, Godfrey S, Beardsmore C, Bar-Yishay E, Castile R. Plethysmographic measurements of lung volume and airway resistance. ERS/ATS Task Force on Standards for Infant Respiratory Function Testing. European Respiratory Society/American Thoracic Society. Eur Respir J. 2001;17:302 312 15. McCoy KS, Castile RG, Allen ED, Fibrun DA, Flucke RL, Bar-Yishay E. Functional residual capacity (FRC) measurements by plethysmography and helium dilution in normal infants. Pediatr Pulmonol. 1995;19:282 290 16. Gerhardt T, Hehre D, Feller R, Reifenberg L, Bancalari E. Serial determination of pulmonary function in infants with chronic lung disease. J Pediatr. 1987;110:448 456 17. Wauer RR, Maurer T, Nowotny T, Schmalisch G. Assessment of functional residual capacity using nitrogen washout and plethysmographic techniques in infants with and without bronchopulmonary dysplasia. Intensive Care Med. 1998;24:469 475 NeoReviews Quiz 6. The measurement of and lung volumes are important for the evaluation of patients, including infants, who have respiratory disease. Of the following, the test most sensitive at detecting airway obstruction in a spontaneously breathing infant involves the technique of: A. Body plethysmography. B. Forced deflation. C. Helium dilution. D. Nitrogen washout. E. Rapid thoracic compression. NeoReviews Vol.5 No.5 May 2004 e207