Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

PART ONE – Basic Principles in Pediatric Anesthesia

Chapter 2 – Respiratory Physiology in Infants and Children

Etsuro K. Motoyama

  

 

Development of the Respiratory System, 12

  

 

Prenatal Development of the Lungs, 12

  

 

Neonatal Respiratory Adaptation, 15

  

 

Postnatal Development of the Lungs and Thorax, 15

  

 

Prenatal Development of Breathing, 16

  

 

Perinatal Adaptation of Breathing, 16

  

 

Control of Breathing, 17

  

 

Neural Control of Breathing, 17

  

 

Chemical Control of Breathing, 20

  

 

Control of Breathing in Neonates and Infants, 23

  

 

Maintenance of the Upper Airway and Airway Protective Reflexes, 25

  

 

Anesthetic Effects on Control of Breathing, 27

  

 

Lung Volumes, 29

  

 

Postnatal Development of the Lungs, 29

  

 

Functional Residual Capacity and Its Determinants, 30

  

 

Mechanics of Breathing, 31

  

 

Elastic Properties, 32

  

 

Dynamic Properties, 36

  

 

Ventilation, 41

  

 

Dead Space and Alveolar Ventilation, 41

  

 

Distribution of Ventilation, 42

  

 

Clinical Implications, 43

  

 

Gas Diffusion, 44

  

 

Pulmonary Circulation, 44

  

 

Perinatal and Postnatal Adaptation, 44

  

 

Nitric Oxide and Pulmonary Circulation, 45

  

 

Distribution of Pulmonary Perfusion, 45

  

 

Ventilation/Perfusion Relationships, 46

  

 

Oxygen Transport, 48

  

 

Oxygen Affinity of Hemoglobin and P50, 48

  

 

Surface Activity and Pulmonary Surfactant, 52

  

 

Ciliary Activity, 54

  

 

Measurements of Pulmonary Function in Infants and Children, 54

  

 

Standard Tests of Pulmonary Function, 55

  

 

Evaluation of Upper Airway Function, 57

  

 

Airway Reactivity, 58

  

 

Pulmonary Function Tests in Infants, 59

  

 

Indication for and Interpretation of Pulmonary Function Tests, 60

  

 

Summary, 61

For an infant to survive in the extrauterine environment, the respiratory and circulatory systems must be developed sufficiently to withstand drastic changes at birth, from the fetal circulatory pattern with liquid-filled lungs to air breathing with transitional circulatory adaptation in a matter of a few minutes. The newborn infant must exercise an effective neuronal drive and respiratory muscles to displace the liquid filling the airway system and to introduce sufficient air against the surface force in order to establish sufficient alveolar surface for gas exchange. At the same time, pulmonary blood vessels must dilate to increase pulmonary blood flow and to establish adequate regional alveolar ventilation-pulmonary perfusion relationships for pulmonary gas exchange. The neonatal adaptation of lung mechanics and respiratory control takes several weeks to complete. Beyond this immediate neonatal period, the infant's lungs continue to mature at a rapid pace and postnatal development of the lungs and the thorax surrounding the lungs continues well beyond the first year of life. Respiratory function in infants and toddlers, especially during the first several months of age, as with cardiovascular system and hepatic function, is both qualitatively and quantitatively different from that in older children and adults.

This chapter reviews clinically important aspects of the development of the respiratory system and respiratory physiology in infants and children and their application to pediatric anesthesia. Such knowledge is indispensable for the proper care of infants and children before, during, and after general anesthesia and surgery, as well as for the care of those with respiratory insufficiency.

The respiratory system consists of the respiratory centers in the brainstem; the central and peripheral chemoreceptors; the phrenic, intercostal, hypoglossal (all efferent), and vagal (afferent) nerves; the thorax (including the thoracic cage; the muscles of the chest, abdomen, and diaphragm); the upper (extrathoracic) and lower (intrathoracic) airways; the lungs; and the pulmonary vascular system. The principal function of the respiratory system is to maintain the oxygen and carbon dioxide equilibrium in the body. The lungs also contribute importantly to the regulation of acid-base balance. The maintenance of body temperature (via loss of water through the lungs) is an additional but secondary function of the lungs. The lung is also an important organ of metabolism. A glossary of abbreviations used in this chapter is compiled in Box 2-1 . An additional glossary of abbreviations specific to the mechanics of respiration is summarized in Box 2-2 .

BOX 2-1 

Glossary of Abbreviations 1 (General Topics)

  

 

ALTE: Apparent life-threatening events (near-miss SIDS)

  

 

ARDS: Acute (adult) respiratory distress syndrome

  

 

cAMP: Cyclic adenosine monophosphate

  

 

CPAP: Continuous positive airway pressure

  

 

CSF: Cerebrospinal fluid

  

 

DPG: Diphosphoglycerate

  

 

DRG: Dorsal respiratory group neurons (versus VRG)

  

 

EGF: Epidermal growth factor

  

 

EMG: Electromyogram

  

 

ET: Endotracheal

  

 

ETT: Endotracheal tube

  

 

HMD: Hyaline membrane disease (IRDS)

  

 

HPV: Hypoxic pulmonary vasoconstriction

  

 

IRDS: Idiopathic (infantile) respiratory distress syndrome

  

 

Pa: Pulmonary arterial pressure

  

 

PA: Alveolar pressure

  

 

Pao: Airway opening pressure

  

 

Palv: Alveolar pressure

  

 

PV: Pulmonary venous pressure

  

 

P50: Arterial oxygen tension (Pao2) at 50% hemoglobin saturation

  

 

PC: Phosphatidylcholine

  

 

Pco2: Partial pressure of carbon dioxide

  

 

Pao2: Arterial oxygen tension (or partial pressure)

  

 

PETCO2: End-tidal carbon dioxide tension

  

 

PE: Phosphatidylethanolamine

  

 

PEEP: Positive end-expiratory pressure

  

 

PG: Phosphatidylglycerol

  

 

Po2: Partial pressure of oxygen

  

 

Pao2: Arterial oxygen tension (or partial pressure)

  

 

Pvo2: Venous oxygen tension

  

 

PPHN: Persistent pulmonary hypertension of the neonate

  

 

PRG: Pontine respiratory group of neurons

  

 

PS: Phosphatidylserine

  

 

   : Pulmonary blood flow

  

 

   P/   S: Pulmonary-to-systemic blood flow ratio

  

 

R: Resistance

  

 

Raw: Airway resistance

  

 

Rint: Resistive component of Rrs

  

 

Rrs: Total resistance of the respiratory system

  

 

ΔR: Viscoelastic component of Rrs

  

 

RARs: Rapidly adapting (irritant) receptors

  

 

REM: Rapid eye movement (sleep)

  

 

SARs: Slowly adapting (pulmonary stretch) receptors

  

 

SIDS: Sudden infant death syndrome

  

 

So2: Oxygen saturation of hemoglobin

  

 

Sao2: Arterial So2

  

 

Spo2 Sao2: As measured with a pulse oximeter

  

 

SP-A (B, C, D): Surfactant protein A (B, C, D)

  

 

TGFβ: Transforming growth factor-β

  

 

TNFα: Tumor necrosis factor-α

  

 

   A/   : Ventilation/pulmonary perfusion ratio

  

 

VRG: Ventral respiratory groups of neurons

BOX 2-2 

Glossary of Abbreviations 2 (Respiratory Mechanics)

  

 

CL: Compliance of lungs

  

 

Crs: Compliance of respiratory system

  

 

Cw: Compliance of chest wall

  

 

ERV: Expiratory reserve volume

  

 

f: Respiratory frequency

  

 

FEV1.0: Forced expiratory volume at 1.0 second

  

 

FRC: Functional residual capacity

  

 

FVC: Forced vital capacity

  

 

Gaw: Airway conductance (reciprocal of Raw)

  

 

IC: Inspiratory capacity

  

 

IRV: Inspiratory reserve volume

  

 

MEFV: Maximum expiratory flow-volume (curve)

  

 

MMEFR: Maximum mid-expiratory flow rate (same as FEF25-75)

  

 

PEFR: Peak expiratory flow rate

  

 

Pao: Airway opening pressure

  

 

Palv: Alveolar pressure

  

 

PB: Atmospheric pressure

  

 

Ppl: Pleural pressure

  

 

Pstl: Static recoil pressure of the lungs

  

 

Raw: Airway resistance

  

 

Rrs: Resistance of respiratory system

  

 

Rus: Airway resistance of upstream segment

  

 

RV: Residual volume

  

 

TI: Inspiratory time

  

 

TI/TTOT: Respiratory duty cycle

  

 

TE: Expiratory time

  

 

TTOT: Total respiratory time (T1 + TE)

  

 

TLC: Total lung capacity

  

 

VT: Tidal volume

  

 

VT/TI: Mean inspiratory flow (neural drive)

  

 

VC: Vital capacity

  

 

Visov: Volume of isoflow

  

 

   E: Minute volume (   = VT × f = VT/TI × TI/TTOT)

  

 

   max25: Maximum expiratory flow at 25% FVC (FEF75 or MEF25)

▪ DEVELOPMENT OF THE RESPIRATORY SYSTEM

▪ PRENATAL DEVELOPMENT OF THE LUNGS

The morphologic development of the human lung is seen as early as several weeks into the embryonic period and continues well into the first decade and beyond of postnatal life ( Fig. 2-1 ). The fetal lungs begin to form within the first several weeks of the embryonic period, when the fetus is only 3 mm long. A groove appears in the ventral aspect of the foregut, creating a small pouch. The outgrowth of the endodermal cavity, with a mass of surrounding mesenchymal tissue, projects into the pleuroperitoneal cavity and forms lung buds. The future alveolar membranes and mucous glands are derived from the endoderm, whereas the cartilage, muscle, elastic tissue, and lymph vessels originate from the mesenchymal elements surrounding the lung buds ( Emery, 1969 ). During the pseudoglandular period, which extends until the seventeenth week of gestation, the budding ofthe bronchi and lung growth rapidly takes place, forming a loose mass of connective tissue. The morphologic development of the human lung is illustrated in Figure 2-2 .

 
 

FIGURE 2-1  Stages of human lung development and their timing. Note the overlap between stages, particularly between the alveolar stage and the stage of microvascular maturation. Open-ended bars indicate uncertainty as to exact timing.  (From Zeltner TB, Burri PH:Respir Physiol 67:269, 1987, with permission from Elsevier.)

 



 
 

FIGURE 2-2  Development of the acinus in human lungs at various ages. TB, Terminal bronchiole; RB, respiratory bronchiole; TD, transitional duct; S, saccule; TS, terminal saccule; AD, alveolar duct; At, atrium; AS, alveolar sac.  (From Hislop A, Reid L: Thorax 29:90, 1974.)

 

 

 

By 16 weeks gestation, preacinar branching of the airways (down to the terminal bronchioli) is complete ( Reid, 1967 ). A disturbance of the free expansion of the developing lung during this stage, as occurs with diaphragmatic hernia, results in hypoplasia of the airways and lung tissue ( Areechon and Reid, 1963 ).

During the canalicular period, in mid-gestation, the future respiratory bronchioli develop as the relative amount of connective tissue diminishes. Capillaries grow adjacent to the respiratory bronchioli, and the whole lung becomes more vascular ( Emery, 1969 ).

At about 24 weeks gestation, the lung enters the terminal sac (alveolar) period, which is characterized by the appearance of clusters of terminal air sacs, termed saccules, with flattened epithelium ( Hislop and Reid, 1974 ). These saccules are large and irregular with thick septa and have few capillaries in comparison with the adult alveoli ( Boyden, 1969 ). At about 26 to 28 weeks gestation, proliferation of the capillary network surrounding the terminal air spaces becomes sufficient for pulmonary gas exchange ( Potter, 1961 ). These morphologic developments may occur earlier in some premature infants born at 24 to 25 weeks gestation who have survived with neonatal intensive care.

Air space wall thickness decreases rapidly starting at 28 weeks gestation. From 28 weeks gestation to term, there is further lengthening of saccules with possible growth of additional generations of air spaces. Some species, such as the rat, have no mature alveoli at birth ( Burri, 1974 ). Alveolar development from saccules begins in some human fetuses as early as 32 weeksgestation, but alveoli are not uniformly present until 36 weeks of gestation ( Langston et al., 1984 ). Most alveolar formation, however, takes place during the first 12 to 18 months of postnatal life ( Langston et al., 1984 ). Development of respiratory bronchioles by transformation of preexisting terminal airways does not take place until after birth ( Langston et al., 1984 ).

The fetal lung produces a large quantity of liquid, which expands the airways while the larynx is closed. This expansion helps to stimulate lung growth and development. The lung fluid is periodically expelled into the uterine cavity and contributes about one third of the total amniotic fluid. Prenatal ligation or occlusion of the trachea was tried in the 1990s with some success for the treatment of the fetus with congenital diaphragmatic hernia. This treatment causes the expansion of the fetal airways and results in an accelerated growth of the otherwise hypoplastic lung (see Chapter 15 , Anesthesia for Fetal Surgery).

The type II pneumocytes, which produce pulmonary surfactant that forms the alveolar lining layer and stabilizes air spaces, appear at about 24 to 26 weeks gestation, but occasionally as early as 20 weeks (Spear et al., 1969 ; Lauweryns, 1970 ). Idiopathic (or infantile) respiratory distress syndrome (IRDS), also known as hyaline membrane disease (HMD), occurring in prematurely born infants, is caused by the immaturity of the lung, with its insufficient pulmonary surfactant production, and its inactivation by plasma proteins exudating onto the alveolar surface (see discussion under Surface Activity and Pulmonary Surfactant).

Experimental evidence from animals indicates that certain pharmacologic agents such as cortisol ( deLemos et al., 1970 ; Motoyama et al., 1971 ) and thyroxin ( Wu et al., 1973 ) administered to the mother or directly to the fetus accelerate the maturation of the lungs, resulting in the early appearance of type II pneumocytes and surfactant ( Smith and Bogues, 1982 ; Rooney, 1985 ). In 1972, Liggins and Howie reported accelerated maturation of human fetal lungs after the administration of corticosteroids to mothers 24 to 48 hours before the delivery of premature babies. Despite initial concern that steroids are potentially toxic to other organs of the fetus, particularly to the development of the central nervous system, prenatal glucocorticoid therapy has been used widely since the 1980s to induce lung maturation and surfactant synthesis in mothers at risk of premature delivery (Avery, 1984, 1986 [16] [17]).

▪ NEONATAL RESPIRATORY ADAPTATION

Respiratory rhythmogenesis occurs in the fetus long before partition. The clamping of the umbilical cord and increasing arterial oxygen tensions with air breathing (but not transient hypoxia) initiate and maintain rhythmic breathing at birth.

To introduce air into the fluid-filled lungs at birth, the newborn infant must overcome large surface force with the first few breaths. Usually a negative pressure of 30 cm H2O is necessary to introduce air into the fluid-filled lungs. In some normal full-term infants, even with sufficient surfactant, a force of as much as -70 cm H2O or more must be exerted to overcome the surface force ( Karlberg et al., 1962 ) ( Fig. 2-3 ). Usually fluid is rapidly expelled via the upper airways. The residual fluid leaves the lungs through the pulmonary capillaries and lymphatic channels over the first few days of life, and changes in compliance parallel this time course. All changes are delayed in the prematurely born infant.

 
 

FIGURE 2-3  (A) Typical pressure-volume curve of expansion of a gas-free lung. (A, B) Initial expansion. In the example, approximately 30 cm H2O pressure will be necessary to overcome surface forces. (C) Deflation to zero pressure with gas trapping. (D, E) Subsequent breaths with a further increase in FRC. (B) Pressure-volume relationships during the first breath of a newborn weighing 4.3 kg. Here, 60 to 70 cm H2O negative pressure was necessary to overcome the surface forces.  (From Karlberg P, Cherry RB, Escardo FE, Koch G: Acta Paediatr Scand 51:121, 1962.)

 

 

 

As the lungs expand with air, pulmonary vascular resistance decreases dramatically and pulmonary blood flow increases markedly, thus allowing gas exchange between alveolar air and pulmonary capillaries to occur. Changes in Po2, Pco2, and pH are largely responsible for this decrease in pulmonary vascular resistance ( Cook et al., 1963 ). With the expansion of the lung, arterial oxygen tension (Pao2) increases and reduces pulmonary vascular resistance dramatically. The resultant large increases in pulmonary blood flow and the increase in left atrial pressure with a decrease in right atrial pressure reverse the pressure gradient across the atria and functionally close the foramen ovale, a left-to-right one-way valve. With these adjustments, the cardiopulmonary system approaches adult levels of    A/   balance within a few days (Nelson et al., 1962, 1963 [301] [302]). The process of expansion of the lungs during the first few hours of life and the resultant circulatory adaptation for establishing pulmonary gas exchange are greatly influenced by the adequacy of pulmonary surfactant. It should be remembered that these changes are delayed in immature newborns.

▪ POSTNATAL DEVELOPMENT OF THE LUNGS AND THORAX

The development and growth of the lung and surrounding thorax continue with amazing speed during the first year of life. Although the formation of the airway system, all the way to the terminal bronchioles, is completed by the 16th week of gestation, alveolar formation begins only at about the 36th week. At birth, the number of terminal air sacs (most of which are saccules) is between 20 and 50 million, only one tenth that of adults. Most of the postnatal development of alveoli from primitive saccules occurs during the first year and is essentially completed by 18 months of age ( Langston et al., 1984 ). The morphologic and physiologic development of the lungs, however, continues throughout the first decade of life ( Mansell et al., 1972 ).

During the early postnatal period, the lung volume of infants is disproportionately small in relation to body size. In addition, because of higher metabolic rates in infants (oxygen consumption per unit body weight is twice as high as that of adults), the ventilatory requirement per unit of lung volume in infants is markedly increased. Infants have much less reserve of lung surface area for gas exchange. This is the primary reason why infants and young children become rapidly desaturated with hypoventilation or apnea of relatively short duration.

In the neonate, static (elastic) recoil pressure of the lung is very low (i.e., compliance, normalized for volume, is high), not dissimilar to that of geriatric or emphysematous lungs, because the elastic fibers do not develop until the postnatal period (whereas elastic fibers in geriatric lungs are not functional ( Fagan, 1976 ; Mansel et al., 1972 ; Bryan and Wohl, 1986 ). In addition, the elastic recoil pressure of the infant's thorax (chest wall) is extremely low due to its compliant cartilaginous rib cage with poorly developed thoracic muscle mass, which does not add rigidity. These unique characteristics make infants more prone to lung collapse, especially under general anesthesia (see later). Throughout infancy and childhood, static recoil pressure of the lung steadily increases (compliance, normalized for volume, decreases) toward normal values for young adults ( Zapletal et al., 1971 ; Motoyama, 1977 ).

The actual size of the airway from the larynx to the bronchioles in infants and children, of course, is much smaller than in adolescents and adults, and flow resistance in absolute terms is extremely high. When normalized for lung volume or body size, however, infants—airway size is much larger and airway resistance is much lower than in adults ( Polgar, 1967 ; Motoyama, 1977 ; Stocks and Godfrey, 1977 ). Infants and toddlers, however, are more prone to severe obstruction of upper and lower airways because their absolute (not relative) airway diameters are much smaller than those in adults. As a consequence, relatively mild airway inflammation, edema, or secretions can lead to far greater degrees of airway obstruction like subglottic croup (laryngotracheobronchitis) or acute supraglottitis (epiglottitis) compared with adults.

Further description on the development of the lungs and thorax and their effects on lung function, especially under general anesthesia, are described later in the chapter. Perinatal and postnatal adaptations of respiratory control are included in the following section on the control of breathing.

▪ PRENATAL DEVELOPMENT OF BREATHING

Respiratory rhythmogenesis occurs long before parturition. Dawes and others (1970) were the first to demonstrate “breathing” activities with rhythmic diaphragmatic contractions in the fetal lamb. They found it to be episodic and highly variable in frequency. Boddy and Robinson (1971) recorded movement of the human fetal thorax with an ultrasound device and interpreted this as evidence of fetal breathing. Later studies ( Patrick et al., 1980 ) have shown that in the last 10 weeks of pregnancy, fetal breathing is present approximately 30% of the time. The breathing rate in the fetus at 30 to 31 weeks gestation is higher (58/min) than that in the near-term fetus (47/min). A significant increase in fetal breathing movements occurs 2 to 3 hours after a maternal meal and is correlated with the increase in the maternal blood sugar level ( Patrick et al., 1980 ).

Spontaneous breathing movements in the fetuses occur only during their active or rapid eye movement (REM) sleep and with low voltage electrocortical activity and appear to be independent of the usual chemical and nonchemical stimuli of postnatal breathing ( Dawes et al., 1972 ; Jansen and Chernick, 1983 ). Later studies, however, have clearly shown that the fetus can respond to chemical stimuli known to modify breathing patterns postnatally ( Dawes et al., 1982 ; Jansen et al., 1982 ; Rigatto et al., 1988 ; Rigatto, 1992 ). In contrast, hypoxemia in the fetus abolishes, rather than stimulates, breathing movements. This may be related to the fact that hypoxemia diminishes the incidence of REM sleep ( Boddy et al., 1974 ). It appears that normally low Pao2 (19 to 23 mm Hg) in the fetus is a normal mechanism inhibiting breathing activities in utero ( Rigatto, 1992 ). Severe hypoxemia induces gasping, which is independent of the peripheral chemoreceptors and apparently entirely independent of rhythmic fetal breathing ( Jansen and Chernick, 1974 ).

The near-term fetus is relatively insensitive to Pao2 changes. Extreme hypercapnia (Pao2 > 60 mm Hg) in the fetal lamb, however, can induce rhythmical breathing movement that is preceded by a sudden activation of inspiratory muscle tone with expansion of the thorax and inward movement (inhalation) of amniotic fluid, as much as 30 to 40 mL/kg (an apparent increase in functional residual capacity [FRC]) (E. K. Motoyama, unpublished observation). When Pao2 was reduced, breathing activities ceased, followed by a reversal of the sequence of events noted above (i.e., relaxation of the thorax, decreased FRC as evidenced by outward flow of amniotic fluid) ( Motoyama, 2001 ).

The inflation reflex of Hering-Breuer is present in the fetus. Distension of the lungs by saline infusion slows the frequency of breathing ( Dawes et al., 1982 ). Transection of the vagi, however, does not change the breathing pattern ( Dawes, 1974 ).

Maternal ingestion of alcoholic beverages abolishes human fetal breathing for up to 1 hour. Fetal breathing movement is also abolished by maternal cigarette smoking. These effects may be related to fetal hypoxemia resulting from changes in placental circulation ( Jansen and Chernick, 1983 ).

It is unclear why the fetus must “breathe” in utero, when gas exchange is handled by the placental circulation. Dawes (1974) suggested that fetal breathing might represent “prenatal practice”to ensure that the respiratory system is well developed and ready at the moment of birth. Another reason may be that the stretching of the airways and lung parenchyma is an important stimulus for lung development; bilateral phrenic nerve sectioning in the fetal lamb results in hypoplasia of the lungs ( Alcorn et al., 1980 ).

▪ PERINATAL ADAPTATION OF BREATHING

During normal labor and vaginal delivery, the human fetus goes through a period of transient hypoxemia, hypercapnia, and acidemia. The traditional view of the mechanism of the onset of breathing at birth was that the transient fetal asphyxia stimulates the chemoreceptors and produces gasping followed by rhythmic breathing at birth. Subsequent observations have challenged this concept. First, in full-term fetal lambs, severe hypoxemia stimulates fetal gasping and ventilation even after denervation of the carotid and aortic chemoreceptors ( Chernick et al., 1975 ). Second, total peripheral chemodenervation does not alter the pattern of fetal breathing or the initiation of continuous breathing at birth. Third, continuous breathing can be initiated and maintained by ventilating the fetal lamb through the endotracheal tube with 100% oxygen in utero and raising fetal Paco2 ( Baier et al., 1990 ). The occlusion of the umbilical cord also initiates the onset of rhythmic breathing, independent of Pao2 ( Baier et al., 1990 ;Rigatto, 1992 ). The current concept regarding the mechanism of continuous neonatal breathing is summarized in Box 2-3 .

BOX 2-3 

Mechanism of Continuous Neonatal Breathing

  

1.   

The onset of breathing activities occurs not at birth but in utero, as a part of normal fetal development.

  

2.   

The clamping of the umbilical cord initiates rhythmic breathing.

  

3.   

Relative “hyperoxia” with air breathing, compared with low fetal Pao2, augments and maintains continuous and rhythmic breathing.

  

4.   

Continuous breathing is independent of the level of Paco2.

  

5.   

Breathing is unaffected by carotid denervation.

  

6.   

Hypoxia depresses or abolishes continuous breathing.

Once the newborn has begun rhythmic breathing, ventilation is adjusted to achieve a lower Pao2 ( Table 2-1 ) than is found in older children and adults. The reason for this difference is not clear but most likely is related to a poor buffering capacity in the neonate and a ventilatory compensation for metabolic acidosis. The Pao2 of the infant approximates the adult level within a few weeks after birth ( Nelson, 1976 ).


TABLE 2-1   -- Normal blood-gas values

 

Pao2 (mm Hg)

Sao2 (%)

Paco2 (mm Hg)

pH

Pregnant woman at term (artery)

88[*]

96

32

7.40

Umbilical vein

31

72[*]

42

7.35

Umbilical artery

19

38[*]

51

7.29

1 Hour of life (artery)

62

95

28

7.36

24 Hours of life (artery)

68

94

29

7.37

Child and adult (artery)

99

97

41

7.40

*

Estimated values.

 

Control of breathing in the neonate evolves gradually during the first month of extrauterine life and beyond and is different from that in older children and adults, especially in their response to hypoxemia and hyperoxia. The neonates—breathing patterns and responses to chemical stimuli are detailed later, following a general overview of the control of breathing.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ CONTROL OF BREATHING

The mechanism that regulates and maintains pulmonary gas exchange is remarkably efficient. In a normal person, the level of arterial Pco2 is maintained within a very narrow range, whereas oxygen demand and carbon dioxide production vary greatly during rest and exercise. This control is achieved by a precise matching of the level of ventilation to the output of carbon dioxide. Breathing is produced by the coordinated action of a number of inspiratory and expiratory muscles. Inspiration is produced principally by the contraction of the diaphragm, which creates negative intrathoracic pressure that draws air into the lungs. Expiration, on the other hand, is normally produced passively by the elastic recoil of the lungs and thorax. It may be increased actively by the contraction of abdominal and thoracic expiratory muscles during exercise. During the early phase of expiration, sustained contraction of the diaphragm with decreasing intensity (braking action) and the upper airway muscles activities impede and smoothen the rate of expiratory flow.

Rhythmic contraction of the respiratory muscles is governed by the respiratory centers in the brainstem and tightly regulated by feedback systems so as to match the level of ventilation to metabolic needs (Cherniack and Pack, 1988 ) ( Fig. 2-4 ). These feedback mechanisms include central and peripheral chemoreceptors, stretch receptors in the airways and lung parenchyma via the vagal afferent, and segmental reflexes in the spinal cord provided by muscle spindles ( Cherniack and Pack, 1988 ). The control of breathing comprises neural and chemical controls, which are closely interrelated.

 
 

FIGURE 2-4  Block diagram of multi-input, multi-output system that controls ventilation.  (From Cherniak NS, Pack AI: Control of ventilation. In Fishman AP, editor: Pulmonary diseases and disorders, ed 2. New York, 1988, McGraw-Hill Book Co.)

 

 

 

▪ NEURAL CONTROL OF BREATHING

Respiratory neurons in the medulla have inherent rhythmicity even when they are separated from the higher levels of the brainstem. In the cat, respiratory neurons are concentrated in two bilaterally symmetric areas in the medulla near the level of the obex. The dorsal respiratory group of neurons (DRG) is located in the dorsomedial medulla just ventrolateral to the nucleus tractus solitarius and contains predominantly inspiratory neurons. The ventral respiratory group (VRG) of neurons, located in the ventrolateral medulla, consists of both inspiratory and expiratory neurons ( von Euler, 1986 ; Tabatabai and Behnia, 1995 ; Berger, 2000 ) ( Fig. 2-5 ).

 
 

FIGURE 2-5  Schematic representation of the respiratory neurons on the dorsal surface of the brainstem. Crosshatched areas contain predominantly inspiratory neurons, blank areas contain predominantly expiratory neurons, and dashed areas contain both inspiratory and expiratory neurons. Böt C, Bötzinger complex; C1, first cervical spinal nerve; CP, cerebellar peduncle; DRG, dorsal respiratory group; 4th Vent, fourth ventricle; IC, inferior colliculus; NA, nucleus ambiguus; NPA, nucleus para-ambigualis; NPBL, nucleus parabrachialis lateralis; NPBM, nucleus parabrachialis medialis; NRA, nucleus retroambigualis; PRG, pontine respiratory group; VRG, ventral respiratory group.  (From Tabatabai M, Behnia R: Neurochemical regulation of respiration. In Collins VJ, editor: Physiological and pharmacological basis of anesthesia. Philadelphia, 1995, Williams & Wilkins.)

 

 

 

Dorsal Respiratory Group (DRG) of Neurons

The DRG is spatially associated with the tractus solitarius, which is the principal tract for the ninth and tenth cranial (glossopharyngeal and vagus) nerves. These nerves carry afferent fibers from the airways and lungs, heart, and peripheral arterial chemoreceptors. The DRG may constitute the initial intracranial site for processing some of these visceral sensory afferent inputs into a respiratory motor response (Berger, 2000 ).

On the basis of lung inflation, three types of neurons have been recognized in the DRG: type Iα (I stands for inspiratory), type Iβ, and pump (P) cells. Type Iα is inhibited by lung inflation ( Cohen, 1981a ). The axons of these neurons project to both the phrenic and the external (inspiratory) intercostal motoneurons of the spinal cord. Some type Iα neurons have medullary collaterals that terminate among the inspiratory and expiratory neurons of the ipsilateral VRG ( Merrill, 1970 ).

The second type, Iβ, is excited by lung inflation and receives synaptic inputs from pulmonary stretch receptors. There is controversy as to whether Iβ axons project into the spinal cord respiratory neurons; the possible functional significance of such spinal projections is unknown. Both Iα and Iβ neurons receive excitatory inputs from the central pattern generator (or central inspiratory activity) for breathing, so that when lung inflation is terminated or the vagi in the neck are cut, the rhythmic firing activity of these neurons continues (Cohen, 198la, 1981b [71] [72]; Feldman and Speck, 1983 ).

The third type of neurons in the DRG receives no input from the central pattern generator. The impulse of these neurons, called pump, or P cells, closely follows lung inflation during either spontaneous or controlled ventilation ( Berger, 1977 ). The P cells are assumed to be relay neurons for visceral afferent inputs ( Berger, 2000 ).

The excitation of Iβ neurons by lung inflation is associated with the shortening of inspiratory duration. The Iβ neurons appear to promote inspiration-to-expiration phase-switching by inhibiting Iα neurons. This network seems to be responsible for the Hering-Breuer reflex inhibition of inspiration by lung inflation (Cohen, 198la, 1981b [71] [71]; von Euler, 1986, 1991 [441] [443]).

The DRG thus functions as an important primary and possibly secondary relay site for visceral sensory inputs via glossopharyngeal and vagal afferent fibers. Because many of the inspiratory neurons in the DRG project to the contralateral spinal cord and make excitatory connections with phrenic motoneurons, the DRG serves as a source of inspiratory drive to phrenic and possibly to external intercostal motoneurons ( Berger, 2000 ).

Ventral Respiratory Group (VRG) of Neurons

The VRG extends from the rostral to the caudal end of the medulla and has three subdivisions (see Fig. 2-5 ). The Bötzinger complex, located in the most rostral part of the medulla in the vicinity of the retrofacial nucleus, contains mostly expiratory neurons ( Lipski and Merrill, 1980 ; Merrill et al., 1983 ). These neurons send inhibitory signals to DRG and VRG neurons and project into the phrenic motoneurons of the spinal cord, causing its inhibition ( Bianchi and Barillot, 1982 ; Merrill et al., 1983 ). The physiologic significance of these connections may be to ensure inspiratory neuronal silence during expiration (reciprocal inhibition) and to contribute to the “inspiratory off-switch” mechanism.

The nucleus ambiguus (NA) and nucleus para-ambigualis (NPA), lying side by side, occupy the middle portion of the VRG. Axons of the respiratory motoneurons originating from the NA project along with other vagal efferent fibers and innervate the laryngeal abductor (inspiratory) and adductor (expiratory) muscles via the recurrent laryngeal nerve ( Barillot and Bianchi, 1971 ; Bastel and Lines, 1975 ). The NPA contains mainly inspiratory (Iγ) neurons, which respond to lung inflation in a manner similar to that of Iα neurons. The axons of these neurons project both to phrenic and external (inspiratory) intercostal motoneuron pools in the spinal cord. The nucleus retroambigualis (NRA) occupies the caudal part of the VRG and contains expiratory neurons whose axons project into the spinal motoneuron pools for the internal (expiratory) intercostal and abdominal muscles ( Merrill, 1970 ; Miller et al., 1985 ).

The inspiratory neurons of the DRG send collateral fibers to the inspiratory neurons of the NPA in the VRG. These connections may provide the means for ipsilateral synchronization of the inspiratory activity between the neurons in the DRG and those in the VRG (Merrill, 1979, 1983 [266] [267]). Furthermore, axon collaterals of the inspiratory neurons of the NPA on one side project to the inspiratory neurons of the contralateral NPA, and vice versa. These connections may be responsible for the bilateral synchronization of the medullary inspiratory motoneuron output, as evidenced by synchronous bilateral phrenic nerve activity (Merrill, 1979, 1983 [266] [267]).

Pontine Respiratory Group of Neurons

In the dorsolateral portion of the rostral pons, both inspiratory and expiratory neurons have been found. Inspiratory neuronal activity is concentrated ventrolaterally in the region of the nucleus parabrachialis lateralis (NPBL). The expiratory activity is centered more medially in the vicinity of the nucleus parabrachialis medialis (NPBM) ( Cohen, 1979 ; Mitchell and Berger, 1981 ) (see Fig. 2-5 ). The respiratory neurons of these nuclei are referred to as the pontine respiratory group (PRG) ( Feldman, 1986 ), which was, and sometimes still is, called the pneumotaxic center, although the term is generally considered obsolete. There are reciprocal projections between the PRG neurons and the DRG and VRG neurons in the medulla. Electrical stimulation of the PRG produces rapid breathing with premature switching of respiratory phases ( Cohen, 1971 ), whereas transaction of the brainstem at a level caudal to the PRG prolongs inspiratory time ( Feldman and Gautier, 1976 ). Bilateral cervical vagotomies produce a similar pattern of slow breathing with prolonged inspiratory time; a combination of PRG lesions and bilateral vagotomy in the cat results in apneusis (apnea with sustained inspiration) or apneustic breathing (slow rhythmic respiration with marked increase end-inspiratory hold) ( Feldman, 1986 ; Feldman and Gaultier, 1976) . The PRG probably plays a secondary role in modifying the inspiratory off-switch mechanism ( Gautier and Bertrand, 1975 ; von Euler and Trippenbach, 1975 ).

Respiratory Rhythm Generation

Rhythmic breathing in mammals can occur in the absence of feedback from peripheral receptors. Because transection of the brain rostral to the pons or high spinal transection has little effect on the respiratory pattern, respiratory rhythmogenesis apparently takes place in the brainstem. The PRG, DRG, and VRG have all been considered as possible sites of the central pattern generator, although its exact location is still unknown ( Cohen, 1981b ; von Euler, 1983, 1986 [441] [442]). A study with an in vitro brainstem preparation of neonatal rats has indicated that respiratory rhythm is generated in the small area in the ventrolateral medulla just rostral to the Bötzinger complex (pre-Bötzinger complex), which contains pacemaker neurons ( Smith et al., 1991 ).

The current consensus is that the pre-Bötzinger complex contains a group of neurons that is responsible for respiratory rhythmogenesis ( Smith et al., 1991 ; Pierrefiche et al., 1998 ; Rekling and Feldman, 1998 ). Although the specific cellular mechanism responsible for rhythmogenesis is not known, two possible mechanisms have been proposed ( Funk and Feldman, 1995 ; Ramirez and Richter, 1996 ). One hypothesis is that the pacemaker neurons possess intrinsic properties associated with various voltage- and time-dependent ion channels that are responsible for rhythm generation. Rhythmic activity in these neurons may depend on the presence of an input system that may be necessary to maintain the neuron's membrane potential in a range in which the voltage-dependent properties of the cell's ion channels result in rhythmic behavior. The network hypothesis is the alternative model in which the interaction between the neurons produces respiratory rhythmicity, such as reciprocal inhibition between inhibitory and excitatory neurons and recurrent excitation within any population of neurons ( Berger, 2000 ). The output of this central pattern generator is influenced by various inputs from chemoreceptors (central and peripheral), mechanoreceptors (pulmonary receptors, muscle and joint receptors), thermoreceptors (central and peripheral), nociceptors, and higher central structures (such as the PRG). The function of these inputs is to modify the breathing pattern to meet and adjust to ever-changing metabolic and behavioral needs ( Smith et al., 1991 ).

Airway and Pulmonary Receptors

The upper airways, trachea and bronchi, lungs, and chest wall have a number of sensory receptors sensitive to mechanical and chemical stimulation. These receptors affect ventilation as well as circulatory and other nonrespiratory functions.

Upper Airway Receptors

Stimulation of receptors in the nose can produce sneezing, apnea, changes in bronchomotor tone, and the diving reflex, which involves both the respiratory and the cardiovascular systems. Stimulation of the epipharynx causes the sniffing reflex, a short, strong inspiration to bring material (mucus, foreign body) in the epipharynx into the pharynx to be swallowed or expelled. The major role of receptors in the pharynx is associated with swallowing. It involves the inhibition of breathing, closure of the larynx, and coordinated contractions of pharyngeal muscles ( Widdicombe, 1985 ; Nishino, 1993 ;Sant'Ambrogio et al., 1995) .

The larynx has a rich innervation of receptors. The activation of these receptors can cause apnea, coughing, and changes in the ventilatory pattern (Widdicombe, 1981, 1985 [463] [465]). These reflexes, which influence both the patency of the upper airway and the breathing pattern, are related to transmural pressure and/or airflow. Based on single-fiber action potential recordings from the superior laryngeal nerve in the spontaneously breathing dog preparation in which the upper airway is isolated from the lower airways, three types of receptors have been identified: pressure receptors (most common, about 65%), “drive” (or irritant) receptors (stimulated by upper airway muscle activities), and flow or cold receptors ( Sant'Ambrogio et al., 1983 ; Fisher et al., 1985 ). The laryngeal flow receptors show inspiratory modulation with room air breathing but become silent when inspired air temperature is raised to body temperature and 100% humidity or saturation ( Sant'Ambrogio et al., 1985) . The activity of pressure receptors increases markedly with upper airway obstruction ( Sant'Ambrogio et al., 1983) .

Tracheobronchial and Pulmonary Receptors

Three major types of tracheobronchial and pulmonary receptors have been recognized: slowly adapting (pulmonary stretch) receptors, rapidly adapting (irritant or deflation) receptors, both of which lead to myelinated vagal afferent fibers, and unmyelinated C-fiber endings (J-receptors). Excellent reviews on pulmonary receptors have been published ( Pack, 1981 ; Widdicombe, 1981 ; Sant'Ambrogio, 1982 ;Coleridge and Coleridge, 1984 ).

Slowly Adapting (Pulmonary Stretch) Receptors.

Slowly adapting (pulmonary stretch) receptors (SARs) are mechanoreceptors that lie within the submucosal smooth muscles in the membranous posterior wall of the trachea and central airways ( Bartlett et al., 1976 ). A small proportion of the receptors are located in the extrathoracic upper trachea ( Berger, 2000 ). SARs are activated by the distension of the airways during lung inflation and inhibit inspiratory activity (Hering-Breuer inflation reflex), whereas they show little response to steady levels of lung inflation. The Hering-Breuer reflex also produces dilation of the upper airways from the larynx to the bronchi. Although SARs are predominantly mechanoreceptors, hypocapnia stimulates their discharge, and hypercapnia inhibits it ( Pack, 1981 ). In addition, SARs are thought to be responsible for the accelerated heart rate and systemic vasoconstriction observed with moderate lung inflation ( Widdicombe, 1974 ). These effects are abolished by bilateral vagotomy.

Studies by Clark and von Euler (1972) have demonstrated the importance of the inflation reflex in adjusting the pattern of ventilation in the cat and the human. In cats anesthetized with pentobarbital, inspiratory time decreases as tidal volume increases with hypercapnia, indicating the presence of the inflation reflex in the normal tidal volume range. Clark and von Euler demonstrated an inverse hyperbolic relationship between the tidal volume and inspiratory time. In the adult human, inspiratory time is independent of tidal volume until the latter increases to about twice the normal tidal volume, when the inflation reflex appears ( Fig. 2-6 ). In the newborn, particularly the premature newborn, the inflation reflex is present in the eupneic range for a few months ( Olinsky et al., 1974 ).

 
 

FIGURE 2-6  Relationship between tidal volume (VT) and inspiratory time (TI) as ventilation is increased in response to respiratory stimuli. Note that in region I, VT increases without changes in TI. Also shown as dashed lines are the VT trajectories for three different tidal volumes in region II.  (From Berger AJ: Control of breathing. In Murray JF, Nadel JA: Textbook of respiratory medicine. Philadelphia, 1994, WB Saunders.)

 



Apnea, frequently observed in adult patients at the end of surgery and anesthesia with the endotracheal tube cuff still inflated, may be related to the inflation reflex, since the trachea has a high concentration of stretch receptors ( Bartlett et al., 1976 ; Sant'Ambrogio, 1982) . Deflation of the cuff promptly restores rhythmic spontaneous ventilation.

Rapidly Adapting (Irritant) Receptors.

Rapidly adapting (irritant) receptors (RARs) are located superficially within the airway epithelial cells, mostly in the region of the carina and the large bronchi ( Pack, 1981 ; Sant'Ambrogio, 1982) . RARs respond to both mechanical and chemical stimuli. In contrast to SARs, RARs adapt rapidly to large lung inflation, distortion, or deflation, thus possessing marked dynamic sensitivity ( Pack, 1981 ). RARs are stimulated by cigarette smoke, ammonia, and other irritant gases including inhaled anesthetics, with significant interindividual variability ( Sampson and Vidruk, 1975 ). RARs are stimulated more consistently by histamine ( Vidruk et al., 1977 ) and prostaglandins ( Coleridge et al., 1976 ; Sampson and Vidruk, 1977 ), suggesting their role in response to pathologic states ( Berger, 2000 ). The activation of RARs in the large airways may be responsible for various reflexes, including coughing, bronchoconstriction, and mucus secretion. Stimulation of RARs in the periphery of the lungs may produce hyperpnea. Because RARs are stimulated by deflation of the lungs to produce hyperpnea in animals, they are considered to play an important role in the Hering-Breuer deflation reflex ( Sellick and Widdicombe, 1970 ). This reflex, if it exists in humans, may partly account for increased respiratory drive when the lung volume is abnormally decreased, as in premature infants with IRDS and in pneumothorax.

When vagal conduction is partially blocked by cold, inflation of the lung produces prolonged contraction of the diaphragm and deep inspiration instead of inspiratory inhibition. This reflex, the paradoxical reflex of Head, is most likely mediated by RARs. It may be related to the complementary cycle of respiration, or the sigh mechanism, that functions to reinflate and reaerate parts of the lungs that have collapsed because of increased surface force during quiet, shallow breathing ( Mead and Collier, 1959 ). In the newborn, inflation of the lungs initiates gasping. This mechanism, which was considered to be analogous to the paradoxical reflex, may help to inflate unaerated portions of the newborn lung ( Cross et al., 1960 ).

C-Fiber Endings.

Most afferent axons arising from the lungs, heart, and other abdominal viscera are slow conducting (<2.5 m/sec), unmyelinated vagal fibers (C-fibers). Extensive studies by Paintal (1973) have suggested the presence of receptors supposedly located near the pulmonary or capillary wall (juxtapulmonary capillary or J-receptors) innervated by such C-fibers. C-fiber endings are stimulated by pulmonary congestion, pulmonary edema, pulmonary microemboli, and irritant gases such as anesthetics. Such stimulation causes apnea followed by rapid, shallow breathing, hypotension, and bradycardia. Stimulation of J-receptors also produces bronchoconstriction and increases mucus secretion. All these responses are abolished by bilateral vagotomy. In addition, stimulation of C-fiber endings can provoke severe reflex contraction of the laryngeal muscles, which may be partly responsible for the laryngospasm observed during induction of anesthesia with isoflurane or halothane.

In addition to receptors within the lung parenchyma (pulmonary C-fiber endings), there appear to be similar nonmyelinated nerve endings in the bronchial wall (bronchial C-fiber endings) ( Coleridge and Coleridge, 1984 ). Both chemical and, to a lesser degree, mechanical stimuli excite these bronchial C-fiber endings. They are also stimulated by endogenous mediators of inflammation, including histamine, prostaglandins, serotonin, and bradykinin. Such stimulation may be a mechanism of C-fiber involvement in disease states such as pulmonary edema, pulmonary embolism, and asthma ( Coleridge and Coleridge, 1984 ).

The inhalation of irritant gases or particles causes a sensation of tightness or distress in the chest, probably by activating pulmonary receptors. The pulmonary receptors may contribute to the sensation of dyspnea in lung congestion, atelectasis, and pulmonary edema. Bilateral vagal blockade in patients with lung disease abolished dyspneic sensation and increased breath-holding time ( Noble et al., 1970 ).

Chest Wall Receptors

The chest wall muscles, including the diaphragm and the intercostal muscles, contain various types of receptors that can produce respiratory reflexes. This subject has been reviewed extensively ( Newsom-Davis, 1974 ; Duron, 1981 ). The two types of receptors that have been most extensively studied are muscle spindles, which lie parallel to the extrafusal muscle fibers, and the Golgi tendon organs, which lie in series with the muscle fibers ( Berger, 2000 ).

Muscle spindles are a type of slowly adapting mechanoreceptors that detect muscle stretch. As in other skeletal muscles, the muscle spindles of respiratory muscles are innervated by γ-motoneurons that excite intrafusal fibers of the spindle.

Intercostal muscles have a density of muscle spindles comparable to that of other skeletal muscles. The arrangement of muscle spindles is appropriate for the respiratory muscle load-compensation mechanism ( Berger, 2000 ). By comparison with the intercostal muscles, the diaphragm has a very low density of muscle spindles and is poorly innervated by the γ-motoneurons. Reflex excitation of the diaphragm, however, can be achieved via proprioceptive excitation within the intercostal system ( Decima and von Euler, 1969 ).

Golgi tendon organs are located at the point of insertion of the muscle fiber into its tendon and, like muscle spindles, are a slowly adapting mechanoreceptor. Activation of the Golgi tendon organs inhibits the homonymous motoneurons, possibly preventing the muscle from being overloaded ( Berger, 2000 ). In the intercostal muscles, fewer Golgi tendon organs are present than muscle spindles, whereas the ratio is reversed in the diaphragm.

▪ CHEMICAL CONTROL OF BREATHING

Regulation of alveolar ventilation and maintenance of normal arterial Pco2, pH, and Po2 are the principal functions of the medullary and peripheral chemoreceptors ( Leusen, 1972 ).

Central Chemoreceptors

The medullary, or central, chemoreceptors, located near the surface of the ventrolateral medulla, are anatomically separated from the medullary respiratory center ( Fig. 2-7 ). They respond to changes in hydrogen ion concentration in the adjacent cerebrospinal fluid rather than to changes in arterial Pco2 or pH ( Pappenheimer et al., 1965 ). Since carbon dioxide rapidly passes through the blood-brain barrier into the cerebrospinal fluid, which has poor buffering capacity, the medullary chemoreceptors are readily stimulated by respiratory acidemia. In contrast, ventilatory responses of the medullary chemoreceptors to acute metabolic acidemia and alkalemia are limited because changes in the hydrogen ion concentration in arterial blood are not rapidly transmitted to the cerebrospinal fluid. In chronic acid-base disturbances, the pH of cerebrospinal fluid (and presumably that of interstitial fluid) surrounding the medullary chemoreceptors is generally maintained close to the normal value of about 7.3 regardless of arterial pH ( Mitchell et al., 1965 ). Under these circumstances, ventilation becomes more dependent on the hypoxic response of peripheral chemoreceptors.

 
 

FIGURE 2-7  View of the ventral surface of the medulla shows the chemosensitive zones. The rostral (R) and caudal (C) zones are chemosensitive. The intermediate (I) zone is not chemosensitive but may have a function in the overall central chemosensory response. The roman numerals indicate the cranial nerves.  (Reproduced with permission from Berger AJ, Hornbein TF: Control of respiration. In Patton HD, Fuchs AF, Hille B, et al., editors: Textbook of physiology, ed 21. Philadelphia, 1989, WB Saunders, pp 1026-1045.)

 



Peripheral Chemoreceptors

Peripheral chemoreceptors, particularly the carotid bodies, located near the bifurcation of the common carotid artery, react rapidly to changes in Pao2 and pH. Their contribution to the respiratory drive amounts to about 15% of resting ventilation ( Severinghaus, 1972 ). The carotid body has three types of neural components: type I (glomus) cells, presumably the primary site of chemotransduction; type II (sheath) cells; and sensory nerve fibers ( McDonald, 1981 ). Sensory nerve fibers originate from terminals in apposition to the glomus cells, travel via the carotid sinus nerve to join the glossopharyngeal nerve, and then enter the brainstem. The sheath cells envelop both the glomus cells and the sensory nerve terminals. A variety of neurochemicals have been found in the carotid body, including acetylcholine, dopamine, substance P, enkephalins, and vasoactive intestinal peptide. The exact functions of these cell types and the mechanisms of chemotransduction and the specific roles of these neurochemicals have not been well established ( Berger, 2000 ).

The carotid bodies are perfused with extremely high levels of blood flow and respond rapidly to an oscillating Pao2 rather than a constant Pao2 at the same mean values ( Dutton et al., 1964 ; Fenner et al., 1968 ). This mechanism may be partly responsible for hyperventilation during exercise.

The primary role of peripheral chemoreceptors is their response to changes in arterial Po2. Moderate to severe hypoxemia (Pao2 <60 mm Hg) results in a significant increase in ventilation in all age groups (Dripps and Comroe, 1947 ) except for newborn, particularly premature, infants, whose ventilation is decreased by hypoxemia ( Rigatto et al., 1975) . Peripheral chemoreceptors are also partly responsible for hyperventilation in hypotensive patients. Respiratory stimulation is absent in certain states of tissue hypoxia, such as moderate to severe anemia and carbon monoxide poisoning; despite a decrease in oxygen content, Pao2 in the carotid bodies is maintained near normal levels, so that the chemoreceptors are not stimulated.

In acute hypoxemia, the ventilatory response via the peripheral chemoreceptors is partially opposed by hypocapnia, which depresses the medullary chemoreceptors. When a hypoxemic environment persists for a few days, for example, during an ascent to high altitude, ventilation increases further as cerebrospinal fluid bicarbonate decreases and pH returns toward normal ( Severinghaus et al., 1963 ). However, later studies demonstrated that the return of cerebrospinal fluid pH toward normal is incomplete, and a secondary increase in ventilation precedes the decrease in pH, indicating that some other mechanisms are involved ( Bureau and Bouverot, 1975 ; Foster et al., 1975 ). In chronic hypoxemia lasting for a number of years, the carotid bodies initially exhibit some adaptation to hypoxemia and then gradually lose their hypoxic response. In high altitude natives, the blunted response of carotid chemoreceptors to hypoxemia takes 10 to 15 years to develop and is sustained thereafter ( Sorensen and Severinghaus, 1968 ; Lahiri et al., 1978 ). In cyanotic heart diseases, the hypoxic response is lost much sooner but returns after surgical correction of the right-to-left shunts ( Edelman et al., 1970 ).

In patients who have chronic respiratory insufficiency with hypercapnia, hypoxemic stimulation of the peripheral chemoreceptors provides the primary impulse to the respiratory center. If these patients are given excessive levels of oxygen, the stimulus of hypoxemia is removed, and ventilation decreases or ceases. Pco2 further increases, patients become comatose (carbon dioxide narcosis), and death may follow unless ventilation is supported. Rather than oxygen therapy, such patients need their effective ventilation increased artificially with or without added inspired oxygen.

Response to Carbon Dioxide

The graphic demonstration of relations between the alveolar or arterial Pco2 and the minute ventilation (   .E/Pco2) is commonly known as the CO2 response curve ( Fig. 2-8 ). This curve normally reflects the response of the chemoreceptors and respiratory center to carbon dioxide. The CO2 response curve is a useful means for evaluation of the chemical control of breathing, provided that the mechanical properties of the respiratory system, including the neuromuscular transmission, respiratory muscles, thorax, and lungs, are intact. In normal persons, ventilation increases more or less linearly as the inspired concentration of carbon dioxide increases up to 9% to 10%, above which ventilation starts to decrease ( Dripps and Comroe, 1947 ). Under hypoxemic conditions the CO2 response is potentiated, primarily via carotid body stimulation, resulting in a shift to the left of the CO2 response curve ( Nielsen and Smith, 1951 ) (see Fig. 2-8 ). On the other hand, anesthetics, opioids, and barbiturates in general depress the medullary chemoreceptors and, by decreasing the slope, shift the CO2 response curve progressively to the right as the anesthetic concentration increases ( Munson et al., 1966 ) ( Fig. 2-9 ).

 
 

FIGURE 2-8  Effect of acute hypoxemia on the ventilatory response to steady-state Pao2 in one subject. Inspired oxygen was adjusted in each experiment to keep Pao2 constant at the level as indicated.  (From Nielsen M, Smith H: Acta Physiol Scand 24:293, 1951.)

 

 

 

 
 

FIGURE 2-9  CO2 response curve with halothane. Family of steady-state CO2 response curves in one subject awake and at three levels of halothane anesthesia. Note progressive decrease in ventilatory response to Pao2 with increasing anesthetic depth (MAC) (ventilatory response in awake state was measured in response to end-tidal Pco2).  (Courtesy Dr. Edwin S. Munson; data based on Munson ES, Larson CP Jr, Babad AA, et al.: Anesthesiology 27:716, 1966.)

 

 

 

A shift to the right of the CO2 response curve in an awake human may be caused by decreased chemoreceptor sensitivity to carbon dioxide, as seen in patients whose carotid bodies had been destroyed (Wade et al., 1970 ). It may also be caused by lung disease and resultant mechanical failure to increase ventilation despite intact neuronal response to carbon dioxide. In patients with various central nervous system dysfunctions, the CO2 response may be partially or completely lost (Ondine's curse) ( Severinghaus and Mitchell, 1962 ). In the awake state, these patients have chronic hypoventilation but can breathe on command. During sleep, they further hypoventilate or become apneic to the point of carbon dioxide narcosis and death unless mechanically ventilated or implanted with a phrenic pacemaker (Glenn et al., 1973 ).

It has been difficult to separate the neuronal component from the mechanical failure of the lungs and thorax, because the two factors often coexist in patients with chronic lung diseases( Guz et al., 1970 ).Whitelaw and others (1975) demonstrated that occlusion pressure at 0.1 second (P0.1, or the negative mouth pressure generated by inspiratory effort against airway occlusion at FRC) correlates well with neuronal (phrenic) discharges but is uninfluenced by mechanical properties of the lungs and thorax. The occlusion pressure is a useful means for the clinical evaluation of the ventilatory drive.

As mentioned previously, hypoxemia potentiates the chemical drive and increases the slope of the CO2 response curve (   E/Pco2). Such a change has been interpreted as “a synergistic (or multiplicative) effect” of the stimulus, whereas a parallel shift of the curve has been considered as “an additive effect.” This analysis may be useful for descriptive purposes, but it is misleading. Because ventilation is the product of tidal volume and frequency (   E=VT × f), an additive effect on its components could result in a change in the slope of the CO2 response curve. Obviously the response to carbon dioxide of tidal volume and frequency should be examined separately to understand the effect of various respiratory stimulants and depressants.

Milic-Emili and Grunstein (1975) proposed that ventilatory response to carbon dioxide be analyzed in terms of the mean inspiratory flow (VT/TI, where VT is tidal volume and TI is the inspiratory time) and in terms of the ratio of inspiratory time to total ventilatory cycle duration or respiratory duty cycle (TI/TTOT) ( Fig. 2-10 ). Because the tidal volume is equal to VT/TI × TI and respiratory frequency f is 1/TTOT, ventilation can be expressed as follows:

 
 

FIGURE 2-10  Schematic drawing of tidal volume and timing components on time-volume axes. VT, Tidal volume; TI, inspiratory time; TE, expiratory time; TTOT, total time for respiratory cycle; f, respiratory frequency; VT/TI, mean inspiratory flow rate; TI/TTOT, respiratory duty cycle (see text).

 

 

The advantage of analyzing the ventilatory response in this fashion is that VT/TI, is an index of inspiratory drive, which is independent of the timing element. The tidal volume, on the other hand, is time dependent, because it is (VT/TI) × TI. The second parameter, TI/TTOT, is a dimensionless index of effective respiratory timing (respiratory duty cycle) that is determined by the vagal afferent or central inspiratory off-switch mechanism or by both ( Bradley et al., 1975 ). From this equation, it is apparent that in respiratory disease or under anesthesia, changes in pulmonary ventilation may result from a change in VT/TI, TI/TTOT, or both. A reduction in TI/TTOT indicates that the relative duration of inspiration decreased or that expiration increased. Such a reduction in the TI/TTOT ratio may result from changes in central or peripheral mechanisms. In contrast, a reduction in VT/TI may indicate a decrease in the medullary inspiratory drive or neuromuscular transmission or an increase in inspiratory impedance (i.e., increased flow resistance, decreased compliance, or both). By relating the mouth occlusion pressure to VT/TI, it becomes clinically possible to determine whether changes in the mechanics of the respiratory system contribute to the reduction in VT/TI ( Milic-Emili, 1977 ).

Analysis of inspiratory and expiratory durations provides useful information on the mechanism of anesthetic effects on ventilation. Figure 2-11 illustrates the effect of pentobarbital, which depresses minute ventilation, and diethyl ether, which “stimulates” ventilation in newborn rabbits. With both anesthetics the mean inspiratory flow (VT/TI) did not change, but VT decreased because TI was shortened. With pentobarbital, however, TE was prolonged disproportionately, and TI/TTOT and frequency decreased; consequently, minute ventilation was decreased. With ether, on the other hand, ventilation increased as the result of disproportionate decrease in TE and consequent increases in TI/TTOT and frequency ( Milic-Emili, 1977 ).

 
 

FIGURE 2-11  Schematic summary of changes in the average respiratory cycle in a group of newborn rabbits before and after sodium pentobarbital anesthesia (left) and before and during ether anesthesia (right). Measurements obtained during spontaneous room air breathing. Zero on the time axis indicates onset of inspiration. Mean inspiratory flow is represented by the slope of the ascending limb of the spirograms.

 

 

▪ CONTROL OF BREATHING IN NEONATES AND INFANTS

Response to Hypoxemia in Infants

During the first 2 to 3 weeks of age, both full-term and premature infants in a warm environment respond to hypoxemia (15% oxygen) with a transient increase in ventilation followed by sustained ventilatory depression ( Brady and Ceruti, 1966 ; Rigatto and Brady, 1972a, 1972b [370] [371]; Rigatto et al., 1975a ) ( Fig. 2-12 ). In infants born at 32 to 37 weeks gestation, the initial period of transient hyperpnea is abolished in a cool environment, indicating the importance of maintaining a neutral thermal environment ( Cross and Oppe, 1952 ; Ceruti, 1966 ; Perlstein et al., 1970 ). When 100% oxygen is given, a transient decrease in ventilation is followed by sustained hyperventilation. This ventilatory response to oxygen is similar to that of the fetus and is different from that of the adult, in whom a sustained decrease in ventilation is followed by little or no increase in ventilation ( Dripps and Comroe, 1947 ). By 3 weeks after birth, hypoxemia induces sustained hyperventilation, as in older children and adults.

 
 

FIGURE 2-12  Effect on ventilation of 14% oxygen (hypoxia) from room air and then to 100% oxygen (hyperoxia) in three newborn infants. Ventilation (mean ± SEM) is plotted against time. During acute hypoxia there was a transient increase in ventilation followed by depression. Hyperoxia increased ventilation.  (Modified from Lahiri S, Brody JS, Motoyama EK, Valasquez TM: Regulation of breathing in newborns. J Appl Physiol 44:673, 1978. Used with permission of the American Physiological Society.)

 

 

 

The biphasic depression in ventilation has been attributed to central depression rather than to depression of peripheral chemoreceptors ( Albersheim et al., 1976 ). In newborn monkeys, however, tracheal occlusion pressure, an index of central neural drive, and diaphragmatic electromyographic output were increased above the control level during both the hyperpneic and the hypopneic phases in response to hypoxic gas mixture ( LaFramboise et al., 1981 ; LaFramboise and Woodrum, 1985 ). These findings imply that the biphasic ventilatory response to hypoxemia results from changes in the mechanics of the respiratory system (thoracic stiffness or airway obstruction), rather than from neuronal depression, as has been assumed ( Jansen and Chernick, 1983 ). Premature infants continue to show a biphasic response to hypoxemia even at 25 days after birth ( Rigatto, 1986 ). Thus, in terms of a proper response to hypoxemic challenge, maturation of the respiratory system may be related to postconceptional rather than postnatal age.

Response to Carbon Dioxide in Infants

Newborn infants respond to hypercapnia by increasing ventilation but less so than do older infants. The slope of the CO2 response curve increases appreciably with gestational age as well as with postnatal age, independent of postconceptional age (Rigatto et al., 1975a, 1975b, 1982 [372] [373] [374]; Frantz et al., 1976 ). This increase in slope may represent an increase in chemosensitivity, but it may also result from more effective mechanics of the respiratory system. In adults the CO2 response curve both increases in slope and shifts to the left with the severity of hypoxemia (see Fig. 2-8 ). In contrast, in newborn infants breathing 15% oxygen, the CO2 response curve decreases in slope and shifts to the right ( Fig. 2-13 ). Inversely, hyperoxemia increases the slope and shifts the curve to the left ( Rigatto et al., 1975) .

 
 

FIGURE 2-13  Mean steady-state CO2 response curves at different inspired oxygen concentrations in eight preterm infants. The slope of the CO2 response decreases with decreasing oxygen.  (From Rigatto H, de la Torre Verduzco R, Cates DB: Effects of O2 on the ventilatory response. J Appl Physiol 39:896, 1975. Used with permission of the American Physiological Society.)

 

 

 

Upper Airway Receptor Responses in the Neonatal Period

Newborn animals are particularly sensitive to the stimulation of the superior laryngeal nerve either directly or through the receptors (such as water in the larynx), which results in ventilatory depression or apnea. In anesthetized newborn puppies and kittens, negative pressure or airflow through the larynx isolated from the lower airways produced apnea or significant prolongation of inspiratory and expiratory time and a decrease in tidal volume, whereas similar stimulation caused little or no effect in 4- to 5-week-old puppies or in adult dogs and cats ( Al-Shway and Mortola, 1982 ; Fisher et al., 1985 ).

In a similar preparation using puppies anesthetized with pentobarbital, water in the laryngeal lumen produced apnea, whereas phosphate buffer with sodium chloride and neutral pH did not. The principal stimulus for the apneic reflex was the absence or reduced concentrations of chloride ion ( Boggs and Bartlett, 1982 ). In awake newborn piglets, direct electrical stimulation of the superior laryngeal nerve caused periodic breathing and apnea associated with marked decreases in respiratory frequency, hypoxemia, and hypercapnia with minimal cardiovascular effects. Breathing during superior laryngeal nerve stimulation was sustained by an arousal system ( Donnelly and Haddad, 1986 ). The strong inhibitory responses elicited in newborn animals by various upper airway receptor stimulations have been attributed to the immaturity of the central nervous system ( Lucier et al., 1979 ; Boggs and Bartlett, 1982 ).

Active (REM) Versus Quiet (Non-REM) Sleep

During the early postnatal period, full-term infants spend 50% of their sleep time in active or REM sleep compared with 20% REM sleep in adults ( Stern et al., 1969 ; Rigatto et al., 1982 ). Wakefulness rarely occurs in neonates. Premature neonates stay in REM sleep most of the time, and quiet (non-REM) sleep is difficult to define before 32 weeks postconception ( Rigatto, 1992 ). Neonates, particularly prematurely born neonates, therefore, breathe irregularly.

Neurologic and chemical control of breathing in infants is related to the state of sleep ( Scher et al., 1992 ). During quiet sleep, breathing is regulated primarily by the medullary respiratory centers and breathing is regular with respect to timing as well as amplitude and is tightly linked to chemoreceptor input ( Bryan and Wohl, 1986 ). During active (REM) sleep, however, breathing is controlled primarily by the behavioral system and is irregular with respect to timing and amplitude (Phillipson, 1984).

Periodic Breathing and Apnea

Periodic Breathing

Periodic breathing, in which breathing is interposed with repetitive short apneic spells lasting 5 to 10 seconds without hemoglobin desaturation or cyanosis, occurs frequently in neonates and young infants during wakefulness, active (REM) sleep, and quiet (non-REM) sleep (Rigatto et al., 1982a). Periodic breathing tends to be more regular in quiet sleep than in active sleep (Kalapezi et al., 1981) and has been observed more frequently during active sleep ( Rigatto et al., 1982 ) or during quiet sleep ( Kelly et al., 1985 ). Minute ventilation increases during REM sleep due to increases in respiratory frequency with little change in tidal volume (Kalapezi et al., 1981; Rigatto et al., 1982 ).

An addition of 2% to 4% carbon dioxide to the inspired gas mixture abolishes periodic breathing, probably by causing respiratory stimulation ( Chernick et al., 1964 ). Nevertheless, the ventilatory response to hypercapnia seems to be diminished during periodic breathing ( Rigatto and Brady, 1972a ). The decreased hypercapnic response appears to result from changes in respiratory mechanics rather than from a reduction in chemosensitivity, because respiratory center output as determined by airway occlusion pressure is greater during REM sleep than during non-REM sleep.

The incidence of periodic breathing was reported to be 78% in full-term neonates ( Kelly et al., 1985 ), whereas the incidence was much higher (93%) in preterm infants (mean postconceptional age, 37.5 weeks) ( Glotzbach et al., 1989 ). The frequency of periodic breathing diminishes with increasing postconceptual age and decreases to 29% by 10 to 12 months of age ( Fenner et al., 1973 ; Kelly et al., 1985).

Apnea of Prematurity and Hypoxia

Central apnea of infancy is defined as unexplained cessation of breathing for 15 seconds or longer or a shorter respiratory pause associated with bradycardia (heart rate <100), cyanosis, or pallor ( Brooks, 1982 ). Apnea is common in preterm infants and may be related to an immature respiratory control mechanism ( Jansen and Chernick, 1983 ). Most preterm infants with a birth weight of less than 2 kg have apneic spells at some time ( Spitzer and Fox, 1984 ). Glotzbach and others (1989) reported a 55% incidence of central apnea in preterm infants, whereas it was rarely found in full-term infants ( Kelly et al., 1985 ).

The report by the Collaborative Home Infant Monitoring Evaluation (CHIME) Study Group was based on the recordings of respiratory inductive plethysmography (Respitrace), electrocardiography (ECG), and pulse oximetry in normal infants and those with increased risk of sudden infant death syndrome (SIDS), and it involved a total of 1079 infants during the first 6 months after birth (Hunt et al., 1999; Ramanathan et al., 2001). This report has revealed evidence that the control of breathing and oxygenation during sleep in healthy term infants are not as precise as have been assumed. Normal infants, up to 2% to 3%, commonly have prolonged central, obstructive or mixed apnea lasting up to 30 seconds, which is associated with oxygen desaturation (Ramanathan et al., 2001). With a simple upper respiratory infection, prolonged obstructive sleep apneas were recorded in a few normal full-term infants but were present in 15% to 30% of preterm infants. The risk of having such episodes was 20 to 30 times higher among preterm infants than in full-term infants before 43 weeks postconception (Hunt et al., 1999). Healthy term infants had an average baseline Spo2 of 98% throughout the recorded period. However, hypoxia (Spo2 <90%, occasionally in 70%-to-80% range) occurred in 59% of these normal-term infants in 0.6% of recorded epochs (Hunt et al., 1999). Thus, levels of hypoxia previously considered pathologic are relatively common occurrences among normal infants.

Apparent life-threatening events (ALTE) is characterized by an episode of sudden onset characterized by color change (cyanosis or pallor), tone change (limpness or rarely stiffness), and apnea, which requires immediate resuscitation to revive the infant and restore normal breathing (National Institutes of Health Consensus Development Conference, 1987). The incidence of ALTE is as high as 3% and may occur in previously healthy infants. Overnight polysomnography (PSG) is particularly useful in the evaluation of infants with a history of unexplained apnea. Treatable etiology, however, was found only in about 30% of infants and, thus, normal PSG results are not necessarily diagnostic to rule out ALTE.

Postoperative Apnea

Life-threatening apnea has been reported postoperatively in prematurely born infants less than 41 weeks postconception, particularly in those with a history of apneic spells following simple surgical procedures, such as inguinal herniorrhaphy ( Liu et al., 1983 ), and can occur up to 12 hours postoperatively ( Steward, 1982 ). In another report, apnea was reported in 4 of 18 prematurely born infants who were 49 to 55 weeks postconception ( Kurth et al., 1987 ). Malviya and others (1993) analyzed the relationship between the incidence of postoperative apnea and maturation. They reported a high incidence of postoperative apnea (26%) in infants less than 44 weeks postconception, whereas the incidence of apnea in those more than 44 weeks was only 3%.

Subsequently, Coté and others (1995) performed a meta-analysis of the data from previously published studies of postoperative apnea in ex-premature infants following inguinal hernia repairs. They concluded that postoperative apnea was strongly and inversely correlated to both gestational age as well as postconceptual age; was associated with previous history of apnea; and was associated with anemia (hematocrit <30) as a significant risk factor regardless of gestational or postconceptual age (see Chapter 11 , Intraoperative and Postoperative Management).

Both theophylline and caffeine have been effective in reducing apneic spells in preterm infants ( Aranda et al., 1979) . Caffeine is especially useful for prematurely born infants during the postanesthetic period ( Welborn et al., 1988 ). Xanthine derivatives are known to prevent muscle fatigue ( Aubier et al., 1981) , and their respiratory stimulation in the premature infant may occur via both central and peripheral mechanisms.

MAINTENANCE OF THE UPPER AIRWAY AND AIRWAY PROTECTIVE REFLEXES

Pharyngeal Airway

The pharyngeal airway, unlike the laryngeal airway, is not supported by a rigid bony or cartilaginous structure. Its wall consists of soft tissues and is surrounded by muscles for breathing and for swallowing. The pharyngeal airway is easily obstructed by the relaxation of the velopharynx (soft palate), posterior displacement of the mandible (and the base of the tongue) in the supine position during sleep, flexion of the neck, or external compression over the hyoid bone. The pharyngeal airway also is easily collapsed by negative pressure within the pharyngeal lumen created by inspiratory effort, especially when airway-maintaining muscles are depressed or paralyzed ( Issa and Sullivan, 1984 ; Reed et al., 1985 ; Roberts et al., 1985 ). In neonates, with a relatively hypoplastic mandible, the oropharynx and the entrance to the larynx at the level of the aryepiglottic folds are the areas most easily collapsed ( Reed et al., 1985 ).

Mechanical support to sustain the patency of the pharynx against the collapsing force of luminal negative pressure during inspiration is given by both the sustained muscle tension and cyclic contraction of the pharyngeal dilator muscles, acting synchronously with the contraction of the diaphragm. These include the genioglossus, geniohyoid, sternohyoid, sternothyroid, and thyrohyoid muscles ( Bartlett et al., 1973 ; Pack et al., 1988 ; Thach, 1992 ) ( Fig. 2-14 ). Similar phasic activities have been recorded in the scalene and sternomastoid muscles in humans ( Onal et al., 1981 ; Drummond, 1987 ).

 
 

FIGURE 2-14  Lateral view of the musculature of the tongue and its relationship with a mandible and hyoid bone.  (From Kuna ST, Remmers JE: Pathophysiology and mechanisms of sleep apnea. In Fletcher EC, editor: Abnormalities of respiration during sleep. Orlando, FL, 1986, Grune & Stratton.)

 

 

 

A model of pharyngeal airway maintenance proposed by Thach (1988) is shown in Figure 2-15 . In this model, the suction force created in the pharyngeal lumen by the inspiratory activity of the diaphragm must be well balanced by the activities of upper airway-dilating muscles to maintain upper airway patency. Increased nasal and pharyngeal airway resistance exaggerates the suction force. In addition, once pharyngeal closure occurs, the mucosal adhesion force of the collapsed pharyngeal wall becomes an added force acting against the opening of pharyngeal air passages ( Reed et al., 1985 ).

 
 

FIGURE 2-15  A schematic model of pharyngeal airway maintenance illustrating the balance of opposing forces that affect airway diameter. Airway constricting (suction force) and airway dilating forces (pharyngeal muscles) are shown on either side of the fulcrum. The balance of forces is dynamic; for example, a sudden increase in nasal resistance or diaphragm force during the course of an inspiration can result in airway closure in a fraction of a second. Change in neck posture shifts position of the fulcrum and thus can bias the balance toward airway closure or airway patency.  (From Thach BT: Potential role of airway obstruction in SIDS. In Krous H, Culbertson H, editors: Sudden infant death syndrome. Baltimore, 1988, Johns Hopkins University Press.)

 

 

 

Several reflex mechanisms are present to maintain the balance between the dilating and collapsing forces in the pharynx. Chemoreceptor stimuli such as hypercapnia and hypoxemia stimulate the airway dilators preferentially over the stimulation of the diaphragm so as to maintain airway patency ( Brouillette and Thach, 1980 ; Onal et al., 1981, 1982 [316] [317]). Negative pressure in the nose, pharynx, or larynx activates the pharyngeal dilator muscles and simultaneously decreases the diaphragmatic activity (Mathew et al., 1982a, 1982b [255] [256]; Hwang et al., 1984 ; Thach, 1992 ) ( Fig. 2-16 ). Such an airway pressure reflex is especially prominent in infants less than 1 year of age ( Thach et al., 1989 ). Upper airway mechanoreceptors are located superficially in the airway mucosa and are easily blocked by topical anesthesia(Mathew et al., 1982a, 1982b [255] [256]). Sleep, sedatives, and anesthesia depress upper airway muscles more than they do the diaphragm ( Sauerland and Harper, 1976 ; Ochiai et al., 1989, 1992 [312] [313]). The arousal from sleep shifts the balance toward pharyngeal dilation ( Thach, 1992 ).

 
 

FIGURE 2-16  Schematic illustration of sequence of events showing one of the ways in which the upper airway pressure reflex operates to preserve pharyngeal airway patency.  (From Thach BT: Neuromuscular control of the upper airway. In Beckerman RC, Brouillette RT, Hunt CE, editors: Respiratory control disorders in infants and children. Baltimore, 1992, Williams & Wilkins.)

 

 

 

Laryngeal Airway

The larynx is composed of a group of cartilage, connecting ligaments, and muscles. It maintains the airway and functions as a valve to occlude and protect the lower airways from the alimentary tract. It is also an organ for phonation (Proctor, 1977a, 1977b, 1986 [347] [348] [349]; Fink and Demarest, 1978 ).

With the exception of the anterior nasal passages, the larynx at the subglottis is the narrowest portion of the entire airway system in all ages ( Eckenhoff, 1951 ). The cricoid cartilage forms a complete ring, protecting the upper airway from compression. On the other hand, it is vulnerable to stenosis, because mucosal edema from infection can only expand inward, diminishing the lumen. In infants this edema may produce severe obstruction, whereas the same degree of swelling in adults may cause no more than mild discomfort. The mucosa covering the cricoid ring is also a frequent site of trauma and resulting edema from intubation with an oversized endotracheal tube in infants and young children ( Koka et al., 1977 ). Ischemic mucosal edema may cause symptoms of upper airway obstruction (postintubation croup) and, if severe enough, subsequent fibrosis and subglottic stenosis.

The glottis widens slightly during tidal inspiration but narrows during expiration, thus increasing laryngeal airflow resistance ( Bartlett et al., 1973 ). Laryngeal resistance is finely regulated in neonates and young infants to dynamically maintain end-expiratory lung volume (FRC) well above the small volume determined by the opposing elastic recoil forces of the thorax and the lungs, as discussed later (Harding, 1984 ; England and Stogren, 1986 ). In infants with IRDS, expiration is often associated with “grunting” caused by narrowing of the glottic aperture. This grunting maintains intrinsic PEEP during the expiratory phase and presumably reduces premature closure of airways and air spaces. In infants with IRDS, when grunting is eliminated by endotracheal intubation, respiratory gas exchange deteriorates unless continuous positive airway pressure (CPAP) is applied ( Gregory et al., 1971 ).

Airway Protective Reflexes

Upper airway protective mechanisms involve both the pharynx and larynx and include sneezing, swallowing, coughing, and pharyngeal or laryngeal closure. Laryngospasm is a sustained tight closure of the vocal cords caused by the stimulation of the superior laryngeal nerve, a branch of the vagus, and contraction of the adductor muscles that persists beyond the removal of the stimulus. In puppies, it is elicited by repetitive stimulation of the superior laryngeal nerve with typical adductor afterdischarge activity. This response is not evoked by the stimulation of the recurrent laryngeal nerve ( Suzuki and Sasaki, 1977 ). Hyperventilation and hypocapnia as well as light anesthesia increase the activity of adductor neurons, reduce the mean threshold of the adductor reflex, or increase upper airway resistance ( Suzuki and Sasaki, 1977 ; Nishino et al., 1981 ). Hyperthermia and decreased lung volume also facilitate laryngospasm produced by stimulation of the superior laryngeal nerve ( Sasaki, 1979 ; Haraguchi et al., 1983 ). Contrarily, hypoventilation and hypercapnia, positive intrathoracic pressure, and deep anesthesia depress excitatory adductor afterdischarge activity and increase the threshold of the reflex that precipitates laryngospasm ( Suzuki and Sasaki, 1977 ; Ikari and Sasaki, 1980 ; Nishino et al., 1981 ). Hypoxia below an arterial Po2 of 50 mm Hg also increases the threshold for laryngospasm ( Ikari and Sasaki, 1980 ).

These findings are clinically relevant, suggesting a fail-safe mechanism by which asphyxia (hypoxia and hypercapnia) tends to prevent sustained laryngospasm. In healthy, awake adults, laryngospasm by itself is self-limiting and not a threat to life. On the other hand, in the presence of cardiopulmonary compromise, such as may occur during anesthesia (particularly in infants), laryngospasm may indeed become life threatening ( Ikari and Sasaki, 1980 ). Increased depth of anesthesia increases the reflex threshold and diminishes excitatory adductor afterdischarge in puppies ( Suzuki and Sasaki, 1977 ). This finding is in accord with the clinical experience of anesthesia practitioners—that laryngospasm occurs most readily under light anesthesia and that it can be broken by deepening anesthesia or awakening the patient. In puppies, positive intrathoracic pressure inhibits the glottic closure reflex and laryngospasm. This supports the clinical observation that during the emergence from anesthesia in infants and young children, maintenance of PEEP and inflation of the lungs at the time of extubation seem to reduce both the incidence and severity of laryngospasm (E. K. Motoyama, unpublished observation).

Infants are particularly vulnerable to laryngospasm. Animal studies suggest that during a discrete interval after birth and before complete neurologic maturation, there is a period of transient laryngeal hyperexcitability. This may relate to the transient reduction in central latency and a reduction in central inhibition of the vagal afferent. If these observations in puppies are applicable to human infants, they may explain the susceptibility of infants and young children to laryngospasm and have some causal relation in unexpected infant death such as SIDS ( Sasaki, 1979 ).

Infants, particularly premature neonates, exhibit clinically important airway protective responses to fluid at the entrance to the larynx ( Davies et al., 1988 ; Pickens et al., 1989 ). This response seems to trigger prolonged apnea in neonates and breath holding during inhalation induction of anesthesia in children. When a small quantity (<1 mL) of warm saline solution is dripped into the nasopharynx in a sleeping infant, it pools in the piriform fossa and then overflows into the interarytenoid space at the entrance to the larynx. This area is densely populated with various nerve endings, including a structure resembling a taste bud. The most common response to fluid accumulation is swallowing. The infant also develops central apnea with the glottis open or a closure of vocal cords; coughing is rare ( Pickens et al., 1989 ). Apneic responses are more prominent with water than with saline solution ( Davies et al., 1988 ).

These findings appear clinically important in pediatric anesthesia. During inhalation induction, pharyngeal reflexes (swallowing) are abolished, whereas laryngeal reflexes remain intact, as Guedel originally described in ether anesthesia (1937) . Secretions would accumulate in the hypopharynx without swallowing and cause breath holding resulting from central apnea, a closure of the glottis, or both. Positive pressure ventilation using a mask and bag instead of suctioning the pharynx would push secretions farther down into the larynx, stimulate the superior laryngeal nerve, and trigger real laryngospasm.

▪ ANESTHETIC EFFECTS ON CONTROL OF BREATHING

Effects of Anesthetic on Upper Airway Receptors

Inhalation induction of anesthesia is often associated with reflex responses such as coughing, breath holding, and laryngospasm. Volatile anesthetics stimulate upper airway receptors directly and affect ventilation. In dogs spontaneously breathing through tracheostomy under urethane-chloralose anesthesia, an exposure of isolated upper airways to halothane caused depression of respiratory-modulated mechanoreceptors or pressure receptors, whereas irritant receptors and flow (cold) receptors were consistently stimulated in a dose-dependent manner ( Nishino et al., 1993 ). Responses to isoflurane and enflurane were less consistent. Laryngeal respiratory-modulated mechanoreceptors may be a part of a feedback mechanism that maintains the patency of upper airways; the depression of this feedback mechanism may play an important role in the collapse of upper airways during the induction of anesthesia. Furthermore, activation of irritant receptors by halothane and other volatile anesthetics may be responsible for laryngeal reflexes such as coughing, apnea, laryngospasm, and bronchoconstriction seen during inhalation induction of anesthesia ( Nishino et al., 1993 ).

The same group of investigators showed that in young puppies (<2 weeks old), exposure of isolated upper airways to halothane (and to a lesser extent to isoflurane) as described previously resulted in a marked depression of ventilation (<40% of control) associated with decreases in both tidal volume and respiratory frequency ( Sant'Ambrogio et al., 1993) . Ventilatory effects caused by the exposure of isolated upper airways to volatile anesthetics were present but only mildly in 4-week-old puppies, whereas adult dogs were not affected. The superior laryngeal nerve section and topical anesthesia of the nasal cavity completely abolished the effects of halothane and isoflurane in the isolated upper airways of puppies ( Sant'Ambrogio et al., 1993) . Laryngeal receptor output in response to volatile anesthetics was not measured in this study. These findings in puppies appear to be clinically relevant because infants and young children often develop manifestations of upper airway reflexes during inhalation induction.

Effects of Anesthetics on Upper Airway Muscles

The genioglossus, geniohyoid, and other pharyngeal and laryngeal abductor muscles have phasic inspiratory activity synchronous with diaphragmatic contraction, in addition to their tonic activities that maintain upper airway patency in both animals and humans ( Bartlett et al., 1973 ; Brouillette and Thach, 1979 ). The genioglossus and geniohyoid muscles increase the caliber of the pharynx by displacing the hyoid bone and the tongue anteriorly and are the most important muscles for the maintenance of oropharynx patency (see Fig. 2-14 ). They have both phasic inspiratory activity and tonic activity throughout the respiratory cycle in awake humans ( Onal et al., 1981 ). These activities of the genioglossus muscle and presumably other pharyngeal and laryngeal abductor muscles are easily depressed by alcohol ingestion, sleep, and general anesthesia ( Remmers et al., 1978 ; Nishino et al., 1984, 1985 [307] [308]; Bartlett et al., 1990 ); their depression would result in upper airway obstruction ( Brouillette and Thach, 1979 ).

Sensitivity to anesthetics differs among various inspiratory muscles and their neurons. In studies in cats with the use of electromyography, Ochiai, Guthrie, and Motoyama (1989) demonstrated that the phasic inspiratory activity of the genioglossus muscle was most sensitive to the depressant effect of halothane at a given concentration, whereas the diaphragm was most resistant; the sensitivity of inspiratory intercostal muscles was intermediate ( Fig. 2-17 ). In addition, phasic genioglossus activity was more readily depressed in kittens than in adult cats. Phasic genioglossusactivity was abolished with 1.5% halothane or more in all kittens studied, whereas the activity was diminished but present in most adult cats even at 2.5% ( Ochiai, Guthrie, and Motoyama, 1992 ).

 
 

FIGURE 2-17  Decrease in phasic inspiratory muscle activity, expressed as peak height of moving time average (MTA), in percent change from control (1% halothane), during halothane anesthesia in adult cats. Values are mean ± SEM. *P <0.05 compared with the diaphragm (DI); **P < 0.05 compared with the genioglossus muscle (GG).  (From Ochiai R, Guthrie R, Motoyama EK: Anesthesiology 70:812, 1989.)

 

 

 

Early depression of the genioglossus muscle and other pharyngeal dilator muscles appears to be responsible for upper airway obstruction in infants and young children, especially during the induction of inhalation anesthesia. Because of the higher sensitivity to anesthetic depression, the upper airway muscles failed to increase the intensity of contraction to keep the pharynx patent while the diaphragm continues to contract vigorously, while the negative feedback mechanism to attenuate its contraction may be diminished or lost ( Brouillett and Thach, 1979 ; Ochiai et al., 1989 ; Isono et al., 2002 ). Partial upper airway obstruction may occur more often in infants and young children than is clinically apparent during anesthesia by mask without an oral airway. Keidan and others (2000) found in infants and children breathing spontaneously under halothane anesthesia that the work of breathing (as an index of the degree of upper airway obstruction) significantly increased when breathing by mask without an oral airway than with an oral airway in place, even when partial upper airway obstruction was not clinically apparent. An addition of CPAP (5 to 6 cm H2O) further improved airway patency as evidenced by significant decreases in the work of breathing ( Keidan et al., 2000 ) (also see Chapter 10 , Induction of Anesthesia).

Anesthetic Effects on Neural Control of Breathing

Most general anesthetics, opioids, and sedatives depress ventilation. They variably affect minute ventilation (VE and its components (such as tidal volume [VT], respiratory frequency [f], mean inspiratory flow [VT/TI], and respiratory duty cycle [TI/TTOT]). All inhaled anesthetics significantly depress ventilation in a dose-dependent fashion (see Fig. 2-9 ). This subject has been extensively reviewed (Hickey and Severinghaus, 1981 ; Pavlin and Hornbein, 1986 ); information in human infants and children, however, remains limited.

Studies in adult human volunteers using the occlusion technique ( Whitelaw, Derenne, Milic-Emili, 1975 ) and the timing component analysis ( Milic-Emili and Grunstein, 1975 ) have indicated that the reduction in tidal volume with anesthetics results primarily from a reduction in the neural drive of ventilation ( Derenne et al., 1976 ; Wahba, 1980 ). Inspiratory time tends to decrease but the respiratory duty cycle is relatively unaffected. In several studies in children 2 to 5 years of age, breathing was relatively well maintained at a light level of halothane (0.5 minimum alveolar concentration [MAC]) (Murat et al., 1985 ; Lindahl, Yates, Hatch, 1987 ; Benameur et al., 1993) . In deeper, surgical levels of anesthesia (1.0 to 1.5 MAC), breathing was depressed in a dose-dependent manner and hypercapnia resulted. Decreased    E was associated with reduced VT and increased respiratory frequency. The neural respiratory drive was depressed as evidenced by reduced VT/TI, whereas the duty cycle (TI/TTOT) either tended to increase without changes in TI ( Lindahl, Yates, Hatch, 1987 ; Benameur et al., 1993) or decreased slightly ( Murat et al., 1985 ). In infants less than 12 months of age, ventilatory depression was more pronounced and the duty cycle did not increase, partly because of high chest wall compliance and pronounced thoracic deformity (thoracoabdominal asynchrony) compared with older children ( Benameur et al., 1993) .

When an external load was imposed on the airway system of an awake individual, ventilation was maintained by increased inspiratory effort ( Whitelaw, Derenne, Milic-Emili, 1975 ). This response was greatly diminished or abolished by the effect of general anesthetics ( Nunn and Ezi-Ashi, 1966 ; Isaza et al., 1976 ), opioids ( Kryger et al., 1976 ), and barbiturates ( Savoy et al., 1982 ). In children under light halothane anesthesia (0.5 MAC), an addition of a resistive load initially decreased tidal volume. However, tidal volume returned to baseline within 5 minutes ( Lindahl, Yates, Hatch, 1987 ).

Anesthetic Effects on Chemical Control of Breathing

In the dog, inhaled anesthetics diminish or abolish the ventilatory response to hypoxemia in a dose-dependent manner ( Weiskopf et al., 1974 ; Hirshman et al., 1977 ). In human adult volunteers, the hypoxic ventilatory response was disproportionately depressed in light halothane anesthesia compared to the response to hypercapnia ( Knill and Gelb, 1978 ). At 1.1 MAC of halothane, the hypoxic ventilatory response was completely abolished, whereas the hypercapnic response was about 40% of control in the awake state. Even at a subanesthetic or trace level (0.05 to 0.1 MAC), halothane, isoflurane, and enflurane attenuated the hypoxic ventilatory response to about 30% of control, whereas hypercapnic response was essentially intact (Knill and Gelb, 1979; Knill and Clement 1984 ). The site of the anesthetics—action appeared to be at the peripheral (carotid) chemoreceptors, because of the rapid response in humans ( Knill and Clement 1984 ) as well as the direct measurement of neuronal chemoreceptor output in the cat ( Davies, Edwards, Lahiri, 1982 ).

Subsequently, Temp and others (1992, 1994) [429] [430] challenged these findings by demonstrating that 0.1 MAC of isoflurane had no demonstrable ventilatory effect on hypoxia. On the other hand,Dahan and others (1994) confirmed the original findings by Knill and others (1978) . The reason for the conflicting results appeared to be related to the contribution of visual and auditory inputs (Robotham, 1994 ). The study by Temp and others (1994) was conducted while the volunteers were watching television (open-eyed), whereas the volunteers in the study by Dahan and others (1994) were listening to soothing music with their eyes closed (but not asleep).

Pandit (2000) conducted a meta-analysis of 37 studies in 21 publications and analyzed the conflicting response to hypoxia under trace levels of anesthetics. Pandit's analysis supported the prediction byRobotham (1994) that the study condition has a major impact on the outcome of the study. Bandit concluded that the main factor for the difference in hypoxia response was the anesthetic agent used (p < 0.002). Additional factors included subject stimulation (p < 0.014) and agentstimulation interaction (p < 0.04), whereas the rate of induction of hypoxia or the level of Pco2 had no effect (Pandit, 2000).

The effect of subanesthetic concentrations of inhaled anesthetics on ventilation in infants and children has not been studied. However, high incidences of postoperative-hypoxemia in otherwise healthy infants and children without an apparent hypoxic ventilatory response in the postanesthetic period suggest that the hypoxic ventilatory drive in infants and children may be blunted with the presence of residual, subanesthetic levels of inhaled anesthetics ( Motoyama and Glazener, 1986 ).

▪ SUMMARY

The understanding of the control of breathing during the perinatal and early postnatal periods has increased significantly. In general, neural and chemical controls of breathing in older infants and children are similar to those in adolescents and adults. A major exception to this general statement is found in neonates and young infants, especially prematurely born infants less than 40 to 44 weeks postconception. In these infants, hypoxemia is a potent respiratory depressant, rather than a stimulant, either centrally or because of changes in respiratory mechanics. These infants often develop periodic breathing without apparent hypoxemia and occasionally central apnea with possible serious consequence, most likely because of immature respiratory control mechanisms.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ LUNG VOLUMES

▪ POSTNATAL DEVELOPMENT OF THE LUNGS

In the human fetus, alveolar formation does not begin until about 4 weeks before birth ( Langston et al., 1984 ), although the airways, including the terminal bronchioles, are completely formed by 16 weeks—gestation ( Reid, 1967 ). The full-term newborn infant has 20 to 50 million terminal airspaces, mostly primitive saccules from which alveoli later develop ( Thurlbeck, 1975 ; Langston et al., 1984 ). During the early postnatal years, development and growth of the lungs continue at a rapid pace, particularly with respect to the development of new alveoli. By 12 to 18 months of age, the number of alveoli reaches the adult level of 300 million or more; subsequent lung development and growth are associated with increases in alveolar size as well as further structural development ( Dunnill, 1962 ; Langston et al., 1984 ) (see Development of the Respiratory System).

During the early period of postnatal lung development, the lung volume of infants is disproportionately small in relation to body size. Furthermore, because the infant's metabolic rate, in relation to body weight, is nearly twice that of the adult, the ventilatory requirement per unit of lung volume in infants is greatly increased. Infants seem to have far less reserve in lung surface area for gas exchange. Furthermore, general anesthesia markedly reduces the end-expiratory lung volume (FRC or relaxation volume, Vr), especially in young infants, reducing their oxygen reserve severely (see later). Normal values for lung volumes and function in children of various ages are compiled in Table 2-2 .

TABLE 2-2   -- Normal values for lung functions for persons of various ages

 

AGE

 

1 wk

1 yr

3 yr

5 yr

8 yr

12 yr

Male 15 yr

Male 21 yr

Female 21 yr

Height (cm)

48

75

96

109

130

150

170

174

162

Weight (kg)

3.3

10

15

18

26

39

57

73

57

FRC (mL)

75[*]

(263)

(532)

660

1174

1855

2800

3030

2350

FRC/weight (mL/kg)

(25)

(26)

(37)

(36)

(46)

(48)

(49)

(42)

(41)

VC (mL)

100[†]

(475)

(910)

1100

1855

2830

4300

4620

3380

VE (mL/min)

550

(1775)

(2460)

(2600)

(3240)

(4150)

5030

6000

5030

VT (mL)

17

(78)

(112)

(130)

(180)

(260)

360

500

420

f (frequency)

30

(24)

(22)

(20)

(18)

16

14

12

12

VA (mL/min)

385

(1245)

(1760)

(1800)

(2195)

(2790)

3070

4140

3530

VD (mL)

75

21

37

49

75

105

141

150

126

C1 (mL/cm H2O)

5

(16)

(32)

44

71

91

130

163

130

Peak flow rates (L/min)

10

 

 

136

231

325

437

457

365

R (cm H2O/L per sec)

29[‡]

(13)

(10)

8

6

5

3

2

2

DLco (mL/mm Hg per min)[§]

 

 

 

11

15

20

27

28

24

Cardiac output (L/min)

(0.9)

1.9

2.7

3.2

4.4

5.7

(7.0)

(7.6)

(7.2)

Lung weight (g)

49

120

166

211

290

470

640

730

 

Compiled from data in Cook CD, Cherry RB, O’Brien D, et al.: J Clin Invest 34:975, 1955; Cook CD, Sutherland JM, Segal S, et al.: J Clin Invest 36:440, 1957; Comroe JH Jr, et al.: The lung. Chicago, Year Book Medical Publishers, 1962; Bucci G, Cook CD, Barrie H: J Pediatr 58:820, 1961; Murray AB, Cook CD: J Pediatr 62:186, 1963; Cook CD, Hamann JF: J Pediatr 59:710, 1961; Long EC, Hull WE: Pediatrics 27:373, 1961; and Koch G: Respir Physiol 4:168, 1968.

Parentheses, interpolated values.

 

*

Supine.

Crying vital capacity.

Nose breathing.

§

Single-breath technique.

 

 

Total lung capacity (TLC) is the maximum lung volume allowed by the strength of the inspiratory muscles stretching the thorax and lungs. Subdivisions of TLC are shown schematically in Figure 2-18 . Residual volume (RV) is the amount of air remaining in the lungs after maximum expiration and is approximately 25% of TLC in healthy children. FRC is determined by the balance between the outward stretch of the thorax and the inward recoil of the lungs ( Fig. 2-19 ) and is normally roughly 50% of TLC in the upright posture in healthy children and young adults; it is about 40% in the supine position. The two opposing forces create an average negative average pleural pressure of approximately -5 cm H2O in older children and adults. In the neonate the pleural pressure is only slightly negative or nearly atmospheric.

 
 

FIGURE 2-18  TLC and lung volume subdivisions. ERV, Expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve volume; Rv, residual volume; TLC, total lung capacity; VC, vital capacity; VT, tidal volume.  (From Motoyama EK: Int Anesthesiol Clin 26:6, 1988.)

 

 

 

 
 

FIGURE 2-19  Static volume-pressure curves of the lung (Pl), chest wall (Pw), and respiratory system (Prs) during relaxation in the sitting position. The static forces of the lung and chest wall are pictured by the arrows in the side drawings. The dimensions of the arrows are not to scale; the volume corresponding to each drawing is indicated by the horizontal broken lines.  (From Agostoni E, Mead J: Statics of the respiratory system. In Fenn WO, Rahn H, editors: Handbook of physiology. Section 3. Respiration, vol 1. Washington, DC, 1986, American Physiological Society. Used with permission of the American Physiological Society.)

 

 

 

▪ FUNCTIONAL RESIDUAL CAPACITY AND ITS DETERMINANTS

In infants, outward recoil of the thorax is exceedingly low and inward recoil of the lungs is only slightly lower than that of adults ( Agostoni, 1959 ; Bryan and Wohl, 1986 ). Consequently, the FRC (or, more appropriately, Vr) of young infants at static conditions (such as apnea, under general anesthesia, or paralysis) decreases to 10% to 15% of TLC ( Agostoni, 1959 ) ( Fig. 2-20 ), a level incompatible with normal gas exchange because of airway closure, atelectasis, and ventilation/perfusion imbalance. In awake infants and young children, however, FRC is dynamically maintained by a number of mechanisms for preventing the collapse of the lungs, including a sustained inspiratory muscle tension to make the thorax stiffer ( Box 2-4 ) (also see later, Elastic Properties). FRC in young infants, therefore, is dynamically determined; there is no fixed level of FRC.

 
 

FIGURE 2-20  Static pressure-volume curve of lung (right dashed line), chest wall (left dashed line), and total respiratory system (solid line) in newborn and adult.  (From Agostoni E: Volume-pressure relationships of the thorax. J Appl Physiol 14:909, 1959. Used with permission of the American Physiological Society.)

 

 

 

BOX 2-4 

Maintenance of Functional Residual Capacity (FRC) in Young Infants

  

1.   

Sustained tonic activities of inspiratory muscles throughout the respiratory cycle.

  

2.   

Breaking of expiration with continual but diminishing diaphragmatic activity.

  

3.   

Narrowing of the glottis during expiration.[*]

  

4.   

Inspiration starting in mid-expiration.[*]

  

5.   

High respiratory rate in relation to expiratory time constant.[*]

All mechanisms of sustaining FRC are lost with anesthesia or muscle relaxant.

*  Create intrinsic or auto-PEEP (PEEPi)

In normal children and adolescents, lung volumes are related to body size, especially height. In most instances, the relative size of the lung compartment appears to be approximately constant from school-aged children to young adults (see Table 2-2 ). A study in anesthetized and paralyzed infants and children ( Thorsteinsson et al., 1994 ) indicates that TLC, as measured with a tracer gas washout technique, is relatively small in infants (≈60 mL/kg) when the lungs are inflated with relatively low inflation pressure (20 to 25 cm H2O) (the recruitment of previously collapsed air space with this pressure might not have been complete). TLC in children older than 1.5 years of age (determined with inflation pressures of 35 to 40 cm H2O) increases with growth until about 5 years of age (body weight, 20 kg), when it reaches that of older children and adolescents (90 mL/kg).

Negative pressure surrounding the lungs is the same, with respect to lung expansion, as positive pressure within the airways; thus, the net transpulmonary pressure represents the force expanding or contracting the lungs. In contrast, negative intrathoracic pressure has quite a different effect from positive airway pressure with respect to pulmonary circulation and the ventilation-pulmonary perfusion relationship.

Anesthesia, surgery, abdominal distention, and disease may all alter lung volumes. The patient in the prone or supine position has a smaller FRC than the patient standing or sitting because the abdominal contents shift. FRC is further decreased under general anesthesia with or without muscle relaxants ( Westbrook et al., 1973 ). Such a decrease in FRC may result in the closure of small airways, uneven distribution of ventilation, ventilation-pulmonary perfusion imbalance, and hypoxemia. In certain conditions, such as respiratory distress syndrome of the newborn (IRDS), in which the lung resists expansion because of the high surfaceforce, the FRC is further reduced. When the air passages are narrowed, as in asthma or cystic fibrosis, air trapping occurs on expiration, resulting in increased FRC.

The importance of the air remaining in the lungs at the end of normal expiration is often overlooked. This FRC serves as a buffer to minimize cyclic changes in Pco2 and Po2 of the blood during each breath. In addition, the fact that air normally remains in the lungs throughout the respiratory cycle means that relatively few alveoli collapse. Although alveolar collapse does not occur during normal breathing, unusually high pressures are needed to expand the lungs when they are liquid filled at birth, after open-chest surgery, or during general anesthesia without the maintenance of PEEP in infants. Transpulmonary pressure of 30 to 40 cm H2O (and occasionally even more) is needed to reexpand the collapsed lungs. Thereafter, 5 to 6 cm H2O of PEEP appears adequate to prevent airway closure and to maintain FRC.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ MECHANICS OF BREATHING

To ventilate the lungs, the respiratory muscles must overcome certain opposing forces within the lungs themselves. These forces have both elastic and resistive properties. Although respiratory mechanics in adults have been studied extensively over the past four decades, most available information on infants and young children has emerged relatively recently, as reviewed by Bryan and Wohl (1986) . More recently, new information on lung mechanics in infants was carefully scrutinized and compiled by researchers from North America, Europe, and Australia under the auspices of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). A resulting position paper was published ( ATS/ERS Joint Committee, 1993 ).

▪ ELASTIC PROPERTIES

Compliance of the Lungs and Thorax

When the lungs are expanded by the contraction of inspiratory muscles or by positive pressure applied to the airways, elastic recoil of the lungs and thoracic structures surrounding the lungs counterreacts to reduce lung volume. This elastic force is fairly constant over the range of normal tidal volumes, but it increases at the extremes of deflation or inflation ( Fig. 2-21 ). The elastic properties of the lungs or respiratory system (lungs and thorax) are measured and expressed as lung compliance (CL) or respiratorysystem compliance (Crs) in units of volume change per unit of pressure change. The following equation is derived:

 
 

FIGURE 2-21  Schematic representation of the pressure-volume (P-V) curve and compliance of the respiratory system (CRS). At the midpoint of the P-V curve (indicated as FRC awake), the slope and compliance (CRS = ΔP/ΔV) is the highest. When FRC is decreased to the lower, flatter portion of the P-V curve under general anesthesia or paralysis (indicated as FRC anesthetized), CRS decreases even without changes in the mechanics of the lung or the respiratory system.

 

 

where ΔV is usually the tidal volume and ΔP is the change in transpulmonary pressure (the difference between the airway and pleural pressures [ΔP = Pao - Ppl]) for CL, and for Crs, ΔP is transrespiratory pressure (the difference between the airway pressure at end-inspiratory occlusion and atmospheric pressure [ΔP = Pao - PB]) necessary to produce the tidal volume. These measurements are made at points of no flow, that is, at the extremes of tidal volume when there is no flow-resistive component (static compliance). Lung compliance may vary with changes in the mid-position of tidal ventilation with no inherent alteration in the elastic characteristics of the lungs (see Fig. 2-21 ). The elastic properties of the lungs are described more accurately by measuring pressure-volume relationships over the entire range of TLC.

In normal persons, lung compliance measured during the respiratory cycle (i.e., the dynamic compliance during quiet breathing) is approximately the same as the static compliance. When there is airway obstruction, however, the ventilation of some lung units may be functionally decreased, resulting in decreased dynamic compliance, whereas the static compliance is relatively unaffected. This difference between static and dynamic compliance increases with increasing respiratory frequency (frequency dependence of compliance) and is a sign of airway obstruction ( Woolcock et al., 1969 ).

Quiet, normal expiration occurs passively, resulting from the elastic recoil of the lungs and chest wall and involves little or no additional work. The situation in the infant or in the anesthetized and spontaneously breathing patient may be somewhat different because expiration may have an active phase, as discussed later. To consider volume-pressure relationships from another point of view, a normal tidal volume may be obtained using transpulmonary pressures of approximately 4 to 6 cm H2O in persons of all sizes, provided that the lungs are normal and normally expanded initially and the airways are patent. The total transthoracopulmonary pressure needed to ventilate the lungs with positive pressure in a closed chest is, in the adult, approximately twice the required transpulmonary pressure during spontaneous breathing because the thoracic structures must also be expanded. The chest wall in the newborn is extremely compliant and therefore requires almost no force for expansion (see Fig. 2-20 ). The combined compliance of the chest wall and lungs, or the compliance of the total respiratory system (Crs), is expressed as follows:

where Cl is lung compliance and Cw is chest wall compliance. The equation can be expressed in terms of elastance (E), an inverse of compliance (E = 1/C):

where Ers is the elastance of the total respiratory system, EL is lung elastance, and Ew is chest wall elastance.

Lung compliance in normal humans of different sizes is, in general, directly proportional to lung size (see Table 2-2 ). The compliance is expressed per unit of lung volume (e.g., per FRC, VC, or TLC) for comparison (termed “specific compliance”).

Developmental Changes in the Compliance of the Lungs and Thorax

After the initial period of neonatal adaptation, the compliance of the infant's lungs is extremely high (elastic recoil is low) ( Motoyama, 1977 ), probably because of absent or poorly developed elastic fibers (Fagan, 1976, 1977 [120] [121]) ( Fig. 2-22 ). Oddly enough, their functional characteristics resemble those of geriatric, emphysematous lungs with pathologically high compliance caused by the loss of functioning elastic fibers ( Fig. 2-23 ). Thus, at both extremes of human life, the lungs are prone to premature airway closure ( Mansell et al., 1972 ). Elastic recoil pressure of the lungs at 60% TLC increases from about 1 cm H2O in the newborn (Fagan, 1976, 1977 [120] [121]) to 5 cm H2O at 7 years of age and 9 cm H2O at 16 years of age ( Zapletal et al., 1987 ).

 
 

FIGURE 2-22  Pressure-volume curves obtained from excised lungs at autopsy. Data are grouped by postnatal ages as shown by symbols. It is evident that elastic recoil pressure (horizontal distance between nil distending pressure and the curve at a given distending volume) increases with postnatal development of the lungs.  (Based on data from Fagan DG: Thorax 31:534, 1976, and 32:193, 1977.)

 

 

 

 
 

FIGURE 2-23  Static pressure-volume curves (deflation limbs) of the lungs in various conditions as indicated.  (From Bates DV, editor: Respiratory function in disease, ed 3. Philadelphia, 1989, WB Saunders.)

 



In infants the outward recoil of the chest wall is exceedingly small ( Agostoni, 1959 ), because the rib cage is cartilaginous and horizontal and the respiratory muscles are not well developed, whereas the inward recoil of the lungs is only moderately decreased compared with that in adults ( Gerhardt and Bancalari, 1980 ). Consequently, the static balance of these opposing forces would decrease FRC to a very low level (see Fig. 2-20 ). Such a reduction in FRC would make parenchymal airways unstable and subject them to collapse. In reality, however, dynamic FRC in spontaneously breathing infants is maintained at around 40% TLC, a value similar to that in adults in the supine position, because of a number of possible mechanisms or their combinations ( Bryan and Wohl, 1986 ).

Maintenance of Functional Residual Capacity in Infants

Infants terminate the expiratory phase of the breathing cycle before lung volume reaches the relaxation volume (Vr), or true FRC, determined by the balance of opposing chest wall and lung elastic recoil (Kosch and Stark, 1979 ). This “premature” cessation of the expiratory phase, which results in intrinsic PEEP (PEEPi) with higher FRC, probably results partly from the relatively long time constant of the respiratory system in infants in relation to their high respiratory rate ( Olinsky et al., 1974 ). Additional mechanisms may help maintain dynamic FRC above the relaxation volume. Glottic closure, or laryngeal braking, during the expiratory phase of the breathing cycle is animportant mechanism for the establishment of sufficient air space in the lungs during the early postnatal period ( Fisher et al., 1982). Diaphragmatic braking, the diminishing diaphragmatic activity extending to the expiratory phase of breathing, is another important mechanism that extends expiratory time and maintains FRC.

Among all mechanisms that maintain FRC, tonic contractions of both the diaphragm and the intercostal muscles throughout the respiratory cycle in awake infants appear to be most important. This mechanism effectively stiffens the chest wall and maintains a higher end-expiratory lung volume ( Muller et al., 1979 ). Henderson-Smart and Read (1979) have shown a 30% decrease in thoracic gas volume in sleeping infants changing from non-REM to REM sleep. This large reduction in dynamic FRC may result from loss of tonic activity of the respiratory muscles, loss of laryngeal braking, diaphragmatic braking, or all of these factors. All of these important mechanisms for maintaining FRC in infants (and to a lesser extent in older children) are lost with general anesthesia or muscle relaxants, causing marked reductions in FRC, airway closure and atelectasis ( Serafini et al., 1999 ). The physiological mechanisms for maintaining FRC in young infants are listed in Box 2-4 .

When is the FRC no longer determined dynamically but determined by the balance between the recoils of the thorax and the lungs to the opposing direction, as in adults? Colin and others (1989) have shown that, in infants and children during quiet, natural sleep, the transition from dynamically determined to relaxed end-expiratory volume or FRC takes place between 6 and 12 months of age. By 1 year of age the breathing pattern is predominantly that of relaxed end-expiratory volume, just as in older children and adults. These findings coincide with the upright posture and development of thoracic tissue and muscle strength in infants.

The breathing pattern of infants less than 6 months of age is predominantly abdominal (diaphragmatic) and the contribution of the rib cage (external intercostal muscles) to tidal volume is relatively small (20% to 40%), reflecting instability of the thorax or weakness of the intercostal muscles. After 9 months of age, the rib cage component of tidal volume increases to a level (50%) similar to that of older children and adolescents, reflecting the maturation of the thoracic structures ( Hershenson et al., 1990 ). Furthermore, a study by Papastamelos and others (1995) has shown that the stiffening of the chest wall continues throughout infancy and early childhood. By 12 months of age, however, chest wall compliance (which is extremely high in neonates) decreases and nearly equals lung compliance. The chest wall becomes stable and can resist the inward recoil of the lungs and maintain FRC passively. These relatively recent findings support the notion that the stability of the respiratory system is achieved by 1 year of age.

Effects of General Anesthesia on Functional Residual Capacity

General anesthesia with or without muscle relaxation results in a significant reduction of FRC in adult patients in the supine position soon after the induction of anesthesia (Rehder et al., 1971, 1974 [358] [359]; Westbrook et al., 1973 ), whereas FRC is unchanged during anesthesia in the sitting position ( Rehder et al., 1972 ). A decrease in FRC is associated with reductions in both lung and thoracic compliance, but the mechanism responsible for the reduction in FRC and the sequence of events that changes respiratory mechanics were not understood for many years.

In an excellent study, deTroyer and Bastenier-Geens (1979) showed that when a healthy volunteer was partially paralyzed with pancuronium, the outward recoil of the thorax decreased, whereas lung recoil (compliance) did not. This change altered the balance between the elastic recoil of the lung and thorax in opposite directions, and consequently FRC diminished. The compliance of the lungs decreased shortly thereafter, resulting from the reduced FRC and resultant airway closure. Based on their findings, deTroyer and Bastenier-Geens postulated that, in the awake state, inspiratory muscles have intrinsic tone that maintains the outward recoil and rigidity of the thorax. Anesthesia or paralysis would abolish this muscle tone, reducing thoracic compliance followed by a reduction in FRC, and eventually lung compliance in rapid succession (in a matter of a few minutes).

In healthy young adults, a reduction of FRC during general anesthesia is limited to between 9% and 25% from the awake control levels ( Laws, 1968 ; Rehder et al., 1972 ; Westbrook et al., 1973 ; Hewlett et al., 1974 ; Juno et al., 1978 ). In older individuals, the average reduction in FRC is higher (30%), probably because of lower elastic recoil pressure and increased closing capacity ( Bergman, 1963 ).

With the more compliant thoraces of infants and young children, general anesthesia and muscle relaxation would be expected to produce more profound reductions in FRC than in adolescents and adults.Henderson-Smart and Read (1979) have shown a 30% reduction in thoracic gas volume in infants changing the sleep pattern from quiet (non-REM) to active (REM) sleep. In children 6 to 18 years of age under general anesthesia and paralysis, Dobbinson and others (1973) found marked reductions in FRC (average reduction, 35%) from their own awake control values, as measured with a helium dilution technique. The average decrease in FRC among those younger than 12 years of age was 46%. Fletcher and others (1990) demonstrated that compliance of the respiratory system (Crs) in infants and children under general anesthesia decreased about 35%, a value comparable to the reduction reported in adults under similar conditions ( Westbrook et al., 1973 ; Rehder and Marsh, 1986 ). This reduction in Crs occurred both during spontaneous breathing and during manual ventilation with low tidal volume after muscle relaxants were given. When tidal volume was doubled, however, Crs returned to preanesthetic control levels.

These findings are in accord with previous findings in adults ( deTroyer and Bastenier-Geens, 1979 ; Hedenstierna and McCarthy, 1980 ) and support the notion that anesthesia reduces FRC. The finding that a larger tidal volume increases Crs toward control values also indicates that FRC decreases to the lower, flatter portion of the pressure-volume curve (see Fig. 2-21 ). Motoyama and others (1982a)reported moderate decreases in FRC (-46%) in children as measured with helium dilation and a marked decrease (-71%) in infants under halothane anesthesia and muscle paralysis, approaching the relaxation volume in the newborn infant reported by Agostoni (1959) .

Effect of Positive End-Expiratory Pressure (PEEP) Under General Anesthesia

Thorsteinsson and others (1994) reported that the lung volume at FRC (or relaxation volume, Vr) was at a lower, flatter portion of the pressure-volume (P-V) curve in all infants and children studied. To restore FRC to the normal or steepest portion of the P-V curve of the respiratory system seen in the awake state, a PEEP of 5 to 6 cm H2O had to be added to infants younger than 6 months of age and 12 cm H2O in children.

Increased density appearing on computed tomography (CT) scans in the dependent portion of the lung has been described in adult patients shortly after the induction of anesthesia and muscle relaxation. This increased density could be reduced or eliminated by adding PEEP (Brismar et al., 1996). Serafini and others (1999) were the first to report evidence of atelectasis in young children (1 to 3 years; mean age, 1.8 years) on CT scan in the dependent portion of the lungs shortly after the inhalation induction of anesthesia and intubation. These patients were given three deep inflations of the lungs (sighs) with 40% oxygen in nitrogen (air mix) and ventilated with 10 mL/kg of tidal volume. Atelectasis (density on the CT scan) appeared almost immediately when ventilated without PEEP ( Fig. 2-24A ). When the patients were ventilated for 5 minutes with an addition of PEEP (5 cm H2O) with the same ventilator settings and end-tidal Pco2, the density disappeared from the repeated CT scans in all 10 children studied, indicating the recruitment of atelectic lung segments ( Fig. 2-24B ) ( Serafini et al., 1999 ).

 
 

FIGURE 2-24  Computed tomography (CT) scan of the thorax during general endotracheal anesthesia. (A) Transverse CT scan of the thorax 5 minutes after the induction of anesthesia without PEEP. Note the appearance of atelectasis (density) in the dependent regions of both lungs. (B) Transverse CT scan of the thorax during anesthesia with a positive end-expiratory pressure (PEEP) of 5 cm H2O, showing the complete disappearance of atelectasis in the dependent regions of both lungs.  (From Serafini G, Cornara G, Cavalloro F, et al.:Paediatr Anaesth 9:225-228, 1999, with permission.)

 

 

 

As the stability of the thorax increases during the first year of life as stated earlier ( Papastamelos et al., 1995 ), it is likely that the thorax would resist the lung collapse and atelectasis with increasing age.Motoyama (1996) examined this possibility by measuring respiratory system compliance (Crs) in infants andyoung children under 6 years of age undergoing halothane-nitrous oxide endotracheal anesthesia. These patients were ventilated either with or without PEEP (6 cm H2O) for 15 minutes preceded by deep sighs. After a period of ventilation with PEEP, Crs was consistently higher after PEEP than without PEEP. There were significant age-related differences in the degree of increase in Crs after PEEP (6 cm H2O) versus no PEEP (0 cm H2O) ( Fig. 2-25 ). The average increase of Crs with PEEP was greatest in infants less than 8 months of age (75% higher with PEEP versus without PEEP). In contrast, in older infants and toddlers (9 months to 2.5 years), an average increase in Crs with PEEP was 22%; in children (2.5 and 5.5 years), the increase was 9%, the level one would expect in adults. These results reflect greater reductions in FRC (or increases in atelectasis) in the younger age groups (Motoyama, 1996 ) ( Fig. 2-25 ).

 
 

FIGURE 2-25  Compliance of the respiratory system (Crs) under general anesthesia in infants and children and the effect of PEEP. An addition of PEEP (5 to 6 cm H2O) improves (restores) Crs significantly in all age groups studied. The beneficial effect of PEEP was most dramatic in infants younger than 8 months (see text).  (From Motoyama EK: Anesthesiology 85:A1099, 1996.)

 

 

 

Persistent airway closure during general anesthesia would result in resorption atelectasis because alveolar gas (mostly oxygen and nitrous oxide) trapped below the occluded airways would be rapidly absorbed. Resultant pulmonary ventilation/perfusion imbalance and right-to-left shunting of blood in the lung may reduce arterial Po2 in the postanesthetic recovery room. Such an effect would be expected to be more profound in infants. Motoyama and Glazener (1986) studied arterial oxygen saturation with a pulse oximeter (Spo2) in otherwise healthy infants and children before and after general anesthesia for simple, relatively short surgical procedures (inguinal hernia repair, myringotomy tube insertions, etc.). On arrival at the postanesthetic care unit (PACU), the mean Spo2 was 93% (estimated Pao2, 66 mm Hg), significantly reduced from the preoperative value of 97%. In some children, Spo2 decreased to the low 70s (estimated Pao2 <40 mm Hg). These patients showed no sign of hypoxic ventilatory stimulation with normal cutaneous Pco2 ( Motoyama and Glazener, 1986 ).

A large percentage (20% to 40%) of otherwise healthy infants and children develop oxygen desaturation (Spo2 ≤94%) during transport and on arrival at the PACU ( Motoyama and Glazner, 1986 ; Pullerits et al., 1987 ; Patel et al., 1988 ). A later study of postoperative hypoxemia involving 1152 patients ranging from infants to adults has demonstrated that hemoglobin desaturation occurs sooner, is more pronounced, and lasts longer in infants than in children and in children than in adults ( Xue et al., 1996 ). All children, therefore, should be given oxygen by mask during the transport from the operating room and on arrival at the PACU until he or she can maintain satisfactory oxygen saturation by pulse oximeter without supplemental oxygen (see Chapter 11 , Intraoperative and Postoperative Management).

Closing Volume and Closing Capacity

Besides the lungs and chest wall, the air passages themselves have a compliance that may be important. With deep inspiration the air passages of normal persons increase in size (interdependence of airways and lung volume), whereas on forced expiration they decrease to a point at which dynamic compression or airway closure with air trapping may take place. Closing volume is the lung volume above residual volume (RV) at which dependent lung zones (i.e., lower lung segments in the upright position) cease to ventilate, presumably because of the closure of small airways. Closing capacity is the sum of closing volume and RV. Whether this closure is anatomic or merely the result of dynamic compression and reduction in flow (see discussion of maximum expiratory flow-volume curves under Dynamic Properties) is controversial ( Hughes et al., 1970 ; Hyatt et al., 1973 ). Because the patency of small airways depends in part on the elastic recoil of the lungs, closing capacity as a percentage of TLC is relatively high in young children ( Mansell et al., 1972 ) and would be even higher, at least theoretically, in infants. Closing capacity increases with aging as well as with small airway disease, such as chronic bronchitis caused by smoking and emphysema in adults.

Lung compliance is reduced in most situations in which lung volume is decreased (e.g., the removal of lung tissue, atelectasis, intrapulmonary tumors), although it is normal when corrected for lung volumes. Compliance is also decreased when surface forces are increased (as in IRDS with increased surface force [or decreased surfactant]) or elastic recoil is abnormally increased (e.g., in interstitial pulmonary fibrosis).

Emphysema is associated with a loss of elastic recoil and therefore an abnormal increase in compliance. Chest wall compliance decreases with conditions such as scleroderma, kyphoscoliosis, and ankylosing spondylitis involving the thoracic structures.

▪ DYNAMIC PROPERTIES

Breathing involves cyclic contractions of respiratory muscles and the generation of force, which must overcome resistive and elastic properties of the lung and chest wall. The resistive properties of the respiratory system include the resistance to airflow within the airways, the tissue viscoelastic resistance or the resistance of the lung and thoracic tissues themselves to deformation, and inertial resistance (inertance) resulting from the movement of gas molecules within the airways, especially at high velocities. In contrast to compliance (or elastance), which is measured at points of no flow, flow resistance is present only when the lung is in motion.

Airway Resistance

The pressure required to overcome frictional resistance and produce flow between the alveoli (Palv) and the airway opening (Pao) is proportional to flow rate. Airway resistance (Raw) is expressed as pressure gradient across the airways (P = Pao - Palv) per unit flow (   ):

If the respiratory system is assumed to have a single compartment with a constant elastance or compliance (E = 1/C) and a constant resistance (R), the equation of forces acting on the respiratory system can be expressed as follows:

In tidal breathing, inertance (I) is very small and can be ignored. During normal tidal breathing, approximately 90% of the pressure gradient required is needed to overcome the elastic forces and the remaining 10% of the pressure is expended to counter the flow resistance ( Sly and Hayden, 1998 ).

Flow resistance is related to the length (l), radius of the tube (r), and the viscosity of the gas (η) as follows:

Assuming a laminar flow (as seen in small or peripheral airways), it is apparent from this equation (Poiseuille's law) that the most important factor affecting flow resistance is the change in the radius of the tube (airways), because resistance is inversely proportional to the fourth power of the radius. (When the flow is turbulent, as occurs in large airways, the flow resistance increases approximately with r5.) Therefore, airway resistance in infants with smaller airway diameters is much higher, in absolute terms, than airway resistance in older children and adults. It might also be expected that inflammation or secretions in the airway system would result in exaggerated degrees of obstruction in infants compared with older persons ( Fig. 2-26 ). One such example may be the severe and often life-threatening obstruction of upper airways seen only in infants and young children with acute supraglottitis (epiglottitis) and subglottic croup (laryngotracheobronchitis). In terms of body size, however, the caliber of airways in general is wider and airway resistance (specific resistance) lower in infants and children compared with adults ( Motoyama, 1977 ; Stocks and Goddfrey, 1977) .

 
 

FIGURE 2-26  Effect of inflammation on airway resistance in infants and adults. r, Radius of an air passage; R, flow resistance.

 

 

In absolute terms, airway resistance (Raw) in the newborn is very high (19 to 28 cm H2O/L per sec). It decreases to less than 2 cm H2O/L per sec in the adolescent and the adult. In relative terms (as expressed per unit of lung volume, usually FRC), airway resistance is relatively low, or conductance (Gaw, the reciprocal of resistance) is very high, in the newborn. The specific conductance (sGaw = Gaw/FRC) decreases rapidly during the first year of life (Stocks and Godfrey, 1977, 1978 [419] [420]), indicating a rapid increase in lung volume (alveolar formation) in relation to airway size. Between 6 and 18 years of age, Gaw increases linearly with increases in height; sGaw, however, stays fairly constant throughout this period at about 0.2 L/sec/cm H2O (Zapletal et al., 1969, 1976, 1987 [473] [474] [475]).

Distribution of Airway Resistance

Rohrer's earlier work (1915) led to the belief that peripheral airways of small caliber were the major contributors to total airway resistance. However, the elegant morphometric studies of Weibel (1963) with inflated and fixed lungs proved that the total cross-sectional area of each generation of airways increases dramatically toward the periphery ( Fig. 2-27 ). Indeed, about two thirds of the total airway resistance exists between the airway opening and the trachea, and most of the remaining resistance is in the large central airways. The airways smaller than a few millimeters in diameter (peripheral airways) contribute only about 10% of total resistance ( Macklem and Mead, 1967 ).

 
 

FIGURE 2-27  (A) Diagrammatic representation of the sequence of elements in the conductive, transitory, and respiratory zones of the airways. BR, Bronchi; BL, bronchioles; TBL, terminal bronchioles; RBL, respiratory bronchioles; AD, alveolar ducts; AS, alveolar sacs; z, order of generation of branching; T, terminal generation. (B) Total airway cross-sectional area, A(z), in each generation, z.  (From Weibel ER: Morphometry of the human lung. New York, 1963, Academic Press.)

 

 

 

These findings have important clinical implications. If the peripheral airways contribute little to the total airway resistance, disease processes involving small airways, such as emphysema in adults, cystic fibrosis in children, and bronchopulmonary dysplasia (BPD) in infants, will not be detectable by measurement of the total airway resistance. For instance, complete obstruction of one half of peripheral airways would increase the total airway resistance by only 10%, an increase within the usual variation in measurements. For this reason, the peripheral airways formerly were called the “quiet zone” of the lung ( Mead, 1970 ). Apparently the measurement of total airway resistance is not a sensitive clinical test for detecting small airway obstruction.

Upper Airway Resistance

The airway system extends from the airway opening at the nares or the mouth to the alveolar duct at the periphery of the lung. Functionally, the airway system can be subdivided into theupper (extrathoracic) and lower (intrathoracic) airways. During quiet breathing, airflow resistance through the nasal passages accounts for approximately 65% of total airway resistance in adults ( Ferris et al., 1964 ). This is more than twice the resistance during mouth breathing. For air warming, humidification, and particle filtration, it is important that one preferentially or instinctively breathes through the nose despite its higher resistance (Proctor, 1977a, 1977b [347] [348]). Stocks and Godfrey (1978) found nasal resistance comprised approximately 49% of the total airway resistance in European infants, whereas it was significantly less in infants of African origin (31%). Overall, upper airway resistance is approximately two thirds of the total airway resistance.

Except when crying, newborn infants are obligatory nose breathers. The cephalad position of the epiglottis and close approximation of the soft palate to the tongue and epiglottis in neonates may be a reason why mouth breathing is more difficult than nose breathing ( Moss, 1965 ; Sasaki et al., 1977 ). When the nasal airway is occluded, some infants, especially during REM sleep, do not respond sufficiently to initiate adequate mouth breathing and obstructive apnea ensues. In infants, an insertion of a nasogastric tube significantly increases total resistance by as much as 50% and may compromise breathing (Stocks, 1980 ).

Lower Airway Resistance

Between the trachea and the alveolar duct are an average of 23 airway generations ( Weibel, 1963 ) (see Fig. 2-27 ). As gas molecules move from the trachea toward the terminal airways during inspiration, the radius of the successive generations of airways becomes smaller and the flow resistance is expected to increase. In reality, however, the total cross-sectional area of the airway segments increases dramatically toward the periphery, although the diameter of successive single airways decreases. This is because the number of airways increases markedly and, consequently, the flow resistance of airways decreases toward the periphery ( Weibel, 1963 ) (see Fig. 2-27 ). Indeed, using a retrograde catheter technique, Macklem and Mead (1967) demonstrated that the peripheral airways, less than about 1 mm in diameter (around 14th generation), contribute less than 10% of the lower airway resistance (or 3% of the total airway resistance).

Tissue Viscoelastic Resistance

It had been assumed that airway (frictional) resistance represented the majority of total respiratory system resistance during breathing. The pressure needed to overcome tissue viscous resistance during inspiration was estimated to be about 35% in adults and 28% in children ( Bryan and Wohl, 1986 ). Studies since the 1980s on mechanical ventilation, in both animals and humans, however, have indicated that viscoelastic resistance, or the energy required to counter the hysteresis or viscoelasticity of the lungs and thoracic tissues, contributes a significantly greater proportion of the total resistance than previously assumed ( Milic-Emili et al., 1990 ). Furthermore, both airway resistance (Raw) and viscoelastic resistance (ΔR) have been found to be flow and volume dependent (i.e., both Raw and ΔR change with volume or flow changes) and to the opposite directions. Airway resistance (Raw) increases with increasing flow due to higherturbulence, whereas Raw decreases with increasing lung volume because airway caliber also increases with volume. The traditional view had been that the total resistance followed the same direction of flow resistance because it was thought to be the majority of total respiratory system resistance. Paradoxically, ΔR decreases with increasing flow, while the volume is kept constant; and, while the flow rate is kept constant, ΔR increases with increasing lung volume ( D'Angelo et al., 1989) ( Fig. 2-28 ). Furthermore, the direction of changes in total resistance followed that of ΔR, rather than that of Raw. Studies in anesthetized and ventilated children have shown the same flow and volume dependence of ΔR that exist in adults, that is, opposite of the direction of changes in Raw, although the total resistance did not necessarily follow the changes in ΔR ( Kaditis et al., 1999a ) ( Fig. 2-29 ).

 
 

FIGURE 2-28  Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, resistive component (Rint, mostly airway resistance Raw) and viscoelastic component (ΔRrs) (Rrs = Rint + ΔRrs). (IA) Average relationship of Rrs and Rint with increasing inspiratory flow on X-axis at a constant inspiratory volume (0.47 L) in 16 anesthetized and paralyzed adult subjects. (IB) Similar relationship between ΔRrs with variable inspiratory flow. (IIA) Average relationship of Rrs and Rint with variable inspiratory volume on X-axis at a constant inspiratory flow (0.56L/s) in the same subjects as IA. (IIB) Similar relationship in terms of ΔRrs. Bars, 1SD.  (Modified from D—Angelo E, et al.: Respiratory mechanics in anesthetized paralyzed humans. J Appl Physiol 67:2556, 1989. Used with permission of the American Physiological Society.)

 

 

 

 
 

FIGURE 2-29  Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, flow-resistive component (Rint or Raw) and viscoelastic component (ΔR) (Rrs = Rint + ΔR), in eight healthy children aged 2 to 5 years under general endotracheal anesthesia. (A) Average relationship of Rrs, Rint, and ΔR with increasing inspiratory flow on x-axis at a constant end-inspiratory volume (VT, 12 mL/kg). ΔR and Rrs decreased significantly with increasing flow as in adults (see Fig. 2-27 ). (B) Average relationship of Rrs, Rint, and ΔR with increasing volume on x-axis while flow was kept constant (15 mL/sec per kg) in the same subjects as in A. ΔR increased with increasing volume while Rint decreased with volume. Unlike in adults, there was no volume dependence of Rrs. Bars, 1 SEM;    I, inspiratory flow; VT, tidal volume.  (From Kaditis AG, Motoyama EK, Seki I, et al.: Pediatr Res 46:419-428, 1999.)

 

 

 

This new evidence on the behavior of viscoelastic resistance has important clinical implications. Traditionally, the patient with airway obstruction has been treated with large tidal volumes and a slow respiratory rate to allow complete exhalation to avoid intrinsic PEEPi (or auto-PEEP) and air trapping. With the new understanding, it makes more sense to breathe with a smaller VT and higher respiratory rate in order to minimize total respiratory system resistance and decrease work of breathing ( Kaditis et al., 1999b ).

Time Constant of the Respiratory System

When the lung is allowed to empty passively from end-inspiration to FRC, the speed of lung deflation is determined by the product of respiratory system resistance and compliance (R×C or R/E), which is a unit of time (time constant, τ). If the respiratory system is considered as a single compartment with a constant resistance and compliance within the tidal volume range of breathing (which is a reasonable assumption in healthy individuals), then τ = RC.

Under these conditions, the volume-time profile can be represented by an exponential decay and at 1 time constant (1τ), tidal volume is reduced by 63%. It requires 3×τ to nearly complete exhalation to FRC. In healthy children and adults, τ is 0.4 to 0.5 second; it is slightly shorter in neonates (0.2 to 0.3 second) ( Bryan and Wohl, 1986 ). In patients with obstructive lung disease, such as bronchial asthma, τ is increased due to an increase in airway resistance; it is also increased markedly in patients breathing through an endotracheal tube under general anesthesia.

Maximum Expiratory Flow-Volume Curve and the Concept of Flow Limitation

During quiet breathing, pleural pressure remains subatmospheric, whereas during forced expiration, pleural pressure increases considerably above atmospheric pressure and, in turn, increases alveolar pressure. The resultant pressure gradient between the alveoli and the airway opening (atmospheric) produces the expiratory flow. In the periphery of the lungs this pressure within the airways is higher than the pleural pressure because of the elastic recoil of the lung. In comparison, in major intrathoracic airways the pressure within the lumen is near atmospheric and lower than the surrounding pleural pressure. At some point along the airways the pressure within the airway lumen should equal the pleural pressure surrounding the airway (equal pressure point [EPP]) ( Mead et al., 1967 ). During forced expiration, the airway between EPP and the trachea is dynamically compressed, and the flow rates consequently become independent of effort (i.e., additional expiratory effort or pressure does not increase flow) ( Fig. 2-30 ). Under these circumstances (dynamic flow limitation), the maximum expiratory flow rate (   max) is determined by the flow resistance of the upstream segment (Rus) between the alveoli and the EPP and the elastic recoil pressure of the lung (Pstl), as follows ( Mead et al., 1967 ):

 
 

FIGURE 2-30  Flow-volume curves obtained when a subject performs a series of vital capacity expirations of graded effort, varying from a very slow breath out to one of maximal speed and effort.  (From Bates DV, Macklem PT, Christie RV, editors: Respiratory function in disease. An introduction to the integrated study of the lung. Philadelphia, 1971, WB Saunders.)

 



According to the wave-speed theory of expiratory flow limitation ( Dawson and Elliot, 1977) , compliance or collapsibility of lower airways around the EPP (choke point) is an additional determinant of    max ( Hyatt, 1986 ).

The maximum expiratory flow-volume (MEFV) curve obtained during forced expiration from TLC to Rv relates instantaneous maximum expiratory flow rates (   max) to corresponding lung volumes (Fig. 2-31 ). Clinically, the measurement of    max is an extremely sensitive test for the detection of obstruction of the lower airways toward the periphery (silent zone) of the lungs because it eliminates the component of upper airway resistance between the mouth and EPP and is independent of the degree of effort or cooperation by the patient ( Zapletal et al., 1971 ) (also see under Measurements of pulmonary function below).

 
 

FIGURE 2-31  Maximum expiratory flow volume (MEFV) curve on volume-flow axis on the right is contrasted with spirometric tracing (spirogram) on volume-time axis on the left during a single forced vital capacity (VC) maneuver. FEV1.0, Forced expiratory volume in 1 second; PEFR, peak expiratory flow rate;    max50,    max25, maximum expiratory flow at 50% and 25%, respectively, of forced VC.  (From Motoyama EK: Int Anesthesiol Clin 26:6, 1988.)

 

 

 

Distribution of Flow Resistance

On the basis of physiologic measurements in lungs obtained at autopsy, Hogg and others (1970) reported that airway conductance of the peripheral airways in children less than 6 years of age was disproportionately low (i.e., resistance was high). They postulated that the diameter of small airways of the same generation was disproportionately smaller in infants than in older children and adults. Although this theory is consistent with the high incidence of severe lower airway disease in infants, it conflicts with later physiologic data obtained from healthy infants. Studies of MEFV curves in anesthetized infants and children ( Motoyama, 1977 ), and more recently in sedated infants ( Lambert et al., 2004 ), showed that at low lung volumes, the maximum expiratory flow (   max) normalizes for lung volume and the conductance of the upstream segment is disproportionately high in infants and decreases with age ( Motoyama, 1977 ), indicating that lower airway resistance toward the periphery of the lung parenchyma is relatively lower, rather than higher, in the early postnatal years ( Fig. 2-32 ).

 
 

FIGURE 2-32  Maximum expiratory flow rate (   max) at 25% forced vital capacity (FVC) from forced deflation flow-volume curves versus height in anesthetized boys and girls.    max25 is expressed in FVC units per second to normalize for lung size. FVC-adjusted    max25 is disproportionately higher in infants than in older children.  (From Motoyama EK: Pediatr Res 11:220, 1977.)

 

 

 

▪ SUMMARY

Compliance of the respiratory system has both lung and chest wall components. During artificial ventilation of a healthy adult, about one half of the inspiratory pressure is required to expand the lungs and one half to expand the chest wall. In infants, the chest wall is extremely compliant and requires little pressure to expand. Accordingly, airway pressure during artificial ventilation should be reduced. In absolute terms, lung compliance increases with body or lung size. In relative terms, however, lung compliance is relatively high in infants and decreases withage, as elastic recoil pressure of the lungs increases. Most of the flow resistive force against breathing is exerted within the upper and large central airways; the small airways contribute only a fraction of total flow resistance. Flow resistance in absolute terms is largest when air passages are smallest; thus, infants are more prone to airway obstruction of the upper and lower airways. When lung volumes are taken into account, however, total airway resistance is relatively low during the newborn period and increases rapidly during the first year, as lung volume increases with alveolar formation. Resistance of smaller (parenchymal) airways appears to be relatively low at birth and increases with age. The contribution of viscoelastic resistance from the lung and thoracic tissue hysteresis has been found to be much larger than had been recognized in the past. Both flow-resistive and tissue viscoelastic resistance change with increasing flow and volume, but the directions of changes are opposite to each other. Forming a complex mechanism, the tonic activities of the pharyngeal and laryngeal dilator muscles protect the pharyngeal airway from collapse. During spontaneous breathing, the genioglossus and other upper airway muscles contract synchronously with the diaphragm and increase upper airway caliber. These muscles are easily depressed by sleep and anesthesia, causing upper airway obstruction both at the velopharynx and, to a lesser extent, at the base of the tongue, resulting in upper airway obstruction during anesthesia.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ VENTILATION

Ventilation involves the movement of air in and out of the lungs. The diaphragm is the most important muscle for normal inspiration, although the intercostal and accessory respiratory muscles aid in a maximal inspiratory effort. Quiet expiration results from the elastic recoil of the lungs and chest wall and the relaxation of the diaphragm. The expiration of a newborn, even when resting or asleep, appears active rather than passive, as in the older child and adult. A similar active expiration has been observed in anesthetized patients ( Freund et al., 1964 ), but the mechanism is unknown. Forced expiration is accomplished with the aid of the spinal flexors, the intercostal muscles, and especially the abdominal muscles.

Tidal volume (VT) is the amount of air moved into or out of the lungs with each breath. Minute volume (   E) is the amount of air breathed in or out in a minute, or as follows:

The frequency (f) of quiet breathing decreases with increasing age. The exact basis for this change is unknown but may be related to the work of breathing. Humans seem to adjust their respiratory rate and tidal volume so that ventilatory needs are accomplished with a minimum of work ( McIlroy et al., 1954 ). The relatively high rate in newborns (average, 34 breaths/min) as compared with adults (10 to 12 breaths/min) is consistent with this minimum work concept ( Cook et al., 1957 ) ( Fig. 2-33 ). Mead (1960) , however, has presented data indicating that in the normal resting state, respiration is adjusted to require a minimum average force of the respiratory muscles. He postulated that the principal site of the sensory end of the control mechanism is in the lungs. In certain situations, the minimum work of breathing and minimum average force required would occur at the same frequency of respiration, but this would not invariably be true.

 
 

FIGURE 2-33  Calculated pulmonary work in newborns versus respiratory rate. The theoretical minimum work of respiration occurs at a rate of 37 breaths/min. Observed resting respiratory rates were 38 breaths/min.  (From Cook CD, Sutherland JM, Segal S, et al.: J Clin Invest 36:440, 1957.)

 

 

 

▪ DEAD SPACE AND ALVEOLAR VENTILATION

Only part of the minute volume is effective in gas exchange—the alveolar ventilation (   A). The remainder merely ventilates the respiratory dead space. If the minute noneffective ventilation (   E -    A) is divided by the frequency, the physiologic respiratory dead space is calculated. In the normal person, the physiologic and anatomic dead spaces are approximately equal because alveolar dead space is negligible. Because the air passages are compliant structures, the size of the dead space correlates closely with the degree of lung expansion. When airway obstruction and emphysema are present, dead space increases. However, physiologic dead space is influenced more by the evenness of gas distribution within the lungs and by the perfusion of the alveoli. Thus, when ventilation of the lungs is uneven (as in asthma or cystic fibrosis) or the blood supply to various areas of the lungs decreases (as with pulmonary emboli), the physiologic dead space increases.

Although the anatomic dead space represents an inefficient part of the respiratory tract with respect to gas exchange, it does have two important functions: warming and humidifying gas on inspiration. These functions are compromised by endotracheal intubation or tracheostomy.

In a normal person, dead space can be estimated as 1 mL/pound of body weight ( Radford et al., 1954 ). In children and young adults, a more exact estimate may be obtained from its relation to body height ( Hart et al., 1963 ).

The VD/VT ratio in normal lungs is approximately constant (0.3) from infancy to adulthood (see Table 2-2 ). An absolute increase in dead space, however, whether caused by respiratory abnormalities or external apparatus, is much more critical to the infant than to the adult because of the infant's small tidal volume and the relatively larger volume of dead space added.

Alveolar ventilation (   A), or the minute effective ventilation, may be expressed in terms of the carbon dioxide in the peripheral arterial blood. Thus, the following equation is applicable:

where    co2 is the carbon dioxide production per minute, Paco2 is the arterial carbon dioxide tension, and PB-47 is the barometric pressure minus water vapor tension at 37°C.

The difference between minute volume and alveolar ventilation (   E -    A) is the wasted ventilation due to physiologic deadspace. The concept of    A may be easier to understand if considered similar in some way to the renal clearance of a substance; in the lungs, carbon dioxide is the substance being cleared. If    co2 remains constant when    A is halved, Paco2 will double. Measurement of    A provides a far better index of the efficacy of ventilation than measurement of    E.    E may be very large, but if it is composed mostly of dead space or ineffective ventilation,    E may be inadequate and Paco2 may start to increase.

Physiologic dead space is calculated from the carbon dioxide tensions between arterial blood and mixed expired gas (Peco2) and is often expressed as a fraction of the tidal volume:

Alveolar ventilation is considerably higher per unit of lung volume in the normal infant than in the adult. This is expected because the oxygen consumption is also higher per unit of lung volume or body weight in the infant ( Cook et al., 1955 ).

▪ DISTRIBUTION OF VENTILATION

The distribution of ventilation is affected by a number of factors. At end-expiration with the mouth open and the larynx relaxed, alveolar pressure is zero, or atmospheric. The interpleural pressure is negative, and there is a vertical pressure gradient. The pressure surrounding the apex of the lung is more negative than that at the base. Accordingly, the transmural or distending pressure at the apex is greater and the regional FRC is larger than that at the base ( Fig. 2-34A ). At the end of tidal inspiration, a greater proportion of the inspired air is distributed to the base because the regional FRC is at the steepest portion of the pressure-volume curve at the base. In a lateral decubitus position, the lower part of the lung receives a larger tidal volume than the upper part ( Kaneko et al., 1966 ). In adults with unilateral lung disease, pulmonary gas exchange can be improved by positioning with the healthy lung down, or dependent ( Remolina et al., 1981 ).

 
 

FIGURE 2-34  Effect of vertical gradient of pleural surface pressure on distribution of tidal ventilation. (A) At the beginning of lung inflation from functional residual capacity (FRC), lower regions are operating on a steeper part of the compliance curve of lungs than upper regions. Accordingly, during slow inspiration from FRC, ventilation is greater in lower lung regions (arrows). (B) At residual volume (RV), pleural surface pressure at lung base is positive (+4.8 cm H2O) and lower airways are closed. Consequently, at the beginning of slow inspiration from RV, lower lung regions are not ventilated and the uppermost part of the lung is preferentially ventilated (arrows).  (From Milic-Emili J: Pulmonary statics. In Widdicomb JG, editor: Respiratory physiology, MTP International Review of Science. Series I, vol 2. Borough Green, Kent, 1974, Butterworth.)

 

 

 

In infants with unilateral lung disease, however, the opposite seems to be the case. In the lateral decubitus position, oxygenation improves when the healthy lung is uppermost ( Heaf et al., 1983 ; Davies et al., 1985 ). Furthermore, Heaf and others (1983) have shown, by means of a krypton-81m ventilation scan, that in infants and children up to 27 months of age, with or without radiologic evidence of lung disease, ventilation is preferentially increased in the uppermost part of the lung and diminished in the dependent lung ( Fig. 2-35 ). This paradoxical distribution of ventilation in young children may be explained by premature airway closure ( Davies et al., 1985 ). Because the infant's chest wall is extremely compliant the pleural pressure is near atmospheric. The condition resembles that of adults breathing at extremely low lung volumes (or near RV) (see Fig. 2-34B ). Under these circumstances, airway closure occurs and, in the lateral decubitus position, ventilation preferentially shifts to the uppermost part of the lung ( Milic-Emili et al., 1966 ). In paralyzed, mechanically ventilated adults, tidal ventilation is preferentially shifted to the uppermost part of the lung, presumably by a similar mechanism (i.e., reduction of FRC and airway closure) ( Rehder et al., 1972 ).

 
 

FIGURE 2-35  Posterior krypton 81m ventilation lung scan in a healthy 31-year-old man and in a 2-month-old girl. In the adult, ventilation is preferentially distributed to the dependent lung; in the infant, the reverse is seen, with ventilation greater in the uppermost lung. For all scans, the distribution of ventilation to each lung is expressed as a percentage of the total to both lungs.  (From Heaf DP, Helms P, Gordon I, et al.: N Engl J Med 308:1505, 1983, with permission. Copyright © 1983. Massachusetts Medical Society. All rights reserved.)

 

 

 

Distortion of regional mechanical properties in the lungs results in far greater variations in the distribution of ventilation than is produced by gravitational forces. The product of regional flow resistance (R, expressed as pressure/flow in cm H2O/mL/sec) and compliance (C, expressed as volume/pressure in mL/cm H2O) determines the regional ventilation in the lungs. The product of resistance and compliance (RC) is a unit of time, termed the time constant (τ), as has been discussed earlier. In diseased lungs, as in asthma, bronchopulmonary dysplasia, and cystic fibrosis, the regional time constant becomes abnormal in affected areas, resulting in an uneven distribution of ventilation. The distribution of ventilation may be studied by measuring a nitrogen washout curve. The subject breathes 100% oxygen, and the decay of the alveolar nitrogen concentration is measured in successive expirations. Both in normal children and adults, nitrogen concentration is less than 2.5% after 7 minutes of oxygen breathing. This value is increased in patients with an uneven distribution of ventilation because the elimination of nitrogen from poorly ventilated areas is prolonged. In addition, radioactive xenon ventilation scans have been used to demonstrate macroscopic ventilatory abnormalities to aid in the interpretation of perfusion lung scans.

▪ CLINICAL IMPLICATIONS

The anesthesiologist often controls a patient's ventilation manually or mechanically during general anesthesia because most anesthetic techniques cause spontaneous ventilation to decrease or cease. This is because most anesthetics are potent respiratory depressants and because the endotracheal tube and the anesthesia circuit add elastic and resistive loads to breathing. Because anesthesia generally causes a decrease in FRC, the uneven distribution of ventilation, and an increase in physiologic dead space, the tidal volume must be increased. The mechanical dead space and internal compliance of anesthetic equipment also must be taken into account for the proper estimation of a patient's ventilatory requirement. Physiologic dead space is further increased in patients with preexistent lung dysfunction. For these reasons, it is practical to start with a tidal volume of 10 to 15 mL/kg, or roughly 1.5 to 2.0 times that required in awake individuals.

The inspiratory-to-expiratory (I/E) ratio is set to 1:2, a duty cycle (TI/TTOT) of 0.33. Respiratory frequency should be 10 to 14/min in adolescents, 14 to 20/min in children, and 20 to 30/min in infants. Once the mechanical ventilation is established, it can be decreased and refined with the aid of capnographic monitoring. In patients with obstructive lung disease who have a prolonged respiratory system time constant, expiratory time is increased to allow sufficient time for passive lung deflation. Passive expiration is an exponential function and takes three times the time constant to return to FRC (Nunn, 1994). The addition of a low level of PEEP (5 to 7 cm H2O) restores the volume (FRC) lost from the relaxation of inspiratory muscles and helps prevent airway closure.

▪ SUMMARY

Ventilation comprises effective (alveolar) and dead space ventilation. In healthy subjects, ventilation in relation to body size is increased in early infancy and then remains fairly constant throughout childhood and adolescence. Changes in Pao2 reflect changes in alveolar ventilation; thus capnographic monitoring of end-tidal Pco2 is useful for adjusting and maintaining appropriate alveolar ventilation. There is a vertical, hydrostatic gradient in negative pressure in the pleural space. Uneven distribution of ventilation exists both in health and in disease. The regional resting volume (FRC) is highest in the uppermost part of the lung, whereas the regional tidal volume is largest in the lowermost region of the lung in a spontaneously breathing subject. The opposite relationship exists in spontaneously breathing infants as well as in patients under anesthesia who are mechanically ventilated. In diseased lungs, uneven distribution of regional compliance (C), resistance (R), and a time constant (R×C) cause maldistribution of ventilation and increased physiologic dead space.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ GAS DIFFUSION

The ultimate purpose of pulmonary ventilation is to allow the diffusion of oxygen through the alveolar epithelial lining, basement membrane, and capillary endothelial wall into the plasma and red cells and diffusion of carbon dioxide in the opposite direction. The distance for gases to diffuse between the alveolar space and the capillary lumen is extremely small, about 0.3 μm in humans ( Weibel, 1973 ). Because these processes apparently follow the physical laws of diffusion, without any active participation by the lung tissue, pressure gradients must exist or gas exchange will not occur. On the other hand, if the gradient is increased by changes in gas tension either within the alveoli or in the blood, gas exchange is more rapid. Furthermore, since the blood Po2 affects the blood Pco2, changes in one moiety alter diffusion of the other. Carbon dioxide diffuses approximately 20 times faster than oxygen in a gas-liquid environment. Therefore, impairment of carbon dioxide diffusion does not become apparent in clinical situations until extremely severe disease is present.

The diffusing capacity of the lungs may be measured with a foreign gas, carbon monoxide, used in small concentrations (≤0.3%), or with various concentrations of inspired oxygen ( Forster, 1957 ). The subjects of diffusion and diffusing capacity have been reviewed.

The diffusing capacity (DLCO) of carbon monoxide (CO) can be measured with a single breath technique by adding an inert gas to the inhaled gas mixture with a single alveolar gas sample ( Ogilve et al., 1957) . The DLCO test is not exactly a measure of diffusing capacity since “diffusing” implies that the uptake of CO is attributable to diffusion alone and “capacity” implies it is a maximal limit ( Crapo et al., 2001 ). Indeed, the term “transfer factor” (TLCO) has become a standard term in most countries outside of North America ( Forster, 1983 ; Cotes et al., 1993 ). The role of DLCO measurement in lung function testing is to provide information on the transport of gas from alveolar air to hemoglobin in pulmonary capillaries. More specifically, DLCO measures the uptake of CO from the lungs per minute per unit of CO driving pressure, as follows:

where    co is uptake of CO (mL/min), Paco is alveolar partial pressure of CO, and Pcco is average pulmonary capillary partial pressure of CO. Because the basic equation is flow/pressure change (   /ΔP), Dlco is a measure of conductance (G = 1/R).

Although the diffusion of gases within the lung is necessary for survival, comparatively few conditions occurring in children affect diffusion per se. Diffusing capacity is decreased in the “alveolar capillary block syndrome” ( Bates, 1962 ). This decrease was considered to result primarily from increased thickness of the alveolocapillary membranes; but it is now believed that uneven distribution of ventilation with a resulting ventilation/perfusion imbalance is the more important cause of arterial oxygen desaturation ( Finley et al., 1962 ). Diffusing capacity changes with hemoglobin concentrations; it increases as hemoglobin concentration increases. A correction factor has to be used according to the recommendation of American Thoracic Society guidelines (1995) . Anemia, on the other hand, is associated with a decrease in diffusing capacity. This is partially explained by the decreased ability of blood to carry the inspired gases. Patients with congenital heart disease and left-to-right shunts frequently have an increased DLCO caused by increased blood volume and flow in the lungs ( Bucci and Cook, 1961 ). Conversely, diffusing capacity may be reduced when the pulmonary blood flow is markedly decreased, as in pulmonic stenosis.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ PULMONARY CIRCULATION

▪ PERINATAL AND POSTNATAL ADAPTATION

In prenatal life, pulmonary vascular resistance is high and most of the right ventricular output runs parallel to the left ventricular output, bypassing the lungs and flowing into the descending aorta through the ductus arteriosus. With the onset of ventilation at birth, the pulmonary vascular resistance suddenly decreases and blood flow through the lungs increases, enabling the organism to exchange oxygen and carbon dioxide and sustain independent existence. The principal factors that control this vital adjustment in vascular resistance are chemical changes (i.e., changes in Po2 and Pco2 or pH) in the environment of the pulmonary vessels ( Cook et al., 1963 ). An increase in Po2 also produces constriction and subsequent closure of the ductus arteriosus. The pulmonary arterial pressure, which is slightly higher than the pressure in the ascending aorta in the fetus ( Assali and Morris, 1964 ), suddenly decreases at birth and then continues to decrease, with a gradual decline in pulmonary vascular smooth muscle mass approaching the adult level within the first year of life ( Rudolph, 1970 ). If the lungs do not expand adequately (as in RDS of the neonate) and Po2 remains low, the pulmonary vascular resistance and pressure may remain high, and there may be prolonged patency of the ductus arteriosus and persistent right-to-left shunting of blood ( Strang and MacLeish, 1961 ) (also see Chapter 3 , Cardiovascular Physiology).

Under normal postnatal conditions, the systemic and pulmonary vascular beds are connected in series to form a continuous circuit. Although the systemic circulation has a high vascular resistance with a large pressure gradient between the arteries and veins, the pulmonary circulation presents a low resistance to flow.

Both hypoxemia and hypercapnia constrict the pulmonary vascular bed and increase resistance to flow. Chronic hypoxemia is associated with a pulmonary hypertension that returns to or toward normal when the hypoxemia is corrected ( Goldring et al., 1964 ). Pulmonary hypertension that persists for months or years results in right-sided heart failure (cor pulmonale), which then further complicates the existing pulmonary insufficiency.

Under normal circumstances, the arterial blood from the left ventricle contains up to 5% unsaturated blood (venous admixture). This comes mainly from the bronchial circulation but also in part from blood in the pulmonary circulation bypassing the alveoli and from blood flowing through the thebesian veins. This physiologic venous admixture depresses the arterial Po2 from approximately 102 to 97 mm Hg. In certain conditions, such as ventilation/perfusion imbalance (including decreased diffusing capacity), the amount of the venous admixture through the lungs increases sufficiently to cause significant arterial hypoxemia. Venous admixture also occurs because of intrapulmonary shunting as the result of atelectasis, pulmonary arteriovenous fistula, pulmonary hemangiomas, and increased collateral(bronchial) circulation, as in bronchiectasis. In addition, shunting may occur at the cardiac level when there is congenital heart disease with right-to-left shunting.

▪ NITRIC OXIDE AND PULMONARY CIRCULATION

The vascular endothelial cells release various vasoactive factors that affect vascular tone. The endothelium-derived relaxing factor (EDRF), first described by Furchgott and Zawadski (1980) , has been identified as nitric oxide (NO) ( Ignaro et al., 1987 ; Palmer et al., 1987 ). NO is a unique endogenous regulatory molecule involved in a wide variety of biologic activities, including systemic and pulmonary vasodilation, neurotransmission, and immunomodulation ( Welch and Loscalzo, 1994 ). Under physiologic conditions, nitric oxide is produced from the amino acid L-arginine catalyzed by constitutive nitric oxide synthase (cNOS) with a number of cofactors (NADPH, flavoproteins, tetrahydrobiopterin, reduced glutathione, and heme complex) and with the presence of ionized calcium and calmodulin. NO in the vascular endothelial cells diffuses into the adjacent vascular smooth muscle cells, stimulates guanylate cyclase activity, and increases cyclic guanylate monophosphate (cGMP), resulting in controlled smooth muscle relaxation and vasodilation ( Furchgott and Vanhoutte, 1989 ; Moncada et al., 1989 ). In normal lungs, basal release of endothelium-derived NO contributes to the maintenance of low pulmonary vascular resistance ( Celermajer et al., 1994 ; Stamler et al., 1994 ).

Certain cytokines and bacterial endotoxins induce a nitric oxide synthase isoform (inducible NOS [iNOS]) in macrophages, neutrophils, vascular and airway smooth muscles, and other cell types that normally do not produce cNOS. A massive release of NO by iNOS via activated macrophages and other cell types appears to be the primary cause of profound vasodilation and systemic hypotension in septic shock ( Cohen, 1995 ).

NO is one of the principal industrial pollutants oxidized in the atmosphere to form highly toxic nitrogen dioxide (NO2); NO2, in turn, combines with water to form nitric acid (H2NO3), the cause of acid rain. Inhaled NO below the concentration of industrial safety standards (5 to 40 ppm) has been shown to be effective against experimental hypoxic pulmonary vasoconstriction and pulmonary hypertension by selectively dilating the vascular beds surrounding terminal air spaces that are ventilated ( Frostell et al., 1993 ). Consequently, the ventilation/perfusion balance is improved and the venous admixture is decreased ( Fratacci et al., 1991 ; Frostell et al., 1991 ; Pison et al., 1993 ). This selective pulmonary vasodilation results from the inactivation of nitric oxide by hemoglobin ( Rimar and Gillis, 1993 ).

The use of inhaled NO appears safe in clinical settings because the exhaled concentration is extremely low and the production of toxic nitrogen dioxide is miniscule ( Jacob et al., 1994 ). NO combines with hemoglobin and produces nitrosyl hemoglobin, but the level remains extremely low during continuous inhalation of NO (40 ppm) for 4 hours. The level of methemoglobin in blood is relatively low and remains stable during the same period, although the plasma levels of nitrite (NO2) and nitrate (NO3) increase with time ( Jacob et al., 1994 ). Early clinical trials with inhaled NO in newborns with persistent pulmonary hypertension of neonates (PPHN) ( Kinsella et al., 1992 ; Roberts et al., 1992 ), in newborns with congenital diaphragmatic hernia ( Shah et al., 1994 ), in infants with congenital heart disease (Roberts et al., 1993 ; Wessel, 1993 ; Adatia and Wessel, 1994 ), and in those with adult respiratory distress syndrome (ARDS) ( Rossaint et al., 1993 ; Bigatello et al., 1994 ; Puybasset et al., 1994 ) showed effectiveness but such treatment has not always been effective.

Studies have shown that various inhaled anesthetics attenuate endothelium-dependent relaxation of vascular ring preparations in vitro ( Muldoon et al., 1988 ; Johns et al., 1992 ; Toda et al., 1992 ). The mechanism of this paradoxical phenomenon is not clear, but it may be related to the effect of anesthetics that reduces the intracellular influx of ionized calcium, a catalyst essential for NOS to form NO from L-arginine ( Muldoon et al., 1988 ). Yoshida and Okabe (1992) postulated that the anesthetic sevoflurane increases oxygen free radicals, which, in turn, combine with NO and block its vasodilating effect because an addition of superoxide dismutase blocks the effect of anesthetics that antagonize endothelium-derived vasodilation.

▪ DISTRIBUTION OF PULMONARY PERFUSION

As with regional ventilation, gravity results in a nonuniform distribution of pulmonary blood flow in normal lungs. West and others (1965) divided the characteristics of upright lung perfusion into three zones, later modified to four zones, of flow distribution ( Hughes et al., 1968 ) ( Fig. 2-36 ). Perfusion of lung tissue depends on the interrelation among three pressures: alveolar pressure (PA), pulmonary arterial pressure (Pa), and pulmonary venous pressure (PV). Because pulmonary circulation normally is a low-pressure circuit, the pulmonary perfusion pressure varies from the top to the bottom of the lung, barely overcoming the hydrostatic pressure to reach the apex of the tall upright adult lung. Both pulmonary perfusion pressure and flow are relatively increased at the lung base ( West, 1994 ).

 
 

FIGURE 2-36  Four zones of lung perfusion. Zone I has no flow because alveolar pressure exceeds pulmonary arterial pressure, thereby collapsing alveolar vessels. Zone II is present when pulmonary arterial pressure exceeds alveolar pressure and both are greater than pulmonary venous pressure. This is termed the vascular waterfall, because flow is unaffected by downstream (pulmonary venous) pressure. Zone III is characterized by a constant driving force, the difference between pulmonary arterial and venous pressure. Both are greater than alveolar pressure. Flow increases throughout zone III, even though driving pressure is constant because the absolute pressures lower in the lung distend the vessels to a greater extent, thereby lowering resistance. Zone IV has less flow per unit lung volume, probably because of the increased parenchymal pressure surrounding pulmonary vessels.  (From Hughes JMB, Glazier JB, Maloney JE, West JB: Respir Physiol 4:58, 1968. With permission from Elsevier.)

 



In zone I, the apicalmost part, alveolar pressure is higher than both pulmonary arterial and venous pressures. Alveolar capillary blood flow is absent in this zone or is only intermittently occurring with peak pulsatile pressure and flow. Ventilation in zone I is mostly wasted. Excessive PEEP increases zone I, thus increasing alveolar dead space, whereas increased pulmonary perfusion pressure, as occurs in exercise or hypoxemia, decreases or abolishes zone I.

In zone II (waterfall zone), as the vertical distance above the heart decreases (with alveolar pressure uniform throughout the lung), arterial pressure becomes higher than surrounding alveolar pressure while venous pressure remains lower than alveolar pressure. The driving pressure in this zone is the difference between arterial and alveolar pressures (Pa - PA), which determines blood flow regardless of venous or downstream pressure (waterfall phenomenon). The blood flow increases linearly as the driving pressure increases toward the base of the lung until pulmonary venous pressure equals alveolar pressure.

In zone III, both arterial and venous pressures are higher than alveolar pressure. The driving pressure for blood flow becomes the difference between arterial and venous pressures (Pa - PV) throughout this zone. Although the pressure gradient is the same throughout zone III, blood flow is greater toward the base, presumably because both arterial and venous pressures are greater and the pulmonary vascular bed is more distended. The relationships among arterial, venous, and alveolar pressures in zones I to III are summarized as follows:

  

 

Zone I: PA > Pa > PV

  

 

Zone II: Pa > PA > PV

  

 

Zone III: Pa > PV > PA

In zone IV, blood flow is progressively decreased toward the base of the lung, presumably because of increased interstitial pressure surrounding the extra-alveolar vessels. This zone increases in size with reduction in the lung volume toward RV ( Hughes et al., 1968 ; West, 1994 ).

The vertical distance between the top and the bottom of the lung is decreased in the supine position, resulting in the disappearance of zone I. Zone II also decreases as pulmonary venous pressure becomes higher throughout the lung in the supine position. The effect of gravity in infants and small children, particularly in the supine position, would be small, although it has not been documented.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ VENTILATION/PERFUSION RELATIONSHIPS

To achieve normal gas exchange in the lung the regional distribution of ventilation and pulmonary perfusion must be balanced. Without this balance, pulmonary gas exchange is impaired, even when the overall levels of ventilation and perfusion are adequate. The normal value for the ventilation/perfusion (   A/   P but usually    A/   is used instead) ratio is about 0.8. Studies with radioactive gases have shown that the elastic and resistive properties of various parts of the lung, as well as the pulmonary blood flow, are influenced by gravity. Both components of the    A/   ratio are affected by changes in a patient's position ( West, 1965 ).

When the patient is in the upright position, blood flow and ventilation are both less in the apex than in the base of the lungs. Because the difference in blood flow between apex and base is relatively greater than that in ventilation, the    A/   ratio increases from the bottom to the top of the lungs, as shown in Figures 2-37 and 2-38 [37] [38]. The apical regions (high    A/   ) have higher alveolar Po2 and lower Pco2 and PN2, whereas the basal areas (low    A/   ) have lower Po2 and higher Pco2 and PN2. Gravity has a greater effect on the    A/   ratio in hypotensive and hypovolemic patients and may be exaggerated with positive-pressure ventilation. In the supine position, similar differences exist between the anterior and posterior parts of the lung, but they are smaller. During exercise, pulmonary arterial pressure and blood flow, as well as ventilation, are increased and more evenly distributed. In infants and children the distribution of pulmonary blood flow is more uniform than in adults because the pulmonary arterial pressure is relatively high and the gravity effect in the lungs is less.

 
 

FIGURE 2-37  Effect of distribution of ventilation and perfusion on regional gas tensions in erect man. The lung is divided into nine horizontal slices, and the position of each slice is shown by its anterior rib markings. Vol, Relative lung volume;    A, regional alveolar ventilation;    , regional perfusion;    A/   , ventilation/perfusion ratio; R, respiratory exchange ratio.  (From West JB: J Appl Physiol 17:893, 1962.)

 

 

 

 
 

FIGURE 2-38  Effect of vertical height (expressed as the level of the anterior ends of the ribs) on ventilation and pulmonary blood flow (left ordinate) and the ventilation/perfusion ratio (right ordinate).  (From West JB: Ventilation/blood flow and gas exchange, ed 2. Oxford, 1970, Blackwell Scientific Publications Ltd.)

 

 

 

In diseased lungs, changes in the    A/   ratio occur as the result of uneven ventilation, or uneven perfusion, or both; for example, compression or occlusion of pulmonary vessels, reduced pulmonary vascular bed, or intrapulmonary-anatomic right-to-left shunting may contribute to nonuniform perfusion. In congenital heart diseases with increased pulmonary blood flow caused by left-to-right shunting, the    A/   ratio is decreased. When perfusion is diminished, as in tricuspid atresia or pulmonic stenosis with tetralogy of Fallot,    A/   is increased.

The lungs appear to have an intrinsic regulatory mechanism that, to a limited extent, preserves a normal    A/   ratio. In areas with a high    A/   ratio, a low Pco2 tends to constrict airways and dilate pulmonary vessels, and the opposite occurs in areas with a low    A/   ratio. In the latter case, in addition to the effect of Pco2, hypoxic pulmonary vasoconstriction (HPV) decreases regional blood flow and helps to increase    A/   ratios toward normal. The administration of drugs such as isoproterenol, nitroglycerin,theophylline, and sodium nitroprusside diminishes or abolishes HPV and increases intrapulmonary shunting ( Goldzimer et al., 1974 ; Colley et al., 1979 ; Hill et al., 1979 ; Benumof, 1994 ). All inhaled anesthetics depress HPV in vitro ( Sykes et al., 1972 ; Bjertnaes, 1978 ), contributing to an increase in venous admixture during general anesthesia. The effect of inhaled anesthetics on HPV, however, has not been conclusive in vivo (Marshall and Marshall, 1980, 1985 [252] [253]; Pavlin and Su, 1994 ).

Wagner and others (1974) have developed a sophisticated quantitative method of studying the continuous spectrum of    A/   mismatch. The technique is based on the pattern of elimination of multiple inert gases infused intravenously. At steady state after intravenous infusion of test gases dissolved in saline solution, arterial, mixed-venous, and expired gas samples are obtained, and minute ventilation and cardiac output are measured. The ratio of arterial to mixed venous concentration (retention) and the ratio of expired to mixed venous concentration (excretion) are computed for each gas, and retention-solubility and excretion-solubility curves are drawn by the computer. The ratio of the two curves represents the distribution of perfusion and ventilation on the spectrum of    A/   ratios (West, 1974, 1994 [456] [459]; Benumof, 1994 ) ( Fig. 2-39 ).

 
 

FIGURE 2-39  Upper graph shows the average distribution of ventilation/perfusion ratios in young semirecumbent normal subjects. The 95% range covers ventilation/perfusion from 0.3 to 2.1. The corresponding variations of Po2, Pco2, and oxygen saturation in the end-capillary blood can be seen in the lower panel.  (From West JB: Anesthesiology 41:124, 1974.)

 

 

 

Low    A/   and Lung Collapse while Breathing Oxygen

In a lung unit with a low regional    A/   ratio while breathing oxygen, collapse of the lung unit occurs, leading to atelectasis. As alveolar ventilation to the lung unit (   A) decreases, regional expiratory volume (VE) decreases progressively in comparison to regional inspiratory volume (VI) as it approaches the amount of oxygen taken up by regional pulmonary blood flow (   ). A point is reached at which the expired alveolar volume falls to zero (West, 1975). This situation occurs at the “critical” inspired    A/   . With inspired ratios less than the critical    A/   value, the lung unit becomes unstable; oxygen may enter rather than leave the lung unit during the expiratory phase or the unit may gradually collapse (Briscoe et al., 1960) ( Fig. 2-40 ). Figure 2-41 shows the calculated relationship between the critical inspired    A/   (   .AI   ) and the concentration of inspired oxygen (assuming mixed venous Po2 of 40 mm Hg and Pco2 of 45 mm Hg and nonitrogen exchange occurring across the whole lung) (Dantzker et al., 1975). From Figure 2-41 , it can be seen that lung units with    A/   < 0.01 become vulnerable when Fio2 is increased above 0.5 while lung units with inspiratory    AI/   of 0.1 are not at risk even with 100% oxygen (West, 1975). Although a    A/   less than 0.1 is infrequent in normal awake children, lung units with a    A/   less than 0.1 may occur in the diseased lung as well as in the normal lung under general anesthesia.

 
 

FIGURE 2-40  Schematic drawings to explain the development of shunts in lung units with low inspiratory    A/   S (   AI   ) caused by breathing high concentrations of oxygen. A (stable), There is a small expired alveolar ventilation (   A) and the unit is stable. B(critical), Inspired    A is decreased slightly from A and expired    A falls to zero. C (unstable), Inspired    A is further reduced and gas enters in the lung unit during the expiratory phase. D (unstable), Reverse inspiration during expiratory phase is prevented and the unit gradually collapses.  (From West JB: Anesth Analg 54:417, 1975.)

 

 

 

 
 

FIGURE 2-41  Relationship between inspired oxygen concentration and critical inspired    A/   S, the value at which the expired ventilation of a given lung unit falls to zero. Lung units whose    A/   s is less than the critical value may be unstable and easily collapse. (From West JB: Anesth Analg 54:417, 1975.)

 

 

 

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ OXYGEN TRANSPORT

For normal metabolism, oxygen must be transported continuously to all body tissues. Changes in oxygen demand are met by the integrated response of three major functional components of the oxygen transport system: pulmonary ventilation, cardiac output, and blood hemoglobin concentration and characteristics. With acute oxygen demand, such as with severe exercise, high fever, or acute hypoxemia (<60 mm Hg), oxygen transport is increased mainly by increased cardiac output, while alveolar ventilation is increased to maintain proper levels of alveolar Po2 and Pco2. Chronic hypoxemia increases erythropoietin production, thereby increasing erythrocyte production from the normal daily rate of approximately 1% of circulating red cell mass to about 2%. Thus increasing red cell mass in response to chronic hypoxemia is a slow process ( Finch and Lenfant, 1972 ). Hemoglobin concentrations greater than the normal level (15 g/dL) raise viscosity and increase blood flow resistance until the plasma volume is also increased ( Thorling and Erslev, 1968 ).

The amount of oxygen carried by the plasma depends on its solubility and is small (≈0.3 mL/dL per 100 mm Hg). Most oxygen molecules in blood combine reversibly with hemoglobin to form oxyhemoglobin. Each molecule of hemoglobin combines with four molecules of oxygen; 1 g of oxyhemoglobin combines with 1.34 mL of oxygen.

▪ OXYGEN AFFINITY OF HEMOGLOBIN AND P50

The oxygen-hemoglobin dissociation curve reflects the affinity of hemoglobin for oxygen ( Fig. 2-42 ). As blood circulates through the normal lungs, oxygen tension increases from the mixed-venous Po2 of around 40 mm Hg to pulmonary capillary Po2 of above 100 mm Hg, and hemoglobin is saturated to about 97% in arterial blood. (Unfortunately, most pulse oximeters commercially available today are artificially modified to read 100% saturation in healthy subjects breathing room air rather than 97%; see later discussion.) The shape of the dissociation curve is such that further increases in Po2 result in a very small increase in oxygen saturation (So2) of hemoglobin.

 
 

FIGURE 2-42  Schematic representation of oxygen dissociation curve and factors that affect blood oxygen affinity. Oxygen partial pressure at 50% oxygen saturation (P50) is a convenient index of oxygen affinity. P50 of adult blood (at 37°C; pH, 7.40; Pco2, 40 mm Hg) is roughly 27 mm Hg and is influenced by a number of factors. Sao2, arterial oxygen saturation; Pao2, arterial oxygen tension; H+, hydrogen ion concentration; T°, blood temperature; 2,3 DPG, 2,3-diphosphoglycerate (see text).

 

 

As arterial blood circulates through the capillaries, tissues pick up oxygen, and both Po2 and So2 decrease. The blood of normal adults has So2 of 50% when Po2 is 27 mm Hg at 37°C and a pH of 7.4. The P50, which is the Po2 of whole blood at 50% So2, indicates the affinity of hemoglobin for oxygen. An increase in blood pH increases the oxygen affinity of hemoglobin (Bohr effect). Similarly, a decrease in temperature increases oxygen affinity and shifts the oxygen-hemoglobin dissociation curve to the left; a decrease in pH or an increase in temperature has the opposite effect (Comroe, 1974) (see Fig. 2-42 ).

Benesch and Benesch (1967) and Chanutin and Curnish (1967) demonstrated that the oxygen affinity of a hemoglobin solution decreases by the addition of organic phosphates, in particular 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP), which bind to deoxyhemoglobin but not to oxyhemoglobin. Human erythrocytes contain an extremely high concentration of 2,3-DPG, averaging about 4.5 mol/mL, compared with ATP (1 mol/mL) and other organic phosphates ( Oski and Delivoria-Papadopoulos, 1970 ). Thus, an increase in red cell 2.3-DPG decreases the oxygen affinity of hemoglobin, increases P50 (shifts the dissociation curve to the right), and increases the unloading of oxygen at the tissue level. Increases in 2,3-DPG and P50 have been found in chronic hypoxemia.

In the newborn, blood oxygen affinity is extremely high and P50 is low (≈19 mm Hg) ( Fig. 2-43 ) because fetal hemoglobin(HbF) reacts poorly with 2,3-DPG. Oxygen delivery at the tissue level is low despite high red blood cell mass and hemoglobin level. After birth, the total hemoglobin level decreases rapidly as the proportion of HbF diminishes, reaching its lowest level by 2 to 3 months of age (physiologic anemia of infancy) ( Fig. 2-44 ). During the same early postnatal period, P50 increases rapidly ( Oski and Delivoria-Papadopoulos, 1970 ); it exceeds the normal adult value by 3 months of age and remains high during the first decade of life (Oski, 1973a, 1973b [320] [322]) ( Fig. 2-45 ). This high P50 is associated with a relatively low hemoglobin level (11 to 12 g/dL) and increased levels of ATP and 2,3-DPG, probably related to the process of general growth and development and high plasma levels of inorganic phosphate ( Card and Brain, 1973 ). These observations engendered a hypothesis to explain why hemoglobin levels are lower in children than in adults (physiologic “anemia” of childhood). Because children have a lower oxygen affinity for hemoglobin, oxygen unloading at the tissue level is increased. Thus, a lower level of hemoglobin in infants and children is just as efficient, in terms of tissue oxygen delivery, as a higher hemoglobin level in adults ( Oski, 1973a ) ( Table 2-3 ). Table 2-4compares the hemoglobin concentrations at different ages in terms of equal tissue oxygen unloading ( Motoyama et al., 1974 ).

 
 

FIGURE 2-43  Schematic representation of oxygen-hemoglobin dissociation curves with different oxygen affinities. In infants older than 3 months with high P50 (30 mm Hg versus 27 mm Hg in adults), tissue oxygen delivery per gram of hemoglobin is increased. In neonates with a lower P50 (20 mm Hg) and a higher blood oxygen affinity, tissue oxygen unloading at the same tissue Po2 is reduced.

 

 

 
 

FIGURE 2-44  Hemoglobin concentration in infants of different degrees of maturation at birth. Filled circle, full-term infants; open circle, premature infants with birth weights of 1200 to 2350 g; open square, premature infants with birth weights less than 1200 g.  (From Nathan DG, Oski FA: Hematology of infancy and childhood, ed 3. Philadelphia, 1987, WB Saunders.)

 



 
 

FIGURE 2-45  Oxyhemoglobin equilibrium curve of blood from normal term infants at different postnatal ages. The P50 on day 1 is 19.4 ± l.8 mm Hg and has shifted to 30.3 ± 0.7 at age 11 months (normal adults = 27.0 ± 1.1 mm Hg).  (From Oski FA: Pediatrics 51:494, 1973; copyright 1973 American Academy of Pediatrics.)

 

 

 


TABLE 2-3   -- Oxygen unloading changes with age

Age

P50 (mm Hg)

Percent Saturation at Venous Oxygen Tension of 40 mm Hg

Hemoglobin (g/100 mL)

Oxygen Unloaded[*] (mL/100 mL)

1 day

19.4

87

17.2

1.84

3 wk

22.7

80

13.0

2.61

6 to 9 wk

24.4

77

11.0

2.65

3 to 4 mo

26.5

73

10.5

3.10

6 mo

27.8

69

11.3

3.94

8 to 11 mo

30.0

65

11.8

4.74

5 to 8 yr

29.0[†]

67

12.6

4.73

9 to 12 yr

27.9[†]

69

13.4

4.67

Adult

27.0

71

15.0

4.92

*

Assumes arterial oxygen saturation of 95%.

From Oski FA: J Pediatr 83:353, 1973a.

 


TABLE 2-4   -- Hemoglobin requirements for equivalent tissue oxygen delivery

 

P50 (mm Hg)

Hemoglobin for Equivalent O2 Delivery (g/dL)

Adult

27

7

8

9

10

11

12

13

Infant >3 mo

30

5.7

6.5

7.3

8.2

9.0

9.8

10.6

Neonate <2 mo

24

10.3

11.7

13.2

14.7

16.1

17.6

19.1

Calculated from data of Motoyama EK, Zigas CJ, Troll G: Functional basis of childhood anemia. Am Soc Anesthesiol Abstr 283–284, 1974.

 

 


Acceptable Hemoglobin Levels

These findings have important clinical implications for anesthesiologists. It was long assumed, until the 1980s, that children with a hemoglobin level of less than 10 g/dL were not acceptable for general anesthesia and surgery. This level of hemoglobin has been used arbitrarily without the knowledge of different oxygen affinity and tissue oxygen unloading at different ages. It appears from Table 2-4 that if a hemoglobin level of 10 g/dL is acceptable for an adult with a P50 of 27 mm Hg, 8.2 g/dL should theoretically be adequate for an infant more than 3 months of age with an average P50 of 30 mm Hg (without considering the high level of metabolism and oxygen consumption). In contrast, for a 2-month-old premature infant with a P50 of 24 mm Hg, a hemoglobin level of 10 g/dL is equivalent to only 6.8 g/dL in adults, and this may be inadequate to provide sufficient tissue oxygenation in patients with limited cardiac output or oxygen desaturation.

With the advent of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) and the resultant anxiety among the medical community and the lay public about homologous blood transfusion, the criteria for transfusion have changed significantly over the past two decades. At the consensus-developing conference by the National Institutes of Health and the Food and Drug Administration on perioperative red blood cell Transfusion ( Consensus Conference, 1988 ), it was generally agreed that the available evidence does not support the “10/30” rule (that is, hemoglobin, 10 g/dL, or hematocrit, 30%), although the literature is remarkable for its lack of carefully controlled, randomized studies that would provide definitive conclusions. Other data suggest that cardiac output does not increase dramatically in healthy adult humans until the hemoglobin value decreases to approximately 7 g/dL.

It was also agreed that the decision to transfuse red blood cells in a specific patient should take into consideration the many factors that comprise clinical judgment. These factors include the duration of anemia, the intravascular volume, the extent of surgery, the probability of massive blood loss, and the presence of coexisting conditions, such as impaired cardiopulmonary function and inadequate cardiac output. A general consensus on acceptable perioperative levels of hemoglobin and hematocrit in infants and young children has not emerged. According to the data in Table 2-4 , hemoglobin levels exceeding 8.2 g/dL (hematocrit, 25%) should be acceptable in children older than 3 months. Transfusion in otherwise healthy normovolemic infants with 8 g/dL of hemoglobin is hardly justifiable. On the other hand, postoperative hypoxemia is common even among healthy infants and children undergoing simple surgical procedures, such as inguinal hernia repair and myringotomies. These children with borderline hemoglobin levels must be given oxygen via mask and be monitored closely with a pulse oximeter in the recovery room ( Motoyama and Glazener, 1986 ) (see Chapter 11 , Intraoperative and Postoperative Management). The lowest safe limit of hemoglobin for infants less than 2 months of age has not been determined, although in sick infants it is desirable to maintain a hemoglobin level of 12 to 13 g/dL or a hematocrit of 40% (equivalent to 8 to 9 g/dL in adults) (also see Chapter 12 , Blood Conservation).

There has been controversy about what constitutes abnormally low oxygen saturation in infants and children postoperatively and what is considered clinically unsafe. Mok and others (1986) reported that during the first week of life, oxygen saturation as monitored with pulse oximetry (Spo2) was noticeably decreased, especially during active (REM) sleep (mean Spo2, 92%) and during feeding (Spo2, 91%). After 4 weeks of age, however, Spo2 was more stable and was maintained at or above 94% during sleep. Thus, Spo2 less than 94% can be considered as physiologically abnormal in infants beyond the first week of age. A study in preterm infants (mean gestational age, 33 weeks; postconceptional age, 37 weeks) has shown that median Spo2 at the time of discharge was 99.5% and increased to 100% at follow-up 6 weeks later. The preterm infants had higher baseline saturation and no more incidence of desaturation than full-term infants of equivalent postconceptional ages ( Poets et al., 1992 ). It is generally agreed that Spo2 less than 95% in otherwise healthy infants and children is abnormal and that these patients require oxygen supplementation.

The routine use of pulse oximetry has dramatically improved the anesthesiologist's ability to monitor and properly maintain arterial oxygenation (Coté et al., 1988, 1991 [84] [85]). This is especially true for premature infants, who are susceptible to oxygen toxicity and retinopathy of prematurity, even when breathing room air. In prematurely born infants weighing less than 1300 g, the incidence of retinopathy of prematurity increases markedly with exposure to 12 or more hours of Pao2 exceeding 80 mm Hg ( Flynn et al., 1992 ). Arterial oxygen saturation (Sao2) must be adjusted properly so as to maintain Pao2in the normal neonatalrange of 60 to 80 mm Hg ( Orzalesi et al., 1967 ). As mentioned, oxygen affinity to hemoglobin is very high in the neonate and decreases rapidly during the first 3 to 6 months of life (Oski, 1973a, 1973b, 1981 [320] [321] [322]). Estimated Pao2 should be adjusted according to age, as shown in Table 2-5 . In the newborn, whose P50 is 18 to 20 mm Hg, the range of Sao2 to maintain adequate Pao2 (60 to 80 mm Hg) is 97% to 98%, whereas in the adult (P50, 27), it is 91% to 96%. In the neonate, Sao2 of 91% corresponds to Pao2 of 41 mm Hg. Although the values in Table 2-5 , based on Severinghaus's nomogram for the Bohr effect ( Severinghaus, 1966 ), are only estimates, published data comparing arterial Po2 and oxygen saturation seem to agree well with values in the nomogram (Ramanathan et al., 1987 ; Bucher et al., 1989 ).


TABLE 2-5   -- Estimated Po2 at different P50 of hemoglobin[*]

 

AGE

 

1 day

2 wk

6 to 9 wk

6 mo to 6 yr

Adult

P50 (mm Hg)[†]

19

22

24

29

27

So2 (%)

Estimated Po2 (mm Hg) at neutral pH (7.40)

99

108

130

143

171

156

98

77

92

101

122

111

97

64

77

84

101

92

96

56

68

74

89

82

95

52

62

68

82

74

94

48

58

63

76

69

93

45

55

60

72

66

92

43

52

57

68

62

91

41

50

55

66

60

90

40

48

53

63

58

88

37

45

49

59

54

86

35

42

47

56

51

84

34

40

44

53

49

82

32

39

42

51

47

80

31

37

41

49

45

78

30

36

39

47

43

76

29

34

38

45

41

74

28

33

36

44

40

72

27

32

35

42

39

70

26

31

34

41

37

*

Calculated from Severinghaus' (1966) assuming that the shift in oxygen dissociation curve of hemoglobin due to changes in its oxygen affinity at neutral pH (7.40) is the same as the shift due to the Bohr effect.

Po2 at which oxygen saturation of hemoglobin (So2) is 50%.

 

Unfortunately, another factor compounding the confusion (and clinically too important to ignore) is that pulse oximeters by Nelcor (which are the most widely used in the United States) are artificially set to read 2% to 3% higher at the 90% to 95% range than actual arterial oxygen hemoglobin saturation (as measured by means of co-oximetry) and that Ohmeda pulse oximeters (which are more commonly used in Europe) tend to read somewhat lower than actual arterial oxygen saturation ( Jennis and Peabody, 1987 ; Bucher et al., 1989 ). Unfortunately, the newer pulse oximeter (Masimo SET) with less motion artifact, which has increasingly been used in the United States and elsewhere, also artificially increased the reading by 2% to 3% higher to match the reading with the Nelcor pulse oximeter (see Chapter 10 , Induction of Anesthesia). In view of these findings, the range of Spo2 of 93% to 95%, corresponding to an estimated Pao2 of 66 to 74 mm Hg in adults (but only 40 to 50 mm Hg in neonates), often recommended as desirable maintenance levels for neonates and premature infants in intraoperatively or in the intensive care settings, appears much too low for adequate tissue oxygenation. Furthermore, respiratory alkalosis, which may result from assisted or controlled ventilation, would shift the oxygen hemoglobin dissociation curve further to the left (P50, even lower than it already is) and decrease Pao2and tissue oxygen delivery even further at this range of oxygen saturation (see Fig. 2-42 ). In clinical practice, therefore, Spo2 levels of 95% to 97% (corresponding Pao2 of 50 to 70 mm Hg in neonates and 60 to 80 mm Hg in infants 1 to 2 months old) are recommended.

Some anesthetics affect the oxygen affinity of hemoglobin. The presence of cyclopropane (although it has not been used since the 1970s) significantly decreases oxygen affinity and increases P50 by 3 mm Hg without changes in the 2,3-DPG levels, whereas halothane has minimal effects ( Orzalesi et al., 1971 ). Exposure to 50% nitrous oxide, on the other hand, has been reported to produce a marked reversible increase in oxygen affinity; P50 decreased from 26 to 18 mm Hg, a level similar to that of HbF ( Fournier and Major, 1984 ). This finding contrasts with a report based on one patient by Prime (1951) , who found no effect with 70% nitrous oxide, and with a study by Smith and others (1970) , who reported a 3 mm Hg rightward shift of P50 with an unspecified concentration of nitrous oxide. The finding of Fournier and Major may be of considerable clinical importance. Nitrous oxide anesthesia combined with hyperventilation would markedly increase the oxygen affinity of hemoglobin and decrease oxygen unloading at the tissue level. This effect could be hazardous in neonates whose P50 is unusually low even without respiratory alkalosis or nitrous oxide.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ SURFACE ACTIVITY AND PULMONARY SURFACTANT

The alveolar surfaces of human lungs are lined with surface-active materials with unique properties that are responsible for the stability of air spaces. These materials, which contain specific phospholipids and proteins (discussed later), are collectively called pulmonary surfactant.

The relationship among pressure (P), surface tension (T), and radius (r) of a sphere, such as a soap bubble, is expressed by the Laplace equation, as follows:

It can be seen from this equation that if surface tension (T) were constant, in a number of connected spheres the smallest sphere would have the highest pressure. Thus the smaller spheres would empty their gas contents into the larger ones. If this concept applied to lung units, the lungs would be unstable, with most units collapsing into several large ones, as seen in the lung of an infant with IRDS or HMD. Such instability does not exist in normal lungs. As Clements and others (1958) first demonstrated, saline extract of normal lungs has an extremely low surface tension (0 to 5 dynes/cm) during dynamic compression of the surface area and increased tension (30 to 50 dynes/cm) during expansion of the surface area. Their findings indicate that, in normal lungs, the surface tension decreases as the alveolar radius decreases and vice versa; the stability of the air spaces is maintained regardless of the size of each unit ( Fig. 2-46 ).

 
 

FIGURE 2-46  Schematic drawing of stable alveoli of different sizes (see text).

 

 

The alveolar lining layer obtained from lung lavage contains approximately 10% lipoprotein and 90% phospholipid, of which surface-active dipalmiotylphosphatidylcholine is the major fraction. Phosphatidylglycerol was identified as the second major fraction (≈10%) of surface-active phospholipid ( Rooney, Canavan, Motoyama, 1974 ). Other phospholipids include sphingomyelin (also surface active), phosphatidylethanolamine, and phosphatidylinositol ( Rooney, 1985 ). Four surfactant-associated proteins have been isolated and characterized; their locations in specific chromosomes have been identified ( Weaver and Whitsett, 1991 ). These substances are produced by type II alveolar epithelial cells (pneumocytes) stored in the osmiophilic lamellar inclusions within these cells, and are excreted into the air space to form tubular myelins and surface-active alveolar lining layers ( Kikkawa, Motoyama, Cook, 1965 ) (Figs. 2-47, 2-48, and 2-49 [47] [48] [49]).

 
 

FIGURE 2-47  Granular pneumocyte (type II). Cytoplasm around the nucleus (N) contains many organelles, particularly osmophilic lamellar bodies (LB). A, Alveolar space; C, capillary space. Insets show lamellar bodies in freeze-etched preparation revealing form and existence of central core (C) around which lamellae (L) are stacked. (×22,400.)  (From Weibel ER: Physiol Rev 53:419, 1973.)

 

 

 

 
 

FIGURE 2-48  Perfusion-fixed rat lung showing three capillaries (C) and the extracellular lining layer toward the alveolus (A) composed of a base layer (B) and an osmophilic lining layer (short arrows). Base layer contains tubular myelin figures (TM) and extends into a cleft between capillaries closely opposed because of septal folding (long arrow). EP, Alveolar epithelial cell (type I); EN, capillary endothelial cell; IN, interstitium; P, pericyte (×23,000).  (From Weibel ER: Physiol Rev 53:419, 1973.)

 

 

 

 
 

FIGURE 2-49  Life cycle of pulmonary surfactant. SP-A, SP-B, SP-C, and phospholipids are packaged in lamellar inclusion bodies and secreted by type II alveolar epithelial cells (pneumocytes) into the air space. Lamellar bodies unfold into tubular myelin, which gives rise to the phospholipid-surfactant protein film at the air-liquid interface. Used surfactant phospholipids are released from the film as small vesicles, which are taken up and recycled or degraded by type II cells. Alveolar macrophages also take up surfactant and degrade it. SP-A, SP-B, SP-C, surfactant proteins A, B, and C.  (From Whitsett JA, Horowitz AD: Surfactant and associated proteins. In Fishman AP, editor: Fishman's pulmonary diseases and disorders, ed 3. New York, 1998, McGraw-Hill, with permission.)

 

 

 

Surfactant protein-A (SP-A) is a 35-kDa hydrophilic protein and appears in the amniotic fluid by 28 weeks—gestation. Surfactant protein B and C (SP-B [8 kDa]; SP-C [3-5 kDa]) are hydrophobic and are bound to the phospholipid fraction. SP-A, SP-B, and SP-C are involved in the formation of myelin figures and are believed to enhance the rate of formation and the stability of surface monolayers at the air-liquid interface on the alveolar surface ( deMello and Reid, 1995 ). In addition, SP-A increases the phagocytosis of alveolar macrophages and thus plays a role in host defense ( van Iwaarden et al., 1990 ), whereas SP-B and SP-C have a direct immunosuppressive effect on lung lymphocytes (Ansfield and Benson, 1980). Surfactant also plays a role in the maintenance of alveolar fluid homeostasis by reducing transepithelial protein leakage ( Hallman, 1984 ).

The production of phosphatidylcholine increases towards term, whereas that of sphingomyelin decreases. The ratio of these phospholipids (L/S ratio) in the amniotic fluid has been used as an index of fetal lung maturity ( Kulovich, Hallman, Cluck, 1979 ).

Inadequacy or deficiency of the surfactant system is important in several clinical conditions. Historically, Avery and Mead (1959) showed that the minimum surface tension of lung extracts from premature infants dying of IRDS (or HMD) was unusually high when measured on the Wilhelmy balance. Surface-activephosphatidylcholine is markedly decreased or even absent in the alveolar linings in these lungs ( Boughton, Gandy, Gardiner, 1970) . These findings partially explain the atelectasis and low compliance in the lungs of infants with this syndrome.

Fujiwara and others first reported, with impressive results, the instillation in the trachea of bovine surfactant in premature infants born with surfactant deficiency ( Fujiwara et al., 1980 ). Surfactant replacement therapy using human, bovine, or synthetic surfactant in premature infants with IRDS is now established as an important and essential form of therapy, reducing morbidity and mortality ( Merritt et al., 1986 ; Lang et al., 1990 ; Hoekstra et al., 1991 ; Long et al., 1991 ; Holms, 1993 ). Surfactant replacement therapy has been extended to cover other clinical conditions with surfactant deficiency or inactivation not only in premature infants but also in full-term infants, children, and adults. These conditions include (1) neonates with persistent pulmonary hypertension (PPHN) in whom surfactant production by type II pneumocytes is depressed because of severe pulmonary hypoperfusion and hypoxia; (2) neonates with severe congenital diaphragmatic hernia (CDH) whose immature lungs are damaged by ventilator-induced lung injury and surfactant inactivation by plasma protein leak on the alveolar surface (see Chapter 16 , Anesthesia for Neonates and Premature Infants); (3) meconium aspiration syndrome caused by pulmonary hypoperfusion, inflammation, and inactivation of surfactant by protein leak; and (4) ARDS in children and adults ( Jobe, 1993 ; Pramanik, Holtzman, Merritt, 1993 ).

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ CILIARY ACTIVITY

The tracheal and bronchial walls are lined with pseudo-stratified epithelium that consists of ciliated cells, nonciliated serous and brush cells, and abundant mucus-secreting goblet cells. The submucous contains numerous serous and mucous cell glands, which are major contributors of the mucus in the respiratory tract. Under normal circumstances both goblet cells and mucus-secreting glands diminish in number toward the periphery of the airway system. The mucosal surface is covered by a serous fluid layer, in which the cilia beat. Above this periciliary layer of serous fluid lie discontinuous flakes of mucus (rather than the continuous mucous blanket assumed previously), which are moved cephalad by the cilia ( Jeffery and Reid, 1977 ) ( Fig. 2-50 ).

 
 

FIGURE 2-50  The ultrastructure of airway epithelium represented diagrammatically. Cilia beat in a fluid layer of low viscosity above which move flakes of mucus. Ciliated cells (CC), goblet cells (GC), nonciliated “serous” cells (NCC), brush cells (BrC), and basal cells (BC) are shown, as are nerves penetrating the epithelium.  (Reprinted from Jeffery PK, Reid LM: The respiratory mucous membrane. In Brain JD, Procotor DF, Reid LM, editors: Respiratory defense mechanisms. New York, 1977, Marcel Dekker, p 198, by courtesy of Marcel Dekker, Inc.)

 

 

 

The cilia in the respiratory tract play an important role in the removal of mucoid secretions, foreign particles, and cell debris and are an essential defense mechanism of the airway system. These cilia move in a synchronous, whip-like fashion at a rate of 600 to 1300 times/min. They can move particles toward the mouth at the rate of about 1.5 to 2 cm/min ( Lichtiger, Landa, Hirsch, 1975 ).

Ciliary function is influenced by the thickness of the mucous layer and other factors that can occur with dehydration or infection. In tissue culture, some viral infections reduce ciliary motion as much as 50%, and repeated infections in vivo can destroy the cilia completely ( Kilburn and Salzano, 1966 ). Inhalation of warm air with 50% humidity maintains normal ciliary activity, whereas breathing dry air for 3 hours results in a complete cessation of mucus movement. Ciliary activity can be restored by breathing warm, saturated air ( Forbes, 1974 ; Hirsch et al., 1975 ). Breathing 100% oxygen and controlled positive-pressure ventilation also affect ciliary function ( Wolfe, Ebert, Sabiston, 1972 ; Forbes, 1976 ; Forbes and Gamsu, 1979 ).

Inhaled anesthetics seem to decrease ciliary function in both animals and humans. Forbes and Horrigan (1977) observed a dose-related depression of ciliary activity during halothane and enflurane anesthesia. The same group of investigators found delayed mucus clearance during and 6 hours after discontinuation of halothane or diethyl ether anesthesia ( Forbes and Gamsu, 1979 ). These findings suggest that inhaled anesthesia has adverse effects on mucociliary clearance, especially in patients with pulmonary disease. The effect of anesthetics on mucociliary clearance in infants and children has not been reported.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ MEASUREMENTS OF PULMONARY FUNCTION IN INFANTS AND CHILDREN

Airway obstruction is often difficult to assess clinically, particularly in young infants. For instance, what appears to be stridor may not indicate obstruction of the upper or extrathoracic airways. Similarly, although wheezing commonly represents disorders of relatively large intrathoracic airways, such as bronchial asthma, other airway dysfunction, from the upper airways (such as stridors) to the lower airways (such as rhonchi from secretions) can be mistaken as wheezing.

The cause of abnormal breath sounds also include such airway abnormality as narrowing of the airway lumen by mucosal edema, compression, secretions, or foreign objects, and by hyperreactive airway smooth muscles. Stridor and wheezing may also be caused by increased collapsibility of airways, as seen in laryngotracheomalacia involving both the upper and lower (large central) airways. A careful evaluation of the medical history and physical examination are obviously essential and helpful but may be inadequate to determine the exact nature of the disorder.

Pulmonary function tests are most effective in evaluating the respiratory status of infants and children and in documenting the site(s), nature, and extent of airway dysfunction. In addition, pulmonary function tests allow objective and quantitative assessment of a reactive airway disease such as bronchial asthma and bronchopulmonary dysplasia and its response to bronchodilator therapy. For a detailed account of various measurements of pulmonary function in children and adolescents, the publications by Polgar and Promadhat (1971) and by Bates (1989) should be consulted.

The most frequent types of pulmonary disability may be classified under the general headings of (1) restrictive diseases and (2) obstructive diseases, although there is considerable overlap between the two groups. Restrictive disorders, whether intrapulmonary or extrapulmonary in origin, result in reduced lung volumes. Relatively common restrictive disorders in infants and children, from the anesthesiologist's point of view, include persistent PPHN and CDH in the newborn period, congestive heart failure (also obstructive), pulmonary fibrosis, kyphoscoliosis, obesity, and abdominal distention in older children.

In patients after surgery, especially those given muscle relaxants, the vital capacity (VC) is a practical guide to muscle strength. A VC of at least twice the tidal volume (15 mL/kg; normal range, 60 to 70 mL/kg) appears necessary to maintain adequate spontaneous ventilation. The measurement of peak inspiratory and expiratory pressures against airway occlusion at FRC provides additional information. A minimum of 30 cm H2O is needed for effective coughing and adequate spontaneous breathing.

Obstructive pulmonary disorders may be classified into upper and lower airway diseases. Most of the severe upper airway diseases, such as acute epiglottitis and subglottic croup, occur in infancy and early childhood. Occasionally, however, upper airway obstruction can be seen in children with obstructive sleep apnea syndrome (OSAS) (see earlier) with chronic adenotonsillar hypertrophy as well as subglottic stenosis associated with prolonged intubation or tracheostomy. Vascular ring and vascular sling are rare but are associated with severe tracheobronchial (large central airway) obstruction.

The lower airway disorders commonly seen among children include bronchopulmonary dysplasia, cystic fibrosis, bronchial asthma, reactive airway disease associated with gastroesophageal reflux, and heart disease with left-to-right shunting and pulmonary hypertension.

▪ STANDARD TESTS OF PULMONARY FUNCTION

Standard pulmonary function testing is largely limited to children older than 7 years who can understand and cooperate with the test procedures. In newborns, some physiologic indicators of pulmonary function can be measured using modifications of standard tests. The relatively recent introduction of tests that are applicable in infants and young children has considerably broadened the ability to assess their pulmonary dysfunction.

Zapletal and others (1987) compiled pulmonary function indices in children from the data he and his coworkers accumulated over the last two decades. Some of these normal values are reproduced inAppendix C .

Measurement of Lung Volumes

Total lung capacity (TLC) and its subdivisions (see Fig. 2-18 and the discussion of lung volumes) are measured either with spirometry and the gas dilution technique or with body plethysmography. FRC is commonly measured by the gas dilution technique with rebreathing of a known concentration of helium (10% He in O2). TLC is obtained by adding inspiratory capacity (IC) and FRC. Residual volume (RV) is the difference between TLC and VC, the maximum amount of air one can breathe out from TLC. Forced vital capacity (FVC) is the VC obtained during maximum expiratory effort. Normally, FVC and VC in the same healthy person are nearly identical, but in patients with obstructive airway disease, airway closure worsens with effort and FVC may become considerably smaller than VC. VC per se is not a useful indicator for differential diagnosis because it decreases in both obstructive and restrictive lung disorders, such as atelectasis and pulmonary fibrosis. TLC, on the other hand, is decreased in restrictive disease but is increased by air trapping in obstructive disorders.

Gas dilution techniques underestimate TLC in obstructive lung disease because the test gas molecules (helium) do not sufficiently penetrate into trapped gas compartments. Under these circumstances, body plethysmography should be used to measure FRC more accurately. Measurement of FRC (or thoracic gas volume [TGV or VTG]) with body plethysmography is accomplished with a panting (or short, rapid breathing) maneuver against mouth occlusion. TGV is derived from simultaneous changes in lung volume (V) and airway pressure (P) using Boyle's law (P × V = k). When body plethysmography is not available, addition of a low level of end-expiratory positive airway pressure (EPAP) during helium rebreathing increases gas mixing, probably by preventing airway closure or by keeping the collateral channels open. The difference in calculated FRC with and without EPAP correlates well with the degree of air trapping in the lung ( Motoyama et al., 1982 ). In obstructive lung disease, FRC and,in particular, RV, in relation to TLC (FRC/TLC, RV/TLC), are markedly increased.

Flow Function With Spirometry

In clinical pulmonary function laboratories, airway obstruction is usually assessed by the analysis of maximal forced expiration using a spirometer. The resultant volume change in relation to time is displayed on a kymograph ( Fig. 2-51 ). Peak expiratory flow rate (PEFR) is by far the simplest of all expiratory flow measurements. PEFR is decreased most drastically by obstruction of the upper or large lower (central) airways, even when other indices of airway function are within normal limits. It is also decreased in patients with typical asthma, which primarily involves central airways, with severe peripheral airway disease such as cystic fibrosis, and with neuromuscular disorders. The measurement of PEFR is not a sensitive test for discriminating among various types of lung disease. Another major disadvantage of PEFR is that it varies with the degree of effort and cooperation, particularly in young children.

 
 

FIGURE 2-51  A spirometric tracing of forced vital capacity (FVC). FEV1.0, forced expiratory volume in 1 second; MMEFR, maximum mid-expiratory flow rate, or FEF25-75; RV, residual volume; TLC, total lung capacity.  (See text.) (From Motoyama EK: Physiologic alterations in tracheostomy. In Myers EN, Stool SE, Johnson JT, editors: Tracheotomy. New York, 1985, Churchill Livingstone.)

 

 

 

For many decades, the forced expiratory volume in 1 second (FEV1.0) and maximum mid-expiratory flow rate (MMEFR or FEF25-75) have been used extensively to evaluate airway function. These parameters are obtained from spirographic tracings made during an FVC maneuver from maximal inspiration (TLC) down to RV (see Fig. 2-51 ).

A reduction in FEV1.0 correlates well with the clinical severity of lung disease, both in adults and in children. FEV1.0 is expressed both in absolute terms and as a percentage of the value predicted on the basis of sex, age, and height. It is also expressed in relation to FVC (FEV1.0/FVC). In obstructive lung disease, FEV1.0 is decreased both in absolute terms and in relation to FVC because of prolonged expiration. On the other hand, in restrictive lung disease such as pulmonary fibrosis, in which airways are wide open, FEV1.0 is decreased but FEV1.0/FVC may be normal or even increased.

The MMEFR (FEF25-75) is the average flow rate between 25% and 75% of FVC. Compared with FEV1.0, MMEFR is a more sensitive index of airway disease involving smaller airways.

The major limitations of these indices of airway function are that they are variable depending on the patient's effort (effort dependent); they are also inadequate for identifying the site of obstruction (the upper versus lower airways, the central versus peripheral airways).

Measurement of Airway Resistance

The standard technique for evaluating airway obstruction has been the measurement of airway resistance and forced expiratory flow. Airway resistance (Raw) is the most direct index of airway obstruction. It is, however, rarely used in clinical settings for several reasons: it requires a body plethysmograph, which is too costly, needs a trained pulmonology technician to perform it, and is too complicated for routine use. Furthermore, Raw is not a sensitive indicator of disease involving the lower airways, particularly small, peripheral airways, because the latter contribute only a fraction of total Raw, and abnormally high Raw does not indicate the site or location of airway disease.

Raw is influenced by the degree of lung inflation. As the lung volume increases, the airways expand and Raw falls. The airway conductance (Gaw), the reciprocal of resistance, changes linearly with lung volume in children ( Zapletal et al., 1969 ).

Maximum Expiratory Flow-Volume Curves

Unlike other, conventional indices of airway function, which express volume change per unit of time (i.e., flow rates), maximum expiratory flow-volume (MEFV) curves relate maximum expiratory flow rates (   max or MEF) to corresponding lung volumes during a FVC maneuver (see Fig. 2-30 ). As mentioned previously, the intrathoracic airways downstream (toward the mouth) from the equal pressure point (EPP) are subjected to dynamic compression during forced exhalation. As a result, the maximum expiratory flow rate (   max, MEF, or FEF) at low lung volumes (i.e., <50% FVC) becomes independent of effort and is determined by the flow resistance of the upstream segment of airways between the alveoli and EPP (Rus) and by the static recoil pressure of the lung (Pstl):

The measurement of    max is a very sensitive test of lower airway obstruction because it eliminates the component of the upper and lower central airway resistance between the mouth and EPP, which may amount to as much as 80% to 90% of the total airway resistance. Another advantage of MEFV curve analysis over conventional spirometry is the effort independence of    max, particularly in young children, whose effort may be submaximal or inconsistent. The normal values of    max in children are shown in Appendix C .

Figure 2-52 is a schematic representation of MEFV curves from a patient with cystic fibrosis whose flow function is only mildly affected. PEFR is within normal limits, whereas values of    max at 50% and 25% of FVC (FEF50 and FEF75, respectively) are markedly reduced. With MEFV curves, lower airway disease can be further divided into central versus peripheral airway disorders by repeating MEFV curves with air (21% oxygen in nitrogen) versus a 20% oxygen-80% helium mixture.

 
 

FIGURE 2-52  Maximum expiratory flow-volume (MEFV) curve of a 13-year-old boy with cystic fibrosis (dotted line) compared with predicted MEFV curve (bold solid line) breathing air. Note that peak expiratory flow rate (PEFR) is within normal limits, whereas maximum expiratory flows at 50% (   max50 or MEF50) and at 25% (   max25 or MEF25) are markedly reduced, indicating lower airway obstruction. The second MEFV curve (thin solid line) was obtained while he was breathing an 80% helium/20% oxygen mixture (He curve). The He curve crosses the air curve at 30% FVC (   isov.), indicating peripheral airway disease. TLC, total lung capacity; RV, residual volume; FVC, forced vital capacity. (See text.)  (From Motoyama EK: Physiologic alterations in tracheostomy. In Myers EN, Stool SE, Johnson JT, editors: Tracheotomy. New York, 1985, Churchill Livingstone.)

 

 

 

In healthy persons the flow-limiting segment (EPP) is located in the central airways, usually within the first five generations of the tracheobronchial tree ( Zapletal et al., 1969 ). Because the flow pattern here is turbulent and density dependent, air, with an average molecular weight of 29, has a lower flow rate than does the helium-oxygen mixture, with a much lighter average molecular weight of 9.6. In the case of peripheral airway obstruction, EPP moves upstream (peripherally) toward the area of obstruction, where the flow pattern is laminar and thereforeviscosity dependent. The viscosity of helium is higher than that of nitrogen, so flow rates (   max) in helium MEFV curves (He curve) at lower lung volumes become less than those in MEFV curves with air (air curve). In Figure 2-52 , the He curve crosses the air curve at 30% of FVC (volume of isoflow [Visov.]). Visov. of more than 20% of FVC is considered evidence of peripheral airway obstruction ( Hutcheon et al., 1974 ). In children with mild to moderate asthma, both PEFR, an indicator of large airway function, and    max25, an indicator of lower airway function, are decreased because asthma involves constriction of both large and medium or even smaller airways ( Fig. 2-53 ).

 
 

FIGURE 2-53  Maximum expiratory flow-volume (MEFV) curves of a 9-year-old boy with bronchial asthma before (1) and after (2) inhalation of nebulized bronchodilator compared with a predicted MEFV curve (3). The volume between total lung capacity (TLC) and the vertical line for each MEFV curve is the forced expiratory volume in 1 sec (FEV1.0). Note that peak expiratory flow rate (PEFR), FEV1.0, and maximum expiratory flows (   max or MEF) at same volumes are all markedly diminished in the control curve. The bronchodilator produced a marked improvement in all flow parameters. (See text.)  (From Motoyama EK: Int Anesthesiol Clin 26:6, 1988.)

 

 

 

In contrast, in a typical case of mild cystic fibrosis with primary peripheral airway disease,    max25 is markedly reduced and PEFR is within normal limits (see Fig. 2-52 ). Figures 2-53 and 2-54 [53] [54] illustrate changes in flow and volume function in a 9-year-old boy with bronchial asthma. The control or baseline MEFV curve (curve 1 in Fig. 2-53 ) is markedly reduced from the predicted curve (curve 3, dotted line). His FVC is decreased because of air trapping and increases in RV. After an inhalation of nebulized bronchodilator, there is a marked increase in overall expiratory flow rates with decreased air trapping and a resultant increase in FVC (curve 2 in Fig. 2-54 ). TLC is decreased toward the predicted value.

 
 

FIGURE 2-54  Bar graphs representing changes in total lung capacity (TLC) and its subdivisions in a 9-year-old boy with bronchial asthma before (control) and after bronchodilator use in relation to predicted values. Note the increase in TLC and residual volume (RV) and the reduction in vital capacity (VC) in the control period caused by air trapping. The RV/TLC and FRC/TLC ratios are abnormally increased. Bronchodilator use nearly abolished air trapping and restored VC. Compare these values with his flow function in Figure 2-50 . IRV, inspiratory reserve volume; ERV, expiratory reserve volume; VT, tidal volume; IC, inspiratory capacity.  (From Motoyama EK: Int Anesthesiol Clin 26:6, 1988.)

 

 

 

▪ EVALUATION OF UPPER AIRWAY FUNCTION

Upper airway obstruction is not uncommon in infants and young children because of anatomic factors such as a relatively large head, short neck, and small mandible in relation to tongue size. Also, the caliber of the upper airways is smaller in absolute terms than in older children and adults. Frequent causes of upper airway obstruction include, in descending order, obstructive sleep apnea (pharyngeal obstruction), laryngomalacia, vocal cord paralysis and dysfunction, laryngeal papillomas, and subglottic stenosis of various causes. In addition, in older children, severe inspiratory obstruction may occur as the result of conversion reaction ( Appelblatt and Baker, 1981 ). This condition may be mistakenly diagnosed as severe bronchial asthma. In some patients with bronchial asthma the primary site of airway obstruction is in the upper airways, with the clinical manifestation of coughing ( Christopher et al., 1983 ).

The conventional pulmonary function tests already described are used primarily to detect impairment of lower, intrathoracic airway function and are inadequate for the evaluation of upper airway obstruction.

The intrathoracic airways narrow during forced expiration because of dynamic compression, whereas during forced inspiration they expand because of increases in surrounding negative pleural pressure. By contrast, the caliber of the extrathoracictrachea and larynx expands during forced expiration and narrows during forced inspiration, particularly when there is obstruction.

Functionally, obstructive airway lesions in the upper airways and large intrathoracic (central) airways can be classified into “variable” and “fixed” types of obstruction, based on the ability of the obstructed segment of the airways to alter its caliber in response to changes in transmural pressure. In variable extrathoracic airway obstruction, inspiratory flow is markedly reduced, whereas expiratory flow is relatively unchanged ( Fig. 2-55A ). The opposite is true with variable intrathoracic large airway obstruction ( Fig. 2-55B ). Large airway obstruction of a fixed type limits both inspiratory and expiratory flows nearly equally, because the changes in transmural pressure do not affect airway caliber ( Fig. 2-55C ). The measurement of maximum expiratory-inspiratory flow-volume curves is useful in diagnosing the location (extrathoracic versus intrathoracic) and the nature (variable versus fixed) of large airway obstruction ( Kryger et al., 1976 ; Frenkiel et al., 1980 ). Figure 2-55A shows the maximum expiratory-inspiratory flow-volume curve of a 7-year-old girl with laryngeal papillomatosis, who, because of her “wheezing” (in reality, it was stridor) had previously been thought to have bronchial asthma. She had nearly normal MEFV curves with severe reductions in inspiratory flow. She did not respond to bronchodilators.

 
 

FIGURE 2-55  Schematic tracing of maximum expiratory-inspiratory flow-volume curves. (A) Variable upper airway obstruction due to papillomatosis of the larynx. (B) Variable central (intrathoracic) airway obstruction due to tracheomalacia. (C) Fixed-type obstruction due to tracheal stenosis.  (From Motoyama EK: Physiologic alterations in tracheostomy. In Myers EN, Stool SE, Johnson JT, editors: Tracheotomy. New York, 1985, Churchill Livingstone.)

 

 

 

▪ AIRWAY REACTIVITY

Because wheezing is often a manifestation of reactive airway disease, it is important to examine positive response to bronchodilators (hyperresponsiveness) or to stimuli that provoke bronchoconstriction. The most commonly used pulmonary function test for this purpose is the measurement of flow rates during forced expiration. Traditionally, FEV1.0 and MMEFR have been used. More recently, however, the measurement of    max at 25% of 50% of FVC on MEFV curves has been shown to be most sensitive ( Zapletal et al., 1971 ). Some healthy children (up to 15% of the general population) may respond to a bronchomotor challenge, but the degree of response is relatively small, usually less than 5% of the control value in FEV1.0 and not more than 20% of the control value in MMEFR and    max. When the response is beyond these ranges, hyperreactive airway disease is suspected. In children, inhalation of aerosolized β2-adrenergic agonists, such as albuterol (salbutamol) and metaproterenol, is used for bronchodilation. To provoke bronchoconstriction, exercise challenge has been used widely in children. The inhalation of bronchoconstrictors such as methacholine and histamine ( Chatham et al., 1982 ), although a more definitive test, is used less frequently because of its discomfort in patients whose cooperation is less than optimal.

It has been recognized that exercise-induced bronchoconstriction results not from exercise per se but from reduction in tracheobronchial mucosal temperature caused by vigorous mouth breathing of dry air and resultant evaporative heat loss ( McFadden et al., 1982 ). The exercise challenge test, therefore, has been replaced by cold air challenge with normocapnic hyperpnea with added carbon dioxide, which gives more consistent results ( Deal et al., 1980 ). When MEFV curves are used to evaluate bronchial reactivity, expiratory flow rates (   max) must be compared at the same lung volume before and after the challenge, which changes RV and, therefore, FVC. Because the absolute lung volume often is not available in clinical settings,    max (at 50% or 25% FVC) should be compared at the same volume below TLC, rather than at the volume above RV. The rationale for this practice is that TLC is altered relatively little (although affected by severe air trapping or its release) by comparison with large changes in RV.

▪ PULMONARY FUNCTION TESTS IN INFANTS

Advances in neonatal intensive care and improved survival of prematurely born infants with variable degrees of chronic lung disease of prematurity since the 1980s prompted the focused interest and development of innovative techniques for pulmonary function testing in neonates, infants, and young children. A position paper was published by the International Committee on Infant Lung Mechanics based on critical evaluation of these techniques ( American Thoracic Society/European Respiratory Society [ATS/ERS] Joint Committee, 1993 ). Guidelines for laboratory conditions, preparation of infants, sedation, and patient safety have also been published by the same group ( Gaultier et al., 1995 ; Quanjer et al., 1995 ).

Measurements of Dynamic Respiratory Mechanics

Maximum or Partial Expiratory Flow-Volume Curves

Two techniques have been developed to produce flow-volume curves to evaluate lower airway function ( ATS/ERS Joint Committee, 1993 ). Motoyama and others (1977 , 1987) produced MEFV curves by “forced deflation” in infants and young children who were intubated and ventilated under sedation or general anesthesia and paralysis. With this technique, a moderate negative pressure is applied to the endotracheal tube at maximal inflation of the lung (TLC). While the lungs are rapidly deflated (within a few seconds), instantaneous expiratory flow and integrated volume signals produce an MEFV curve.    max is obtained at 25% and 10% of FEV. This forced deflation technique was found to be safe and reproducible and extremely sensitive for the evaluation of smaller airway function. The average normal value for    max25 (FEF75) in full-term infants was 49 mL/kg per sec and    max25/FVC, an index of upstream conductance (or the caliber of airways toward the periphery) was 1.12, whereas in preterm infants without apparent lung disease    max25 was 95 mL/kg per sec and the    max25/FVC was 1.67. This indicates that in preterm infants, airway caliber in relation to lung volume is much larger than in full-term infants ( Nakayama et al., 1991 ; ATS/ERS Joint Committee, 1993 ). A major drawback of this technique, however, is that its application is limited to the infants already intubated under general anesthesia or being cared for in the intensive care unit setting.

Another technique is the infant “squeeze” or “hugging” (thoracoabdominal compression) technique, originally reported by Adler and Wohl (1978) and later improved by Taussig and others (1982) . In this technique a double-layer inflatable “jacket” is wrapped around the thorax and abdomen of a sedated infant. The inner compression bag is attached to a reservoir of compressed air, and the jacket is inflated rapidly at the end of spontaneous tidal inspiration. A partial flow-volume curve is produced, and    max at the end-tidal volume (   maxFRC) is measured. Although the reproducibility of this test is somewhat limited, it has an advantage over the deflation technique in that it can be applied to infants who are not intubated. One major problem with this technique is that although it seems to work in infants with lower airway obstruction by producing flow limitation, the pressure and flow developed by external thoracoabdominal compression are insufficient to produce dynamic compression of the intrathoracic airways in healthy infants; no predicted normal values could be obtained ( ATS/ERS Joint Committee, 1993 ).

Following the discussion at the mentioned ATS/ERS Joint Committee meetings, a modification of the “infant hugging” technique was developed. This technique, a raised volume thoracoabdominal compression technique, is accomplished by increasing the end-inspiratory volume initially to 20 cm H2O and eventually to 30 cm H2O by occluding the expiratory valve and “stacking” several tidal breathing while inspiratory flow is maintained ( Feher et al., 1996 ; Goldstein et al., 2001 ). With this modified squeeze technique, expiratory flow limitation was achieved even in healthy infants ( Lambert, Castile, Tepper, 2004 ). The advantage of this technique over the forced deflation technique is that infants can be studied with sedation alone, rather than under general endotracheal anesthesia or under sedation with muscle relaxation in ICU settings.

Measurements of Passive Respiratory Mechanics

The total respiratory system compliance (dynamic compliance) can be measured during the respiratory cycle by measuring the tidal volume and peak inspiratory pressure. In patients with airway dysfunction, however, dynamic compliance does not reflect the true (static) compliance. This problem is circumvented by a brief occlusion of the airway at end-inspiration. This approach is based on the principle that the active Hering-Breuer reflex in young infants causes a brief period of apnea during occlusion of the airway at lung volumes above FRC. The passive mechanical properties of the respiratory system can then be determined during this brief moment of respiratory muscle relaxation by removing the upper airway occlusion and allowing the lungs to deflate passively to FRC or relaxation volume (Zin, Pengelly, Milic-Emili, 1982 ; Mortola et al., 1982 ). The static compliance of the total respiratory system (Crs) is obtained by dividing the tidal volume by the relaxation pressure at the mouth during the occlusion and relaxation of the respiratory muscles, which reflects the elastic recoil of the respiratory system ( LeSouef et al., 1984 ). In addition, by extrapolation from the plot of a flow-volume loop during passive deflation from airway occlusion, the resistance of the total respiratory system and the time constant can be obtained ( LeSouef, England, Bryan, 1984 ). This technique can also be applied in intubated patients under general anesthesia or in intensive care unit settings, although the resistance of the endotracheal tube per se would be a major component of measured resistance.

According to published data compiled by the ATS/ERS Joint Committee (1993) , dynamic lung compliance values for infants and both term and preterm infants range from 1.1 to 2.0 mL/kg per cm H2O, whereas static compliance values range from 1.0 to 1.6 mL/kg per cm H2O. Quasi-static compliance of the thorax (Cw) in preterm infants (6.4) exceeds that of term infants (4.2) ( ATS/ERS Joint Committee, 1993 ). Compliance of the total respiratory system (Crs) between 1 and 12 months of age can be expressed as follows:

  

 

Crs = 0.87 + 26.3 × Height3 ( Masters et al., 1987 ) or

  

 

Crs = 0.88 × Weight (kg)1.09 (Marchal and Crance, 1987)

  

 

Values for airway resistance (Raw) have been reported as

  

 

Raw = 0.047 - 0.036 × Height3 ( Masters et al., 1987 ) or

  

 

Raw = 5.36 × Weight (kg)-0.75 (Marchal et al., 1988)

FRC is low in infants. As measured with the gas (helium) dilution method in infants sedated with chloral hydrate, the mean FRC was reported as 20.2 ± 4.7 mL/kg (SD; range, 20 to 24 mL/kg) up to 18 months of age, whereas FRC or VTG obtained by means of body plethysmography was higher: 23.8 ± 5.3 mL/kg (range, 29 to 34 mL/kg) ( ATS/ERS Joint Committee, 1993 ; McCoy et al., 1996). The reason for the discrepancy between the two methods is unknown ( ATS/ERS Joint Committee, 1993 ; Gappa et al., 1993; McCoy et al., 1996), but the magnitude of difference in FRC measured with gas dilution versus body plethysmograph (15% to 23%) was similar (McCoy et al., 1996). The values for boys and girls are similar in most studies. Table 2-6 shows the average values of respiratory rate and tidal volume in infants between birth and 12 months of age based on published data ( ATS/ERS Joint Committee, 1993 ). The average respiratory rate is high at birth (47/min) and decreases rapidly with growth (26/min at 12 months). In contrast, average tidal volume is larger in infants (9 mL/kg) than in older children and adults (7 mL/kg) but is remarkably consistent between 3 and 12 months of age, whereas the respiratory rate changes markedly.


TABLE 2-6   -- Predicted values of respiratory rate and tidal volume in infants[*]

Age (mo)

Birth

3

6

9

12

Respiratory rate (/min)

47

38

33

29

26

Tidal volume (mL/kg)

7.4

9

9

9

9

Modified from ATS/ERS Joint Committee: Respiratory mechanics in infants: Physiologic evaluation in health and disease. Am Rev Respir Dis 147:474, 1993. Official Journal of the American Thoracic Society. Copyright © American Lung Association.

*

Weighted mean from published data.

 

 

▪ INDICATION FOR AND INTERPRETATION OF PULMONARY FUNCTION TESTS

Although pulmonary function tests usually do not help in diagnosing the exact location of a pathophysiologic process (for instance, left versus right lung), they do provide qualitative and quantitative assessment of the general type of disability (restrictive versus obstructive, upper versus lower airway, central versus peripheral airway), the extent of impairment, and the efficacy of various treatments, either medical or surgical.

Various indices of pulmonary function, as already described, are expressed in absolute terms as well as in percentage of the predicted normal values. Normal values are based usually on sex and height because height is better correlated with lung volumes and other ventilatory parameters than is body weight or age. More complicated multiple regression formulas include all these parameters. Ideally, each pulmonary function laboratory should establish normal values based on its own sample population, using the same instruments and techniques that are used to evaluate patients with pulmonary dysfunction as recommended by the ATS/ERS Joint Committee (1993) . In reality, however, laboratories usually choose values from published data. Polgar and Promadhat (1971) compiled and compared all of the predicting formulas of pulmonary function in children published by 1969. Their data are still valid and useful today. Once the “normal” values are chosen, it is important to test a sample population of healthy children to make sure that the results fall within the predicted range of values.

For most pulmonary function indices the normal range (mean ± 2 SDs) is within 20% to 25% of the predicted values, with the exception of    max (MEF) values on MEFV curves, which range up to 40% of the mean. This does not necessarily indicate that patients with some pulmonary function indices outside of this range have lung disease. Serial pulmonary function tests in these patients are invaluable for a better understanding of the presence or absence of disease and its progression with time.

What particular test or combination of tests is most useful? In a child who wheezes, it is essential to investigate lower airway function, because wheezing is most often caused by reactive airway disease (bronchial asthma, bronchopulmonary dysplasia, etc.). Wheezing is usually caused by the narrowing of relatively large intrathoracic (lower) airways (i.e., tracheal and large bronchi) and occurs during expiration. It should be kept in mind that both stridors (mostly inspiratory), coming from narrowing of the extrathoracic (laryngopharyngeal) airways, and rhonchi (both inspiratory and expiratory), usually caused by rattling of secretions in the trachea or large bronchi, are often mistaken as wheezing.

If there is considerable lower airway dysfunction, lung volume should be measured to determine the extent of dysfunction and air trapping. Evaluation of bronchial hyperresponsiveness with a bronchodilator must also be done in these patients and, if it is present, the extent of reversibility should be evaluated. Upper airway function should be examined in patients with stridor and in those in whom lower airway dysfunction is absent or mild in relation to overall respiratory symptoms.

Which children should have pulmonary function tests preoperatively? All children with a history of severe neonatal respiratory disease, such as bronchopulmonary dysplasia or meconium aspiration, with severe bronchiolitis, and those who wheeze should have a consultation with a pulmonologist and have a baseline pulmonary function test performed to establish the nature of the lung dysfunction. These children often have lower airway obstruction and abnormal gas exchange with reactive airway disease ( Motoyama, 1988 ). At the least, oxygen saturation should be measured in room air preoperatively as a guide for postoperative management. In addition, children with history of asthma, cystic fibrosis, or gastroesophageal reflux often have moderate to severe lung dysfunction, and they should be evaluated by a pulmonologist. Another condition requiring pulmonary function testing is scoliosis before surgical repair. Adolescents with scoliosis may have a moderate to severe restrictive defect, especially those with muscular dystrophy, and some of these patients cannot generate sufficient airway pressure for effective coughing or lung expansion postoperatively. These patients, as well as surgeons, should know what to expect postoperatively, and the anesthesiologist should make sure that an intensive care unit bed is reserved for postoperative care.

With advanced knowledge and new technology, the ability of a pulmonary function laboratory to evaluate and document pulmonary dysfunction has improved considerably. Standard pulmonary function testing is effective in identifying the site, nature, and extent of airway dysfunction, as well as changes in volume function in children. With new developments in the various noninvasive test methods, it is now possible in an increasing number of pediatric medical centers to evaluate lung function and the presence of reversible (reactive) airway disease in infants, even those in respiratory failure. Pulmonary function test results are helpful for planning the anesthetic approach and postoperative management of infants and children with known pulmonary dysfunction.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ SUMMARY

It is apparent that respiration of pediatric patients, especially neonates and young infants, is considerably different from that of older children and adults. Respiratory control mechanisms are not fully developed until at least 42 to 44 weeks postconception, especially in terms of their response to hypoxia.

The lungs are immature at birth, even in full-term infants. Most alveolar formation and elastogenesis occurs postnatally during the first year of life. Thoracic structure is insufficient to support the negative pleural pressure generated during the respiratory cycle, at least until the infant develops the muscle strength for upright posture toward the end of the first year. Weakness of the thoracic structure is in part compensated by tonic contractions of the intercostal and accessory muscles. Anesthesia and muscle relaxation abolish this compensatory mechanism, and the end-expiratory lung volume (FRC) decreases to the point of airway closure, resulting in widespread alveolar collapse and atelectasis. Infants are prone to upper airway obstruction because of anatomic and physiologic differences, as discussed in this chapter. Anesthesia preferentially depresses tonic and phasic activities of the pharyngeal and other neck muscles, which normally resist the collapsing forces in the pharynx.

Fetal hemoglobin has high oxygen affinity and limits oxygen unloading at the tissue level. These factors, unique to young infants less than 3 months of age, result in decreases in oxygen delivery to the tissues that have much higher oxygen demands than those of adults. Thus, infants and young children are prone to perioperative hypoxemia and tissue hypoxia ( Box 2-5 ).

BOX 2-5 

Infants Are Prone to Perioperative Hypoxemia

  

1.   

Immature respiratory control and irregular breathing Hypoxia does not stimulate, but rather depresses, ventilation.Trace anesthetics abolish hypoxic ventilatory response.

  

2.   

Infants have small FRC and high oxygen demand.

  

3.   

Anesthesia reduces FRC; airway closure and atelectasis result
Prone to hypoxemia (Spo2 <94%) in the PACU (20% to 40%).

  

4.   

Infants are prone to upper airway obstruction.

  

5.   

High oxygen affinity (low oxygen unloading) of fetal hemoglobin.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

REFERENCES

Adatia and Wessel, 1994. Adatia I, Wessel DL: Therapeutic use of inhaled nitric oxide.  Curr Opin Pediatr  1994; 6:583.

Adler and Wohl, 1978. Adler SM, Wohl MEB: Flow-volume relationship at low lung volumes in healthy term newborn infants.  Pediatrics  1978; 61:636.

Agostoni, 1959. Agostoni E: Volume-pressure relationships of the thorax and lung in the newborn.  J Appl Physiol  1959; 14:909.

Albersheim et al., 1976. Albersheim S, Boychuk R, Seshia MMK, et al: Effects of CO2 on immediate ventilatory response to O2 in preterm infants.  J Appl Physiol  1976; 41:609.

Alcorn et al., 1980. Alcorn D, Adamson DT, Maloney JE, et al: Morphological effects of chronic bilateral phrenectomy or vagotomy in the fetal lamb lung.  J Anat  1980; 130:683.

Al-Shway and Mortola, 1982. Al-Shway SE, Mortola JP: Respiratory effects of airflow through the upper airways in newborn kittens and puppies.  J Appl Physiol  1982; 53:805.

American Thoracic Society, 1995. American Thoracic Society : Single-breath carbon monoxide diffusing capacity (transfer factor). Recommendations for a standard technique—1995 Update.  Am J Respir Crit Care Med  1995; 152:2185-2198.

American Thoracic Society/European Respiratory Society Joint Committee, 1993. American Thoracic Society/European Respiratory Society Joint Committee : Respiratory mechanics in infants: Physiologic evaluation in health and disease.  Am Rev Respir Dis  1993; 147:474.

Ansfleld and Benson, 1980. Ansfleld MJ, Benson BJ: Identification of the immunosuppressive components of canine pulmonary surface active material.  J Immunol  1980; 125:1092.

Appelblatt and Baker, 1981. Appelblatt NJ, Baker SR: Functional upper airway obstruction.  Arch Otolaryngol  1981; 107:305.

Aranda and Trumen, 1979. Aranda JV, Trumen T: Methylxanthines in apnea of prematurity.  Clin Perinatal  1979; 6:87.

Areechon and Reid, 1963. Areechon W, Reid L: Hypoplasia of lung with congenital diaphragmatic hernia.  Br Med J  1963; 1:230.

Assali and Morris, 1964. Assali NS, Morris JA: Maternal and fetal circulations and their interrelationships.  Obstet Gynecol Surv  1964; 19:923.

ATS Assembly on Pediatrics and the ERS Paediatrics Assembly, 1993. ATS Assembly on Pediatrics and the ERS Paediatrics Assembly : ATS statement. Respiratory mechanics in infants: Physiologic evaluation in health and disease.  Am Rev Respir Dis  1993; 147:474.

Aubier and Sampson, 1981. Aubier DeTroyer A, Sampson M, et al: Aminophylline improves diaphragmatic contractility.  N Engl J Med  1981; 305:249.

Avery, 1984. Avery ME: The argument for prenatal administration of dexamethasone to prevent respiratory distress syndrome (editorial).  J Pediatr  1984; 104:240.

Avery et al., 1986. Avery ME, Aylward G, Creasy R, et al: Update on prenatal steroid for prevention of respiratory distress. Report of a conference, September 26–28, 1985.  Am J Obstet Gynecol  1986; 155:2.

Avery and Mead, 1959. Avery ME, Mead J: Surface properties in relation to atelectasis and hyaline membrane disease.  Am J Dis Child  1959; 97:517.

Baier et al., 1990. Baier RJ, Hasan SU, Gates DB, et al: Effects of various concentrations of O2 and umbilical cord occlusion on fetal breathing and behavior.  J Appl Physiol  1990; 68:1597.

Barillot and Bianchi, 1971. Barillot JC, Bianchi AL: Activité des motoneurons larynges pendant reflexes de Hering-Breuer.  J Physiol (Paris)  1971; 63:783.

Bartlett et al., 1976. Bartlett Jr D, Jeffrey P, Sand'Ambrogio G, Wise JCM: Location of stretch receptors in the trachea and bronchi of the dog.  J Physiol (Lond)  1976; 258:409.

Bartlett et al., 1990. Bartlett Jr D, Leiter JC, Hollowell E: Control and actions of the genio-glossus muscle.   In: Issa FG, Suratt PM, Remmers JE, ed. Sleep and respiration,  New York: Wiley-Liss; 1990.

Bartlett et al., 1973. Bartlett Jr D, Remmers JE, Gautier H: Laryngeal regulation of respiratory airflow.  Respir Physiol  1973; 18:194.

Bar-Yishay et al., 1987. Bar-Yishay E, Shulman DL, Ecoffey C, Gaultier C: Functional residual capacity in healthy preschool children lying supine.  Am Rev Respir Dis  1987; 135:954.

Bastel and Lines, 1975. Bastel HL, Lines AJ: Neural mechanisms of sneeze.  Am J Physiol  1975; 229:770.

Bates, 1962. Bates DV: Respiratory disorders associated with impairment of gas diffusion.  Annu Rev Med  1962; 13:301.

Bates, 1989. In: Bates DV, ed. Respiratory function in disease,  ed 3. Philadelphia: WB Saunders Co.; 1989.

Bates et al., 1971. Bates DV, Macklem PT, Christie RV: Respiratory Junction in disease,  ed 2. Philadelphia, WB Saunders, 1971.

Benameur et al., 1993. Benameur M, Goldman MD, Ecoffey C, Gaultier C: Ventilation and thoracoabdominal asynchrony during halothane anesthesia in infants.  J Appl Physiol  1993; 74:l591.

Benesch and Benesch, 1967. Benesch R, Benesch RE: The effect of organic phosphates from the human erythrocytes on the allosteric properties of hemoglobin.  Biochem Biophys Res Commun  1967; 26:162.

Benumof, 1994. Benumof JL: Respiratory physiology and respiratory function during anesthesia.   In: Miller RD, ed. Anesthesia,  ed 4. New York: Churchill Livingstone; 1994.

Berger, 1988. Berger AJ: Control of breathing.   In: Murray JF, Nadel JA, ed. Textbook of respiratory medicine,  Philadelphia: WB Saunders; 1988.

Berger, 2000. Berger AJ: Control of breathing.   In: Murray JF, Nadel JA, ed. Textbook of respiratory medicine,  Philadelphia: WB Saunders; 2000.

Berger, 1977. Berger AJ: Dorsal respiratory neurons in the medulla of cat: Spinal projections, responses to lung inflation and superior laryngeal nerve stimulation.  Brain Res  1977; 135:231.

Berger, 1979. Berger AJ: Phrenic motoneurons in the cat: Subpopulations and nature of respiratory drive potentials.  J Neurophysiol  1979; 42:76.

Bergman, 1963. Bergman NA: Distribution of inspired gas during anesthesia and artificial ventilation.  J Appl Physiol  1963; 18:1085.

Betts et al., 1977. Betts EK, Downes JJ, Schaffer DB, Johns R: Retrolental fibroplasia and oxygen administration during general anesthesia.  Anesthesiology  1977; 47:518.

Bianchi and Bariollot, 1982. Bianchi AL, Bariollot JC: Respiratory neurons in the region of the retro-facial nucleus: Pontile, medullary, spinal and vagal projections.  Neuroscience Lett  1982; 31:277.

Bigatello et al., 1994. Bigatello LM, Hurford WE, Kacmarek RM: Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome.  Anesthesiology  1994; 80:761.

Bjertnaes, 1978. Bjertnaes LJ: Hypoxia-induced pulmonary vasoconstriction in man: Inhibition due to diethyl ether and halothane anesthesia.  Acta Anaesthesiol Scand  1978; 22:570.

Boddy et al., 1974. Boddy K, Dawes GS, Fisher R, et al: Fetal respiratory movements, electrocortical and cardiovascular responses to hypoxaemia and hypercapnia in sheep.  J Physiol (Lond)  1974; 243:599.

Boddy and Robinson, 1971. Boddy K, Robinson JS: External method for detection of fetal breathing in utero.  Lancet  1971; 2:1231.

Boggs and Bartlett, 1982. Boggs DF, Bartlett D: Chemical specificity of a laryngeal apneic reflex in puppies.  J Appl Physiol  1982; 53:455.

Boughton et al., 1970. Boughton K, Gandy G, Gairdner D: Hyaline membrane disease. II. Lung lecithin.  Arch Dis Child  1970; 45:311.

Boyden, 1969. Boyden EA: The pattern of the terminal air spaces in a premature infant of 30–32 weeks that lived 19 1/4 hours.  Am J Anat  1969; 126:31.

Bradley et al., 1975. Bradley GW, von Euler C, Marttila I, Roos B: A model of the central and reflex inhibition of inspiration in the cat.  Biol Cybern  1975; 19:105.

Brady and Ceruti, 1966. Brady JP, Ceruti E: Chemoreceptor reflexes in the newborn infant. Effects of varying degrees of hypoxia on heart rate and ventilation in a warm environment.  J Physiol (Lond)  1966; 184:631.

Brody and Thurlbeck, 1986. Brody JS, Thurlbeck WM: Development, growth, and aging of the lung.   In: Geiger SR, Macklem PT, Mead J, Fishman AP, ed. Handbook of physiology. Section 3. The respiratory system. Vol 3. Mechanics of breathing, part 1,  Bethesda, MD: American Physiological Society; 1986.

Brooks, 1982. Brooks JG: Apnea of infancy and sudden infant death syndrome.  Am J Dis Child  1982; 136:1012.

Brouillette and Thach, 1979. Brouillette RT, Thach BT: A neuromuscular mechanism maintaining extra-thoracic airway patency.  J Appl Physiol  1979; 46:772.

Brouillette and Thach, 1980. Brouillette RT, Thach BT: Control of genioglossus muscle inspiratory activity.  J Appl Physiol  1980; 49:801.

Bryan and Wohl, 1986. Bryan AC, Wohl ME: Respiratory mechanics in children.   In: Geiger SR, Macklem PT, Mead J, Fishman AP, ed. Handbook of physiology. Section 3. The respiratory system. Vol 3. Mechanics of breathing, part 1,  Bethesda, MD: American Physiological Society; 1986.

Bucci and Cook, 1961. Bucci G, Cook CD: Studies of respiratory physiology in children. VI. Lung diffusing capacity, diffusing capacity of the pulmonary membrane, and pulmonary capillary blood volume in congenital heart disease.  J Clin Invest  1961; 40:1431.

Bucci et al., 1961. Bucci G, Cook CD, Barrie H: J Pediatr  1961; 58:820.

Bucher et al., 1989. Bucher HU, Fanconi S, Baeckert P, Duc G: Hyperoxemia in newborn infants: Detection by pulse oximetry.  Pediatrics  1989; 84:226.

Bureau and Bouverot, 1975. Bureau M, Bouverot P: Blood and CSF acid-base changes and rate of ventilatory acclimatization of awake dogs to 3,500 m.  Respir Physiol  1975; 24:203.

Burri, 1974. Burri PH: The postnatal growth of the rat lung. III. Morphology.  Anat Rec  1974; 178:711.

Card and Brain, 1973. Card RT, Brain MC: The “anemia” of childhood; evidence for a physiologic response to hyperphosphatemia.  N Engl J Med  1973; 288:388.

Celermajer et al., 1994. Celermajer DS, Dollery C, Burch M, Deanfield JE: Role of endothelium in the maintenance of low pulmonary vascular tone in normal children.  Circulation  1994; 89:2035.

Ceruti, 1966. Ceruti E: Chemoreceptor reflexes in the newborn infant. Effect of cooling on the response to hypoxia.  Pediatrics  1966; 37:556.

Chanutin and Curnish, 1967. Chanutin A, Curnish RR: Effect of organic and inorganic phosphates on the oxygen equilibrium of human erythrocytes.  Arch Biochem  1967; 121:96.

Chatham et al., 1982. Chatham M, Bleecker ER, Norman P, et al: A screening test for airway reactivity. An abbreviated methacholine inhalation challenge.  Chest  1982; 82:15.

Cherniack and Pack, 1988. Cherniack NS, Pack AI: Control of ventilation.   In: Fishman AP, ed. Vol 1, part 2: Physiological principles, . Pulmonary diseases and disorders,  ed 2. New York: McGraw-Hill Book Co; 1988.

Chernick et al., 1975. Chernick V, Faridy EE, Pagtakhan RD: Role of peripheral and central chemoreceptors in the initiation of fetal respiration.  J Appl Physiol  1975; 38:407.

Chernick et al., 1964. Chernick V, Heldrich F, Avery ME: Periodic breathing of premature infants.  J Pediatr  1964; 64:330.

Christopher et al., 1983. Christopher KL, Wood II RP, Eckert C, et al: Vocal cord dysfunction presenting as asthma.  N Engl J Med  1983; 308:1566.

Clark and von Euler, 1972. Clark FJ, von Euler C: On the regulation of depth and rate of breathing.  J Physiol (Lond)  1972; 222:267.

Clements et al., 1958. Clements JA, Brown ES, Johnson RP: Pulmonary surface tension and mucus lining of the lungs; some theoretical considerations.  J Appl Physiol  1958; 12:262.

Cogswell et al., 1975. Cogswell JJ, Hull D, Milner AD, et al: Lung function in childhood. III. Measurement of airflow resistance in healthy children.  Br J Dis Chest  1975; 69:177.

Cohen, 1995. Cohen J: Pathophysiology of sepsis: Role of nitric oxide and other mediators.  Curr Opin Anaesthesiol  1995; 8:109.

Cohen, 1981b. Cohen MI: Central determinants of respiratory rhythm.  Anna Rev Physiol  1981; 43:91.

Cohen, 1981a. Cohen MI: How is respiratory rhythm generated?.  Fed Proc  1981; 40:2372.

Cohen, 1979. Cohen MI: Neurogenesis of respiratory rhythm in the mammal.  Physiol Rev  1979; 59:1105.

Cohen, 1971. Cohen MI: Switching of the respiratory phases and evoked phrenic responses produced by rostral pontine electrical stimulation.  J Physiol (Lond)  1971; 217:133.

Coleridge et al., 1976. Coleridge HM, Coleridge JCG, Ginzel KH, et al: Stimulation of “irritant” receptors and afferent C-fibers in the lungs by prostaglandins.  Nature  1976; 264:451.

Coleridge and Coleridge, 1984. Coleridge JCG, Coleridge HMG: Afferent vagal C fibre innervation of the lungs and airways and its functional significance.  Rev Physiol Biochem Pharmacol  1984; 99:1.

Colin et al., 1989. Colin AA, Wohl MEB, Mead J, et al: Transition from dynamically maintained to relaxed end-expiratory volume in human infants.  J Appl Physiol  1989; 67:2107.

Colley et al., 1979. Colley PS, Cheney Jr FW, Hlastala MP: Ventilation-perfusion and gas exchange effects of sodium nitroprusside in dogs with normal edematous lungs.  Anesthesiology  1979; 30:489.

Comoe, 1974. Comoe JH: Physiology of respiration: An introductory text,  ed 2. Chicago, Year Book Medical Publishers, 1974.

Consensus Conference, 1988. Consensus Conference : Perioperative red blood cell transfusion.  JAMA  1988; 260:2700.

Cook et al., 1955. Cook CD, Cherry RB, O'Brien D, et al: Studies of respiratory physiology in the newborn infant. I. Observations on the normal premature and full-term infants.  J Clin Invest  1955; 34:975.

Cook et al., 1963. Cook CD, Drinker PA, Jacobson HN, et al: Control of pulmonary blood flow in the foetal and newly born lamb.  J Physial (Lond)  1963; 169:10.

Cook et al., 1957. Cook CD, Sutherland JM, Segal S, et al: Studies of respiratory physiology in the newborn infant. HI. Measurements of mechanics of respiration.  J Clin Invest  1957; 36:440.

Coté et al., 1988. Coté CJ, Goldslein EA, Coté MA, et al: A single-blind study of pulse oximetry in children.  Anesthesiology  1988; 68:184.

Coté et al., 1991. Coté CJ, Rolf N, Liu LMP, Gousouzian NG: A single-blind study of pulse oximetry and capnography in children.  Anesthesiology  1991; 74:984.

Coté et al., 1995. Coté CJ, Zaslavsky A, Downes JJ, et al: Postoperative apnea in former preterm infants after inguinal herniorrhaphy. A combined analysis.  Anesthesiology  1995; 82:809-822.

Cotes et al., 1993. Cotes JE, Chinn DJ, Quanjer PH, et al: Official statement of the European Respiratory Society: Standardization of the measurement of transfer factor (diffusing capacity).  Eur Respir J  1993; 6(suppl 16):41-52.

Crapo et al., 2001. Crapo RO, Jensen RL, Wagner JS: Single breath carbon monoxide diffusing capacity.  Clin Chest Med  2001; 22:637-649.

Cross et al., 1960. Cross KW, Klaus M, Tooley WH, Weisser K: The response of the newborn baby to inflation of the lungs.  J Physiol (Lond)  1960; 151:551.

Cross and Oppe, 1952. Cross KW, Oppe TE: The effect of inhalation of high and low concentrations of oxygen on the respiration of the premature infant.  J Physiol (Lond)  1952; 117:38.

Dahan et al., 1994. Dahan A, van den Elsen MJLW, Berkenbosch A, et al: Effects of subanesthetic halothane on the ventilatory response to hypercapnia and acute hypoxia in healthy volunteers.  Anesthesiology  1994; 80:727.

D'Angelo et al., 1989. D'Angelo E, Calderini G, Torri FM, et al: Respiratory mechanics in anesthetized paralyzed humans: Effects of flow, volume and time.  J Appl Physiol  1989; 67:2556.

Davies et al., 1988. Davies AM, Koenig JS, Thach BT: Upper airway chemoreflex response to saline and water in preterm infants.  J Appl Physiol  1988; 64:1412.

Davies et al., 1985. Davies H, Kitchman R, Gordon I, Helms P: Regional ventilation in infancy: Reversal of adult pattern.  N Engl J Med  1985; 313:1626.

Davies et al., 1982. Davies RO, Edwards MW, Lahiri S: Halothane depresses the response of carotid body chemoreceptors to hypoxia and hypercarbia in the cat.  Anesthesiology  1982; 57:153.

Dawes, 1974. Dawes GS: Breathing before birth in animals and man.  N Engl J Med  1974; 290:557.

Dawes et al., 1970. Dawes GS, Fox HE, Leduc MB, et al: Respiratory movements and paradoxical sleep in the fetal lamb.  J Physiol (Lond)  1970; 210:47P.

Dawes et al., 1972. Dawes GS, Fox HE, Leduc MB, et al: Respiratory movements and rapid eye movement sleep in the fetal lamb.  J Physiol (Lond)  1972; 2211:119.

Dawes et al., 1982. Dawes GS, Gardner WN, Johnston BM, Walker DW: Effects of hypercapnia on tracheal pressure, diaphragm and intercostal electromyograms in unanesthetized fetal lambs.  J Physiol (Lond)  1982; 326:461.

Dawson and Elliott, 1977. Dawson SV, Elliott EA: Wave-speed limitation on expiratory flow'A unifying concept.  J Appl Physiol  1977; 43:498.

Deal et al., 1980. Deal EC, McFadden ER, Ingram RH, et al: Airway responsiveness to cold air and hyperpnea in normal subjects and in those with hay fever and asthma.  Am Rev Respir Dis  1980; 121:621.

Decima and von Euler, 1969. Decima EE, von Euler C: Excitability of phrenic motoneurons to afferent input from lower intercostal nerves in the spinal cat.  Acta Physiol Scand  1969; 75:580.

deLemos et al., 1970. deLemos RA, Shermeta DW, Knelson JH, et al: Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids.  Am Rev Respir Dis  1970; 102:459.

deMello and Reid, 1995. deMello DE, Reid LM: Respiratory tract and lungs.   In: Reed GB, Claireaux AE, Cockburn F, ed. Disease of the fetus and newborn,  ed 2. London: Chapman & Hall; 1995.

Derenne et al., 1976. Derenne JP, Couture J, Iscoe S, et al: Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia.  J Appl Physiol  1976; 40:805.

deTroyer and Bastenier-Geens, 1979. deTroyer A, Bastenier-Geens J: Effect of neuromuscular blockade on respiratory mechanics in conscious man.  J Appl Physiol  1979; 47:1162.

Dobbinson et al., 1973. Dobbinson TL, Nisbet HIA, Pelton DA: Functional residual capacity (FRC) and compliance in anaesthetized paralysed children. Part I: In vitro tests with the helium dilution method of measuring FRC.  Can Anaesth Soc J  1973; 20:310.

Don et al., 1987. Don HF, Wahba M, Cuadrado L, Kelkar K: The effects of anesthesia and 100% oxygen on the functional residual capacity of the lungs.  Anesthesiology  1987; 67:695.

Donnelly and Haddad, 1986. Donnelly DF, Haddad GG: Respiratory changes induced by prolonged laryngeal stimulation in awake piglets.  J Appl Physiol  1986; 61:1018.

Dripps and Comroe, 1947. Dripps RD, Comroe Jr JH: The respiratory and circulatory response of normal man to inhalation of 7.6 and 10.4 percent CO2 with a comparison of the maximal ventilation produced by severe muscular exercise, inhalation of CO2 and maximal voluntary hyperventilation.  Am J Physiol  1947; 149:43.

Drummond, 1987. Drummond GB: Reduction of tonic ribcage muscle activity by anesthesia with thiopental.  Anesthesiology  1987; 67:695.

Dunnill, 1962. Dunnill MS: Postnatal growth of the lung.  Thorax  1962; 17:329.

Duron, 1981. Duron B: Intercostal and diaphragmatic muscle endings and afferents.   In: Hornbein TF, ed. Regulation of breathing, part 1,  New York: Marcel Dekker; 1981.

Dutton et al., 1964. Dutton RE, Chernick V, Moses H, et al: Ventilatory response to intermittent inspired carbon dioxide.  J Appl Physiol  1964; 19:931.

Eckenhoff, 1951. Eckenhoff JE: Some anatomic considerations of the infant larynx influencing endotracheal anesthesia.  Anesthesiology  1951; 12:401.

Edelman et al., 1970. Edelman NH, Lahiri S, Brando L, et al: The blunted ventilatory response to hypoxia in cyanotic congenital heart disease.  N Engl J Med  1970; 282:405.

Emery, 1969. Emery JL: The anatomy of the developing lung,  London, Heinemann Medical Books, Ltd, 1969.

England and Stogren, 1986. England SJ, Stogren HAF: Influence of the upper airway on breathing pattern and expiratory time constant in dog pups.  Respir Physiol  1986; 66:181.

Enhorning et al., 1985. Enhorning G, Shennan A, Possmayer F, et al: Prevention of neonatal respiratory distress syndrome by tracheal instillation of surfactant: A randomized clinical trial.  Pediatrics  1985; 76:145.

Fagan, 1976. Fagan DG: Post-mortem studies of the semistatic volume-pressure characteristics of infants' lungs.  Thorax  1976; 31:534.

Fagan, 1977. Fagan DG: Shape changes in static V-P loops for children's lungs related to growth.  Thorax  1977; 32:193.

Feher et al., 1996. Feher A, Castile R, Kisling J, et al: Flow limitation in normal infants: A new method for forced expiratory maneuvers from raised lung volumes.  J Appl Physiol  1996; 80:2019-2025.

Feldman, 1986. Feldman JL: Neurophysiology of breathing in mammals.   In: Bloom FE, ed. Handbook of physiology. Section I. Nervous system. Vol 4. Intrinsic regulatory systems of the brain,  Bethesda, MD: American Physiological Society; 1986.

Feldman and Gautier, 1976. Feldman JL, Gautier H: Interaction of pulmonary afferents and pneumotaxic center in control of respiratory pattern in cats.  J Neurophysiol  1976; 39:31.

Feldman and Speck, 1983. Feldman JL, Speck DF: Interaction among inspiratory neurons in dorsal and ventral respiratory groups in cat medulla.  J Neurophysiol  1983; 49:472.

Fenner et al., 1968. Fenner A, Jansson EH, Avery ME: Enhancement of the ventilatory response to carbon dioxide by tube breathing.  Respir Physiol  1968; 4:91.

Fenner et al., 1973. Fenner A, Schalk U, Hoenicke H, et al: Periodic breathing in premature and neonatal babies: Incidence, breathing pattern, respiratory gas tensions, response to changes in the composition of ambient air.  Pediatr Res  1973; 7:174.

Ferris et al., 1964. Ferris BG, Mead J, Opie LH: Partitioning of respiratory flow resistance in man.  J Appl Physiol  1964; 19:653.

Finch and Lenfant, 1972. Finch CA, Lenfant C: Oxygen transport in man.  N Engl J Med  1972; 286:407.

Fink and Demarest, 1978. Fink BR, Demarest RJ: Laryngeal biomechanics,  Cambridge, MA, Harvard University Press, 1978.

Finley et al., 1962. Finley TN, Swenson EW, Comroe Jr JH: The cause of arterial hypoxemia at rest in patients with “alveolar-capillary block syndrome.”.  J Clin Invest  1962; 41:618.

Fisher et al., 1985. Fisher JT, Mathew OP, Sant'Ambrogio FB, Sant'Ambrogio G: Reflex effects and receptor responses to upper airway pressure and flow in developing puppies.  J Appl Physiol  1985; 58:258.

Fisher et al., 1982. Fisher JT, Mortola JP, Smith GS, et al: Respiration in newborns: Development of the control of breathing.  Am Rev Respir Dis  1982; 125:650.

Fletcher et al., 1990. Fletcher ME, Ewert M, Stack C, et al: Influence of tidal volume on respiratory compliance in anesthetized infants and young children.  J Appl Physiol  1990; 68:1127.

Flynn et al., 1992. Flynn JT, Bancalari E, Snyder ES, et al: A cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity.  N Engl J Med  1992; 326:1050.

Forbes, 1974. Forbes AR: Temperature, humidity and mucous flow in the intubated trachea.  Br J Anaesth  1974; 46:29.

Forbes, 1976. Forbes AR: Halothane depresses mucociliary flow in the trachea.  Anesthesiology  1976; 45:59.

Forbes and Gamsu, 1979. Forbes AR, Gamsu G: Lung mucociliary clearance after anesthesia and spontaneous and controlled ventilation.  Am Rev Respir Dis  1979; 120:857.

Forbes and Horrigan, 1977. Forbes AR, Horrigan RW: Mucociliary flow in the trachea during anesthesia with enflurane, ether, nitrous oxide, and morphine.  Anesthesiology  1977; 46:319.

Forster, 1957. Forster RE: Exchange of gases between alveolar air and pulmonary capillary blood; pulmonary diffusing capacity.  Physiol Rev  1957; 37:391.

Forster, 1983. Forster II RE: The single breath carbon monoxide transfer test 25 years: A reappraisal 1. Physiological considerations.  Thorax  1983; 38:1-5.

Foster et al., 1975. Foster HV, Dempsey JA, Chosy LW: Incomplete compensation of CSF (H+) in man during acclimatization to high altitude (4,300 m).  J Appl Physiol  1975; 38:1067.

Fournier and Major, 1984. Fournier L, Major D: The effect of nitrous oxide on the oxyhaemoglobin dissociation curve.  Can Anaesth Soc J  1984; 31:173.

Frantz et al., 1976. Frantz III ID, Adler SM, Thach BT, Taeusch Jr HW: Maturational effects on respiratory responses to carbon dioxide in premature infants.  J Appl Physiol  1976; 41:634.

Fratacci et al., 1991. Fratacci MD, Frostell CG, Chen TY, et al: Inhaled nitric oxide: A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.  Anesthesiology  1991; 75:990.

Frenkiel et al., 1980. Frenkiel S, Desmond K, Coates AL, et al: Upper airway obstruction in children: The value of inspiratory-expiratory flow-volume curves.  J Otolaryngol  1980; 9:7.

Freund et al., 1964. Freund F, Roos A, Dood RB: Expiratory activity of the abdominal muscles in man during general anesthesia.  J Appl Physiol  1964; 19:963.

Frostell et al., 1993. Frostell CG, Blomqvist H, Hedenstierna G, et al: Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation.  Anesthesiology  1993; 78:427.

Frostell et al., 1991. Frostell C, Fratacci MD, Wain JC, et al: Inhaled nitric oxide: A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.  Circulation  1991; 83:2083.

Fujiwara et al., 1980. Fujiwara T, Maeta H, Chida S, et al: Artificial surfactant therapy in hyaline membrane disease.  Lancet  1980; 1:55.

Funk and Feldman, 1995. Funk GD, Feldman JL: Generation of respiratory rhythm and pattern in mammals: Insights from developmental studies.  Curr Opin Neurobiol  1995; 5:778-785.

Furchgott and Vanhoutte, 1989. Furchgott RF, Vanhoutte PM: Endothelium-derived relaxing and contracting factors.  FASEB J  1989; 3:2007.

Furchgott and Zawadzki, 1980. Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature  1980; 288:373.

Gaultier et al., 1979. Gaultier C, Boule M, Allaire Y, et al: Growth of lung volumes during the first three years of life.  Bull Eur Physiopathol Respir  1979; 15:1103.

Gaultier et al., 1995. Gaultier C, Fletcher ME, Beardsmore C, et al: Respiratory function measurement in infants: Measurement conditions.  Am J Respir Crit Care Med  1995; 151:2058.

Gautier and Bertrand, 1975. Gautier H, Bertrand F: Respiratory effects of pneumotaxic center lesions and subsequent vagotomy in chronic cats.  Respir Physiol  1975; 23:71.

Gerhardt and Bancalari, 1980. Gerhardt T, Bancalari E: Chest wall compliance in full term and premature infants.  Acta Paediatr Scand  1980; 69:359.

Gerhardt and Bancalari, 1982. Gerhardt T, Bancalari E: Components of effective elastance and their maturational changes in human newborns.  J Appl Physiol  1982; 53:766.

Gerhardt et al., 1986. Gerhardt T, Reifenberg L, Hehre D, et al: Functional residual capacity in normal neonates and children up to 5 years of age determined by a N2 washout method.  Pediatr Res  1986; 20:668.

Glenn et al., 1973. Glenn WWL, Holcomb WG, Hogan J, et al: Diaphragm pacing by radiofrequency transmission in the treatment of chronic ventilatory insufficiency.  J Thorac Cardiovasc Surg  1973; 66:505.

Glezen and Denny, 1973. Glezen WP, Denny FW: Epidemiology of acute lower respiratory disease in children.  N Engl J Med  1973; 288:498.

Glotzbach et al., 1989. Glotzbach SF, Tansey PA, Baldwin RB, Ariagno RL: Periodic breathing in preterm infants: Influence of bronchopulmonary dysplasia and theophylline.  Pediatr Pulmonol  1989; 7:78.

Goldberg and Milic-Emili, 1977. Goldberg MS, Milic-Emili J: Effect of sodium pentobarbital on respiratory control in newborn rabbits.  J Appl Physiol  1977; 42:845.

Goldring et al., 1964. Goldring RM, Fishman AP, Turino GM, et al: Pulmonary hypertension and cor pulmonale in cystic fibrosis of the pancreas.  J Pediatr  1964; 65:501.

Goldstein et al., 2001. 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.

Goldzimer et al., 1974. Goldzimer EL, Konopka RG, Moser KM: Reversal of the perfusion defect in experimental canine labor pneumococcal pneumonia.  J Appl Physiol  1974; 37:85.

Gregory et al., 1971. Gregory GA, Kitterman JA, Phibbs RH, et al: Treatment of the idiopathic respiratory-distress syndrome with continuous positive airway pressure.  N Engl J Med  1971; 284:1333.

Guedel, 1937. Guedel A: Inhalation anesthesia,  New York, MacMillan Publishing Co., 1937.

Guz et al., 1970. Guz A, Noble MIM, Eisel JH, Trenchard D: The role of vagal inflation reflexes in man and other animals.   In: Porter R, ed. Breathing: Hering-Breuer Centenary Symposium,  London: Churchill Livingstone; 1970.

Hallman, 1984. Hallman M: Antenatal diagnosis of lung maturity.   In: Robertson B, van Golde LMG, Batenvurg JJ, ed. Pulmonary surfactant,  Amsterdam: Elsevier; 1984.

Haraguchi et al., 1983. Haraguchi S, Fung R, Sasaki CT: Effect of hyperthermia on the laryngeal closure reflex: Implications for the sudden infant death syndrome.  Ann Otol Rhinol Laryngol  1983; 92:24.

Harding, 1984. Harding R: Function of the larynx in the fetus and newborn.  Annu Rev Physiol  1984; 46:645.

Hart et al., 1963. Hart MC, Orzalesi MM, Cook CD: Relation between anatomic respiratory dead space and body size and lung volume.  J Appl Physiol  1963; 18:519.

Heaf et al., 1983. Heaf DP, Helms P, Gordon I, Turner HM: Postural effects on gas exchange in infants.  N Engl J Med  1983; 308:1505.

Hedenstierna and McCarthy, 1980. Hedenstierna G, McCarthy GS: Airway closure and closing volume during mechanical ventilation.  Acta Anaesth Scand  1980; 24:299.

Henderson-Smart and Read, 1979. Henderson-Smart DJ, Read DJC: Reduced lung volume during behavior active sleep in the newborn.  J Appl Physiol  1979; 46:1081.

Hershenson et al., 1990. Hershenson MB, Colin AA, Wohl MEB, Start AR: Changes in contribution of the rib cage to tidal breathing during infancy.  Am Rev Respir Dis  1990; 141:922.

Hewlett et al., 1974. Hewlett AM, Hulands GH, Nunn JF, Milledge JS: Functional residual capacity during anesthesia. III. Artificial ventilation.  Br J Anaesth  1974; 46:495.

Hickey and Severinghaus, 1981. Hickey RF, Severinghaus JW: Regulation of breathing: Drug effect.   In: Hornbein TF, ed. Lung biology in health and disease. Regulation of breathing,  New York: Dekker; 1981.

Hill et al., 1979. Hill AB, Chir B, Sykes MK, et al: A hypoxic pulmonary vasoconstrictor response in dogs during and after infusion of sodium nitroprusside.  Anesthesiology  1979; 50:484.

Hirsch et al., 1975. Hirsch JA, Tokayer JL, Robinson MJ, et al: Effects of dry air and subsequent humidification on tracheal mucous velocity in dogs.  J Appl Physiol  1975; 39:242.

Hirshman et al., 1977. Hirshman CA, McCullough RE, Cohen PJ, Weil JV: Depression of hypoxic ventilatory response by halothane, enflurane and isoflurane in dogs.  Br J Anaesth  1977; 49:957.

Hislop and Reid, 1974. Hislop A, Reid L: Development of the acinus in the human lung.  Thorax  1974; 29:90.

Hoekstra et al., 1991. Hoekstra RE, Jackson JC, Myers TF, et al: Improved neonatal survival following multiple doses of bovine surfactant in very premature neonates at risk for respiratory distress syndrome.  Pediatrics  1991; 88:10.

Hogg et al., 1970. Hogg JC, Williams J, Richardson JB, et al: Age as a factor in the distribution of lower airway conductance and in the pathologic anatomy of obstructive lung disease.  N Engl J Med  1970; 282:1283.

Holms, 1993. Holms BA: Surfactant replacement therapy. New levels of understanding.  Am Rev Respir Dis  1993; 148:834.

Hughes et al., 1968. Hughes JMB, Glazier JB, Maloney JE, West JB: Effect of lung volume on the distribution of pulmonary blood flow in man.  Respir Physiol  1968; 4:58.

Hughes et al., 1970. Hughes JMB, Rosenzweig DY, Kivitz PB: Site of airway closure in excised dog lung: Histologic demonstration.  J Appl Physiol  1970; 29:340.

Hutcheon et al., 1974. Hutcheon M, Griffin P, Levison H, Zamel N: Volume of isoflow: A new test in detection of mild abnormalities of lung mechanics.  Am Rev Respir Dis  1974; 110:458.

Hwang et al., 1984. Hwang JC, St. John WM, Bartlett D: Afferent pathways for hypoglossal and phrenic responses to changes in upper airway pressure.  Resp Physiol  1984; 55:341.

Hyatt, 1986. Hyatt RE: Forced expiration.   In: Geiger SR, Macklem PT, Mead J, Fishman AP, ed. Handbook of physiology. Section 3. The respiratory system. Vol 3. Mechanics of breathing, part 1,  Bethesda, MD: American Physiological Society; 1986.

Hyatt et al., 1973. Hyatt RE, Okeson GC, Rodarte JR: Influence of expiratory flow limitation on the pattern of lung emptying in normal man.  J Appl Physiol  1973; 35:411.

Ignarro et al., 1987. Ignarro LJ, Buga GM, Woods KS, et al: Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.  Proc Natl Acad Sci USA  1987; 84:9265.

Ikari and Sasaki, 1980. Ikari T, Sasaki CT: Glottic closure reflex: Control mechanisms.  Ann Otol Rhinol Laryngol  1980; 89:220.

Isaza et al., 1976. Isaza GD, Posner JD, Altose MD, et al: Airway occlusion pressure in awake and anesthetized goats.  Respir Physiol  1976; 27:87.

Isono et al., 2002. Isono S, Tanaka A, Nishino T: Lateral position decreases collapsibility of the passive pharynx in patients with obstructive sleep apnea.  Anesthesiology  2002; 97:780.

Issa and Sullivan, 1984. Issa FQ, Sullivan CE: Upper airway closing pressures in obstructive sleep apnea.  J Appl Physiol  1984; 57:520.

Jacob et al., 1994. Jacob TD, Nakayama DK, Seki I, et al: Hemodynamic effects and metabolic fate of inhaled nitric oxide in hypoxic piglets.  J Appl Physiol  1994; 77:1794.

Jammes and Speck, 1955. Jammes Y, Speck DF: Respiratory control by diaphragmatic and respiratory muscle afferents.   In: Dempsey JA, Pack AI, ed. Regulation of breathing,  New York: Marcel Dekker; 1955:543-582.

Jansen and Chernick, 1974. Jansen AH, Chernick V: Respiratory response to cyanide in fetal sheep after peripheral chemodenervation.  J Appl Physiol  1974; 36:1.

Jansen and Chernick, 1983. Jansen AH, Chernick V: Development of respiratory control.  Physiol Rev  1983; 63:437.

Jansen et al., 1982. Jansen AH, Ioffe S, Russell BJ, Chernick V: Influence of sleep state on the response to hypercapnia in fetal lambs.  Respir Physiol  1982; 48:125.

Jeffery and Reid, 1977. Jeffery PK, Reid LM: The respiratory mucous membrane.   In: Brain JD, Proctor DF, Reid LM, ed. Respiratory defense mechanisms,  New York: Marcel Dekker; 1977.

Jennis and Peabody, 1987. Jennis MS, Peabody JL: Pulse oximetry: An alternative method for the assessment of oxygenation in newborn infants.  Pediatrics  1987; 79:524.

Jobe, 1993. Jobe AH: Pulmonary surfactant therapy.  N Engl J Med  1993; 328(12):861.

Johns et al., 1992. Johns RA, Moscicki JC, DiFazio CA: Nitric oxide synthase inhibitor dose-dependently and reversibly reduces the threshold for halothane anesthesia.  Anesthesiology  1992; 77:779.

Juno et al., 1978. Juno P, March HM, Knopp TJ, Render K: Closing capacity in awake and anesthetized-paralysed man.  J Appl Physiol  1978; 44:238.

Kaditis et al., 1999a. Kaditis AG, Motoyama EK, Seki I, et al: Flow and volume dependence of respiratory mechanics in anesthetized children.  Pediatr Res  1999; 46:419.

Kaditis et al., 1999b. Kaditis AG, Venkataraman ST, Zin WA, et al: Partitioning of respiratory system resistance in children with respiratory insufficiency.  Am J Respir Crit Care Med  1999; 159:389.

Kaneko et al., 1966. Kaneko K, Milic-Emili J, Dolovich MB, et al: Regional distribution of ventilation and perfusion as a function of body position.  J Appl Physiol  1966; 21:767.

Karlberg et al., 1962. Karlberg P, Cherry RB, Escardo FE, Koch G: Respiratory studies in newborn infants. II. Pulmonary ventilation and mechanics of breathing in the first minutes of life, including the onset of respiration.  Acta Paediatr Scand  1962; 51:121.

Keidan et al., 2000. Keidan I, Fine GF, Kagawa T, et al: Work of breathing during spontaneous ventilation in anesthesized children: A comparative study among the face mask, laryngeal mask airway and endotracheal tube.  Anesth Analg  2000; 91:1381-1388.

Kelly et al., 1985. Kelly DL, Stellwagen LM, Kaitz E, Shannon DC: Apnea and periodic breathing in normal full-term infants during the first twelve months.  Pediatr Pulmonol  1985; 1:215.

Kikkawa et al., 1965. Kikkawa Y, Motoyama EK, Cook CD: Ultrastructure of lungs of lambs; the relation of osmiophilic inclusions and alveolar lining layer to fetal maturation and experimentally produced respiratory distress.  Am J Pathol  1965; 47:877.

Kilburn and Salzano, 1966. Kilburn KH, Salzano JV: Symposium on structure, function and measurement of respiratory cilia.  Am Rev Respir Dis  1966; 93:1.

Kinsella et al., 1992. Kinsella JP, Neish SR, Shaffer E, Abman SH: Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn.  Lancet  1992; 340:819.

Knill and Clement, 1984. Knill RL, Clement JL: Site of selective action of halothane on the peripheral chemoreflex pathway in humans.  Anesthesiology  1984; 61:121.

Knill and Gelb, 1978. Knill RL, Gelb AW: Ventilatory response to hypoxia and hypercapnia during halothane sedation and anesthesia in man.  Anesthesiology  1978; 49:244.

Koka et al., 1977. Koka BV, Jeon S, Andre JM, et al: Post intubation croup in children.  Anesth Analg (Cleve)  1977; 56:501.

Kosch and Stark, 1979. Kosch PC, Stark AR: Determination and homeostasis of functional residual capacity (FRC) in infants.  Physiologist  1979; 22:71.

Kryger et al., 1976. Kryger M, Bode F, Antic R, Anthonisen N: Diagnosis of obstruction of upper and central airways.  Am J Med  1976; 61:85.

Kryger et al., 1976. Kryger MH, Jacob O, Dosman J, et al: Effect of meperidine on occlusion pressure response to hypercapnia and hypoxia with and without external inspiratory resistance.  Am Rev Respir Dis  1976; 114:133.

Kulovich et al., 1979. Kulovich MV, Hallman M, Cluck L: The lung profile. I. Normal pregnancy.  Am J Obstet Gynecol  1979; 135:57.

Kuna and Remmers, 1986. Kuna ST, Remmers JE: Pathophysiology and mechanisms of sleep apnea.   In: Fletcher EC, ed. Abnormalities of respiration during sleep,  Orlando, FL: Grune & Stratton; 1986.

Kurth et al., 1987. Kurth CD, Spitzer AR, Broennle AM, Downes JJ: Postoperative apnea in preterm infants.  Anesthesiology  1987; 66:483.

Lacourt and Polgar, 1971. Lacourt G, Polgar G: Interaction between nasal and pulmonary resistance in newborn infants.  J Appl Physiol  1971; 30:870.

LaFramboise et al., 1981. LaFramboise WA, Standaert TA, Woodrum DE, Guthrie RD: Occlusion pressures during the ventilatory response to hypoxemia in the newborn monkey.  J Appl Physiol  1981; 51:1169.

LaFramboise and Woodrum, 1985. LaFramboise WA, Woodrum DE: Elevated diaphragm electromyogram during neonatal hypoxic ventilatory depression.  J Appl Physiol  1985; 59:1040.

Lahiri et al., 1978. Lahiri S, Brody JS, Motoyama EK, Valasquez TM: Regulation of breathing in newborns in high altitude.  J Appl Physiol  1978; 44:673.

Lahiri and DeLaney, 1975. Lahiri S, DeLaney RG: Stimulus interaction in the responses of carotid body chemoreceptor single afferent fibers.  Respir Physiol  1975; 24:249.

Lambert et al., 2004. Lambert RK, Castile RG, Tepper RS: Model of forced expiratory flows and airway geometry in infants.  J Appl Physiol  2004; 96:688-692.

Lang et al., 1990. Lang MJ, Hall RT, Reddy NS, et al: A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants.  J Pediatr  1990; 116:295.

Langston et al., 1984. Langston C, Kida K, Reed M, Thurlbeck WM: Human lung growth in late gestation and in the neonate.  Am Rev Respir Dis  1984; 129:607.

Lauweryns, 1970. Lauweryns JM: “Hyaline membrane disease” in newborn infants: Macroscopic, radiographic and light and electron microscopic studies.  Hum Pathol  1970; 1:175.

Laws, 1968. Laws AK: Effects of induction of anaesthesia and muscle paralysis on functional residual capacity of the lungs.  Can Anaesthesiol Soc J  1968; 15:325.

LeSouef et al., 1984. LeSouef PN, England SJ, Bryan AC: Passive respiratory mechanics in newborns and children.  Am Rev Respir Dis  1984; 129:552.

Leusen, 1972. Leusen I: Regulation of cerebrospinal fluid composition with reference to breathing.  Physiol Rev  1972; 52:1.

Levy et al., 1967. Levy AM, Tabakin BS, Hanson JS, Narkewicz RM: Hypertrophied adenoids causing pulmonary hypertension and severe congestive heart failure.  N Engl J Med  1967; 277:506.

Lichtiger et al., 1975. Lichtiger M, Landa JF, Hirsch JA: Velocity of tracheal mucus in anesthetized women undergoing gynecologic surgery.  Anesthesiology  1975; 41:753.

Liggins and Howie, 1972. Liggins GC, Howie RN: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.  Pediatrics  1972; 50:515.

Lindahl et al., 1987. Lindahl SGE, Yates AP, Hatch DJ: Respiratory depression in children at different end tidal halothane concentrations.  Anaesthesia  1987; 42:1267.

Lipski and Merrill, 1980. Lipski J, Merrill EG: Electrophysiological demonstration of the projection from expiratory neurons in rostral medulla to contralateral dorsal respiratory group.  Brain Res  1980; 197:521.

Litman and Keon, 1991. Litman RS, Keon TP: Postintubation croup in children.  Anesthesiology  1991; 75:1122.

Liu et al., 1983. Liu LMP, Coté CJ, Goudsouzian NG, et al: Life-threatening apnea in infants recovering from anesthesia.  Anesthesiology  1983; 59:506.

Long and Duffin, 1984. Long SE, Duffin J: The medullary respiratory neurons: A review.  Can J Physiol Pharmacol  1984; 62:161.

Long et al., 1991. Long WA, Corbet A, Cotton R, et al: A controlled trial of synthetic surfactant in infants weighing 1250 grams or more with the American Exosurf Neonatal Study Group I and the Canadian Exosurf Neonatal Study Group.  N Engl J Med  1991; 325:1696.

Lucier et al., 1979. Lucier GE, Storey AT, Sessle BJ: Effects of upper respiratory tract stimuli on neonatal respiration; reflex and single neuron analysis in the kitten.  Biol Neonate  1979; 35:82.

Macklem and Mead, 1967. Macklem PT, Mead J: Resistance of central and peripheral airways measured by a retrograde catheter.  J Appl Physiol  1967; 22:395.

Mansell et al., 1972. Mansell A, Bryan C, Levison H: Airway closure in children.  J Appl Physiol  1972; 33:711.

Marcal and Crance, 1987. Marcal F, Crance JP: Measurement of ventilatory system compliance in infants and young children.  Respir Physiol  1987; 68:311.

Marcal et al., 1988. Marcal F, Haouzi P, Gallina C, Crance JP: Measurement of ventilatory system resistance in infants and young children.  Respir Physiol  1988; 73:201.

Marshall and Marshall, 1985. Marshall BE, Marshall C: Anesthesia and pulmonary circulation.   In: Covino BJ, Fozzard HA, Rehder K, Strichartz, ed. Effects of anesthesia,  Bethesda, MD: American Physiological Society; 1985.

Marshall and Marshall, 1980. Marshall BE, Marshall C: Continuity of response to hypoxic pulmonary vasoconstriction.  J Appl Physiol  1980; 49:189.

Masters et al., 1987. Masters IB, Seidenberg J, Hudson I, et al: Longitudinal study of lung mechanics in normal infants.  Pediatr Pulmonol  1987; 3:3.

Mathew et al., 1982a. Mathew OP, Abu-Osba YK, Thach BT: Genioglossus muscle responses to upper airway pressure changes: Afferent pathways.  J Appl Physiol  1982; 52:445.

Mathew et al., 1982b. Mathew OP, Abu-Osba YK, Thach BT: Influence of upper airway pressure changes on genioglossus muscle inspiratory activity.  J Appl Physiol  1982; 52:438.

McCoy et al., 1995. McCoy KS, Castile RG, Allen ED, et al: Functional residual capacity (FRC) measurements by plethysmography and helium dilution in normal infants.  Pediatr Pulmonol  1995; 19:282-290.

McDonald, 1981. McDonald DM: Peripheral chemoreceptors: Structure-function relationships of the carotid body.   In: Hornbein TF, ed. Regulation of breathing, part 1,  New York: Marcel Dekker; 1981.

McFadden et al., 1982. McFadden Jr ER, Denison DM, Waller JF, et al: Direct recordings of the temperature in the tracheobronchial tree in normal man.  J Clin Invest  1982; 69:700.

McIlroy et al., 1954. McIlroy MB, Marshall R, Christie RV: The work of breathing in normal subjects.  Clin Sci  1954; 13:127.

Mead, 1960. Mead J: Control of respiratory frequency.  J Appl Physiol  1960; 15:325.

Mead, 1970. Mead J: The lung's “quiet zone.”.  N Engl J Med  1970; 28:1318.

Mead and Collier, 1959. Mead J, Collier C: Relation of volume history of lungs to respiratory mechanics in anesthetized dogs.  J Appl Physiol  1959; 14:668.

Mead et al., 1967. Mead J, Turner JM, Macklem PT, Little JB: Significance of the relationship between lung recoil and maximum expiratory flow.  J Appl Physiol  1967; 22:95.

Merrill, 1970. Merrill EG: The lateral respiratory neurons of the medulla: Their association with nucleus ambiguus, nucleus retroambigualis, the spinal accessory nucleus and the spinal cord.  Brain Res  1970; 24:11.

Merrill, 1979. Merrill EG: Is there reciprocal inhibition between medullary inspiratory and expiratory neurons?.   In: von Euler C, Lagercrantz H, ed. Central nervous control mechanisms in breathing, 32. New York: Pergamon Press; 1979.

Merrill et al., 1983. Merrill EG, Lipski J, Kubin L: Origin of the expiratory inhibition of nucleus tractus solitarius inspiratory neurons.  Brain Res  1983; 263:43.

Merritt et al., 1986. Merritt TA, Hallman M, Bloom BT, et al: Prophylactic treatment of very premature infants with human surfactant.  N Engl J Med  1986; 315:785.

Milic-Emili, 1974. Milic-Emili J: Pulmonary statics.   In: Widdicomb JG, ed. Respiratory physiology, MTP International Review of Science, Series I, 2. Borough Green Kent: Butterworth; 1974.

Milic-Emili, 1977. Milic-Emili J: Recent advances in the evaluation of respiratory drive.  Int Anesthesiol Clin  1977; 15:39.

Milic-Emili and Grunstein, 1975. Milic-Emili J, Grunstein MM: Drive and Timing components of ventilation.  Chest  1975; 70(suppl):181.

Milic-Emili et al., 1966. Milic-Emili J, Henderson JAM, Dolovich MB, et al: Regional distribution of gas in the lung.  J Appl Physiol  1966; 21:749.

Milic-Emili et al., 1990. Milic-Emili J, Robatto FM, Gates JH: Respiratory mechanics in anaesthesia.  Br J Anaesth  1990; 65:4.

Miller et al., 1985. Miller AD, Erure K, Suzuki I: Control of abdominal muscles by brain stem respiratory neurons in the cat.  J Neurophysiol  1985; 54:155.

Miserocchi et al., 1973. Miserocchi G, Mortola J, Sant'Ambrogio G: Localization of pulmonary stretch receptors in the airways of the dog.  J Physiol (Lond)  1973; 235:775.

Mitchell, 1966. Mitchell RA: Cerebrospinal fluid and the regulation of respiration.   In: Caro CG, ed. Advances in respiratory physiology,  Baltimore: Williams & Wilkins; 1966.

Mitchell and Berger, 1981. Mitchell RA, Berger AJ: Neurol regulation of respiration.   In: Hornbein TF, ed. Regulation of breathing, part I,  New York: Marcel Dekker; 1981.

Mitchell et al., 1965. Mitchell RA, Carman CT, Severinghaus JW, et al: Stability of cerebrospinal fluid pH in chronic acid-base disturbances in blood.  J Appl Physiol  1965; 20:443.

Mok et al., 1986. Mok JY, McLaughlin FJ, Pintar M, et al: Transcutaneous monitoring of oxygenation: What is normal?.  J Pediatr  1986; 108:365.

Moncada et al., 1989. Moncada S, Palmer RMJ, Higgs EA: Biosynthesis of nitric oxide for L-arginine. A pathway for the regulation of cell function and communication.  Biochem Pharmacol  1989; 38:1709.

Mortola et al., 1982. Mortola JP, Fisher JT, Smith B, et al: Dynamics of breathing in infants.  J Appl Physiol  1982; 52:1209.

Moss, 1965. Moss ML: The veloepiglottic sphincter and obligate nose breathing in the neonate.  J Pediatr  1965; 67:330.

Motoyama, 1988. Motoyama EK: Airway function tests in infants and children.  Int Anesthesiol Clin  1988; 26:6.

Motoyama, 1996. Motoyama EK: Effects of positive end expiratory pressure (PEEP) on respiratory mechanics and oxygen saturation (SpO2) in infants and children under general anesthesia.  Anesthesiology  1996; 85:A1099.

Motoyama, 1985. Motoyama EK: Physiologic alterations in tracheostomy.   In: Myers EN, Stool SE, Johnson JT, ed. Tracheostomy,  New York: Churchill Livingstone; 1985.

Motoyama, 1977. Motoyama EK: Pulmonary mechanics during early postnatal years.  Pediatr Res  1977; 11:220.

Motoyama, 2001. Motoyama EK: Respiratory physiology.   In: Bissonnette B, Dalens B, ed. Pediatric Anesthesia: Principles and Practice,  New York: McGraw-Hill; 2001:43-75.

Motoyama et al., 1982a. Motoyama EK, Brinkmeyer SD, Mutich RL, Walczak SA: Reduced FRC in anesthetized infants: Effect of low PEEP.  Anesthesiology  1982; 57:A418.

Motoyama et al., 1987. Motoyama EK, Fort MD, Klesh KW, et al: Early onset of airway reactivity in premature infants with bronchopulmonary dysplasia.  Am Rev Respir Dis  1987; 136:50.

Motoyama and Glazener, 1986. Motoyama EK, Glazener CH: Hypoxemia after general anesthesia in children.  Anesth Analg  1986; 65:267.

Motoyama et al., 1982. Motoyama EK, Hen J, Tamas L, Dolan FT: Spirometry with positive airway pressure: A simple method to evaluate obstructive lung disease in children.  Am Rev Respir Dis  1982; 126:766.

Motoyama et al., 1971. Motoyama EK, Orzalesi MM, Kikkawa Y, et al: Effect of cortisol on the development of fetal rabbit lungs.  Pediatrics  1971; 48:547.

Motoyama et al., 1974. Motoyama EK, Zigas CJ, Troll G: Functional basis of childhood anemia [abstract].  Am Soc Anesthesiology  1974; 283:

Muldoon et al., 1988. Muldoon SM, Hart JL, Bowen KA, Freas W: Attenuation of endothelium-mediated vasodilation by halothane.  Anesthesiology  1988; 68:31.

Muller et al., 1979. Muller N, Volgyesi G, Becker L, et al: Diaphragmatic muscle tone.  J Appl Physiol  1979; 47:279.

Munson et al., 1966. Munson ES, Larson CP, Babad AA, et al: The effects of halothane, fluroxene and cyclopropane on ventilation: A comparative study in man.  Anesthesiology  1966; 27:716.

Murat et al., 1985. Murat I, Delleur MM, Maggee K, Saint-Maurice C: Changes in ventilatory patterns during halothane anaesthesia in children.  Br J Anaesth  1985; 57:569.

Nakayama et al., 1991. Nakayama DK, Mutich R, Motoyama EK: Pulmonary dysfunction in surgical conditions of the newborn infant.  Crit Care Med  1991; 19:926.

Nathan and Oski, 1987. Nathan DG, Oski FA: Hematology of infancy and childhood,  ed 3. Philadelphia, WB Saunders, 1987.

Nelson, 1976. Nelson NM: Respiration and circulation after birth.   In: Smith CA, Nelson NM, ed. The physiology of the newborn infant,  ed 4. Springfield, IL: Charles C Thomas; 1976.

Nelson et al., 1962. Nelson NM, Prod'hom LS, Cherry RB, et al: Pulmonary function in the newborn infant. II. Perfusion-estimation by analysis of the arterial-alveolar carbon dioxide differences.  Pediatrics  1962; 30:975.

Nelson et al., 1963. Nelson NM, Prod'hom LS, Cherry RB, et al: Pulmonary function in the newborn infant: The alveolar-arterial oxygen gradient.  J Appl Physiol  1963; 18:534.

Newsom-Davis, 1974. Newsom-Davis J: Control of the muscles of breathing.   In: Widdicombe JG, ed. Respiratory physiology, 2. Baltimore: University Park Press; 1974.

Nielsen and Smith, 1951. Nielsen M, Smith H: Studies on the regulation of respiration in acute hypoxia.  Acta Physiol Scand  1951; 24:293.

Nishino, 1993. Nishino T: Swallowing as a protective reflex for the upper respiratory tract.  Anesthesiology  1993; 79:588.

Nishino et al., 1993. Nishino T, Anderson JW, Sant'Ambrogio G: Effects of halothane, enflurane, and isoflurane on laryngeal receptors in dogs.  Respir Physiol  1993; 91:247.

Nishino et al., 1985. Nishino T, Kohchi T, Yonezawa T, Honda Y: Response of recurrent laryngeal, hypoglossal, and phrenic nerves to increasing depth of anesthesia with halothane or enflurane in vagotomized cats.  Anesthesiology  1985; 63:404.

Nishino et al., 1984. Nishino T, Shirahata M, Yonezawa T, Honda Y: Comparison of changes in the hypoglossal and the phrenic nerve activity in response to increasing depth of anesthesia in cats.  Anesthesiology  1984; 60:19.

Nishino et al., 1981. Nishino T, Yonezawa T, Honda Y: Modification of laryngospasm in response to changes in PaO2 in the cat.  Anesthesiology  1981; 55:286.

Noble et al., 1970. Noble MIM, Eisele JH, Trenchard D, Guz A: Effect of selective peripheral nerve blocks on respiratory sensations.   In: Porter R, ed. Breathing: Hering-Breuer Centenary Symposium,  London: Churchill Livingstone; 1970.

Nunn and Ezi-Ashi, 1966. Nunn JF, Ezi-Ashi TI: The respiratory effects of resistance to breathe in anesthetized man.  Anesthesiology  1966; 22:174.

Ochiai et al., 1992. Ochiai R, Guthrie R, Motoyama EK: Differential sensitivity of halothane anesthesia on the genioglossus, intercostals, and diaphragm in kittens.  Anesth Analg  1992; 74:338.

Ochiai et al., 1989. Ochiai R, Guthrie RD, Motoyama EK: Effects of varying concentrations of halothane on the activity of the genioglossus, intercostals, and diaphragm in cats: An electromyographic study.  Anesthesiology  1989; 70:812.

Ogilvie et al., 1957. Ogilvie CM, Forster RE, Blakemore WS, et al: A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide.  J Clin Invest  1957; 36:1-17.

Olinsky et al., 1974. Olinsky A, Bryan MH, Bryan AC: Influence of lung inflation on respiratory control in neonates.  J Appl Physiol  1974; 36:426.

Onal et al., 1981. Onal E, Lopata M, O'Conner TD: Diaphragmatic and genioglossal electromyogram response to CO2 rebreathing in humans.  J Appl Physiol  1981; 49:638.

Onal et al., 1982. Onal E, Lopata M, O'Connor TD: Diaphragmatic and genioglossal electromyogram responses to chemical stimulation and loading.  J Appl Physiol  1982; 53:1133.

Orzalesi et al., 1971. Orzalesi MM, Cowan MJ, Motoyama EK: The in vitro effect of cyclopropane and halothane on the oxygen affinity of human blood [abstract].  Am Soc Anesthesiol  1971; 187:

Orzalesi et al., 1967. Orzalesi MM, Mendicini M, Bucci G, et al: Arterial oxygen studies in premature newborns with and without mild respiratory disorders.  Arch Dis Child  1967; 42:174.

Oski, 1973a. Oski FA: Designation of anemia on a functional basis.  J Pediatr  1973; 83:353.

Oski, 1981. Oski FA: The erythrocyte and its disorders.   In: Nathan DG, Oski FA, ed. Hematology of infancy and childhood,  ed 2. Philadelphia: WB Saunders; 1981.

Oski, 1973b. Oski FA: The unique fetal red cell and its function.  Pediatrics  1973; 51:494.

Oski and Delivoria-Papadopoulos, 1970. Oski FA, Delivoria-Papadopoulos M: The red cell, 2,3-diphosphoglycerate, and tissue oxygen release.  J Pediatr  1970; 77:941.

Pack, 1981. Pack AI: Sensory inputs to the medulla.  Annu Rev Physiol  1981; 43:73.

Pack et al., 1988. Pack AI, Kline LR, Hendricks JC, Morrison AR: Control of respiration during sleep.   In: Fishman AP, ed. Pulmonary diseases and disorders, ed 2. Vol 1, part 2: Physiological principles,  New York: McGraw-Hill Book Co.; 1988.

Paintal, 1973. Paintal AS: Vagal sensory receptors and their reflex effects.  Physiol Rev  1973; 53:159.

Palmer et al., 1987. Palmer RMJ, Ferrige AG, Moncada S: Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor.  Nature  1987; 327:524.

Papastamelos et al., 1995. Papastamelos C, Panitch H, England S, Allen J: Developmental changes in chest wall compliance in infancy and early childhood.  J Appl Physiol  1995; 78:179.

Pappenheimer et al., 1965. Pappenheimer JR, Fenci V, Heisey SR, Held D: Role of cerebral fluids in control of respiration as studied in unanesthetized goats.  Am J Physiol  1965; 208:436.

Patel et al., 1988. Patel RI, Norden J, Hannallah RS: Oxygen administration prevents hypoxemia during postanesthetic transport in children.  Anesthesiology  1988; 69:616.

Patrick et al., 1980. Patrick J, Campbell K, Carmichael L, et al: Patterns of human fetal breathing during the last 10 weeks of pregnancy.  Obstet Gynecol  1980; 56:24.

Pavlin and Hornbein, 1986. Pavlin EG, Hornbein TF: Anesthesia and control of ventilation.   In: Fishman AP, Cherniack NS, Widdicombe JG, ed. Handbook of physiology. Section 3. The respiratory system. Vol II. Control of breathing,  Bethesda, MD: American Physiological Society; 1986.

Pavlin and Su, 1994. Pavlin EG, Su JY: Cardiopulmonary pharmacology.   In: Miller RD, ed. Anesthesia,  ed 4. New York: Churchill Livingstone; 1994.

Perlstein et al., 1970. Perlstein PH, Edward NK, Sutherland JM: Apnea in premature infants and incubator-air-temperature changes.  N Engl J Med  1970; 282:461.

Phillipson, 1994. Phillipson EA: Sleep disorders.   In: Murray JF, Nalel JA, ed. Textbook of respiratory medicine,  2nd ed.. Philadelphia: WB Saunders; 1994.

Pickens et al., 1989. Pickens DL, Schefft GL, Thach BT: Pharyngeal fluid clearance and aspiration preventive mechanisms in sleeping infants.  J Appl Physiol  1989; 66:1164.

Pierrefiche et al., 1998. Pierrefiche O, Schwarzacher SW, Bischoff AM, et al: Blockade of synaptic inhibition within the pre-Boetzinger complex in the cat suppresses respiratory rhythm generation in vivo.  J Physiol Lond  1998; 509:245-254.

Pison et al., 1993. Pison U, Lopez FA, Heidelmeyer CF, et al: Inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction without impairing gas exchange.  J Appl Physiol  1993; 74:1287.

Pitts, 1946. Pitts RF: Organization of the respiratory center.  Physiol Rev  1946; 26:609.

Poets et al., 1992. Poets CF, Stebbens VA, Alexander JR, et al: Arterial oxygen saturation in preterm infants at discharge from the hospital and six weeks later.  J Pediatr  1992; 120:447.

Polgar, 1967. Polgar G: Opposing forces to breathing in newborn infants.  Biol Neonate  1967; 11:1.

Polgar and Promadhat, 1971. Polgar G, Promadhat V: Pulmonary function testing in children: Techniques and standards,  Philadelphia, WB Saunders, 1971.

Possmayer, 1988. Possmayer F: A proposed nomenclature for pulmonary surfactant-associated proteins.  Am Rev Respir Dis  1988; 136:990.

Potter, 1961. Potter EL: Pathology of the fetus and infant,  Chicago, Year Book Medical Publishers, 1961.

Pramanik et al., 1993. Pramanik AK, Holtzman RB, Merritt TA: Surfactant replacement therapy for pulmonary diseases.  Pediatr Clin North Am  1993; 40:913.

Prime, 1951. Prime FJ: Oxygen dissociation curves of whole blood in the presence of anaesthetic gases.  Br J Anaesth  1951; 23:171.

Proctor, 1977a. Proctor DF: The upper airways. I. Nasal physiology and defense of the lung.  Am Rev Respir Dis  1977; 115:97.

Proctor, 1977b. Proctor DF: The upper airways. II. The larynx and trachea.  Am Rev Respir Dis  1977; 115:315.

Proctor, 1986. Proctor DF: Modifications of breathing for phonation.   In: Geiger SR, Macklem PT, Mead J, Fishman AP, ed. Handbook of physiology. Section 3. The respiratory system. Vol 3. Mechanics of breathing, part 1,  Bethesda, MD: American Physiological Society; 1986.

Pullerits et al., 1987. Pullerits J, Burrows FA, Roy WL: Arterial desaturation in healthy children during transfer to the recovery room.  Can J Anaesth  1987; 34:470.

Puybasset et al., 1994. Puybasset L, Stewart TE, Rouby JJ, et al: Inhaled nitric oxide reverses the increase in pulmonary vascular resistance induced by permissive hypercapnia in patients with acute respiratory distress syndrome.  Anesthesiology  1994; 80:1254.

Quanjer et al., 1995. Quanjer PH, Sly PD, Stocks J, et al: Respiratory function measurements in infants: symbols, abbreviations and units.  Am J Respir Crit Care Med  1995; 151:2041-2057.

Radford et al., 1954. Radford Jr EP, Ferns Jr BJ, Kriet BC: Clinical use of nomogram to estimate proper ventilation during artificial respiration.  N Engl J Med  1954; 251:877.

Ramanathan et al., 1987. Ramanathan R, Durand M, Larrazabal C: Pulse oximetry in very low birth weight infants with acute and chronic lung disease.  Pediatrics  1987; 79:612.

Ramirez and Richter, 1996. Ramirez JM, Richter DW: The neuronal mechanisms of respiratory rhythm generation.  Curr Opin Neurobiol  1996; 6:817-825.

Reed et al., 1985. Reed R, Roberts JL, Thach BT: Factors influencing regional patency and configuration of the upper airway in human infants.  J Appl Physiol  1985; 58:635.

Rehder et al., 1972. Rehder K, Hatch DJ, Sessler AD, Fowler WS: The function of each lung of anesthetized and paralyzed man during mechanical ventilation.  Anesthesiology  1972; 37:16.

Rehder et al., 1971. Rehder K, Hatch DJ, Sessler AD, et al: Effects of general anesthesia, muscle paralysis, and mechanical ventilation on pulmonary nitrogen clearance.  Anesthesiology  1971; 35:591.

Rehder et al., 1974. Rehder K, Mallow JE, Fibuch EE, et al: Effects of isoflurane anesthesia and muscle paralysis on respiratory mechanics in normal man.  Anesthesiology  1974; 41:477.

Rehder and Marsh, 1986. Rehder K, Marsh HM: Respiratory mechanics during anesthesia and mechanical ventilation.   In: Fishman A, Macklem PT, Mead J, ed. Handbook of physiology. Section 3. The respiratory system. Vol 3. Mechanics of breathing,  Bethesda, MD: American Physiological Society; 1986.

Rehder et al., 1972. Rehder K, Sittipong R, Sessler AD: The effect of thiopental-meperidine anesthesia with succinylcholine paralysis on functional residual capacity and dynamic lung compliance in normal sitting man.  Anesthesiology  1972; 37:395.

Reid, 1967. Reid L: The embryology of the lung.   In: DeReuck AVS, Porter R, ed. Development of the lung. Ciba Foundation Symposium,  London: Churchill Livingstone; 1967.

Rekling and Feldman, 1998. Rekling JC, Feldman JL: Pre-Boetzinger complex and pacemaker neurons: Hypothesized site and kernel for respiratory rhythm generation.  Annu Rev Physiol  1998; 60:385-405.

Remmers et al., 1978. Remmers JE, deGroot WJ, Sauerland EK, Anch AM: Pathogenesis of upper airway occlusion during sleep.  J Appl Physiol  1978; 44:931.

Remolina et al., 1981. Remolina C, Khan AU, Santiago TV, Edelman NH: Positional hypoxemia in unilateral lung disease.  N Engl J Med  1981; 304:523.

Richard and Bachman, 1961. Richard CC, Bachman L: Lung and chest wall compliance in apneic paralyzed infants.  J Clin Invest  1961; 40:273.

Richter, 1982. Richter DW: Generation and maintenance of the respiratory rhythm.  J Exp Biol  1982; 100:93.

Rigatto, 1986. Rigatto H: Apnea.   In: Thibeault DW, Gregory GA, ed. Neonatal pulmonary care,  Norwalk, CT: Appleton-Century-Crofts; 1986.

Rigatto, 1992. Rigatto H: Maturation of breathing control in the fetus and newborn infant.   In: Beckerman RC, Brouillette RT, Hunt CE, ed. Respiratory control disorders in infants and children,  Baltimore: Williams & Wilkins; 1992.

Rigatto and Brady, 1972a. Rigatto H, Brady JP: Periodic breathing and apnea in preterm infants. II. Hypoxia as a primary event.  Pediatrics  1972; 50:219.

Rigatto and Brady, 1972b. Rigatto H, Brady JP: Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression.  Pediatrics  1972; 50:202.

Rigatto et al., 1975a. Rigatto H, Brady JP, Chir B, de la Tone Verduzco R: Chemoreceptor reflexes in preterm infants. II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide.  Pediatrics  1975; 55:614.

Rigatto et al., 1975b. Rigatto H, Brady JP, de La Torre Verduzco R: Chemoreceptor reflexes in preterm infants. I. The effect of gestational and postnatal age on the ventilatory response to inhalation of 100% and 15% oxygen.  Pediatrics  1975; 55:604.

Rigatto et al., 1982. Rigatto H, Kalapesi Z, Leahy FN, et al: Ventilatory response to 100% and 15% O2 during wakefulness and sleep in preterm infants.  Early Hum Dev  1982; 7:1.

Rigatto et al., 1988. Rigatto H, Lee D, Devi M, et al: Effect of increasing arterial CO2 on fetal breathing and behavior in sheep.  J Appl Physiol  1988; 64:982.

Rimar and Gillis, 1993. Rimar S, Gillis CN: Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation.  Circulation  1993; 88:2884.

Roberts et al., 1993. Roberts JD, Lang P, Bigatello LM, et al: Inhaled nitric oxide in congenital heart disease.  Circulation  1993; 87:447.

Roberts et al., 1992. Roberts JD, Polaner DM, Lang P, Zapol WM: Inhaled nitric oxide in persistent pulmonary hypertension of the newborn.  Lancet  1992; 340:818.

Roberts et al., 1985. Roberts JL, Reed WR, Mathew OP, et al: Assessment of pharyngeal airway stability in normal and micrognathic infants.  J Appl Physiol  1985; 58:290.

Robinson et al., 1985. Robinson SL, Richardson CA, Willis MM, Gregory GA: Halothane anesthesia reduces pulmonary function in the newborn lamb.  Anesthesiology  1985; 62:578.

Robotham, 1994. Robotham JL: Do low-dose inhalation anesthetic agents alter ventilatory control?.  Anesthesiology  1994; 62:578.

Rohrer, 1915. Rohrer F: Der Stromungswiderstand in den menschlichen Atemwegen und der Einfluss der unregelmassigen Verzweigung des Bronchialsystems auf den Atmungsverlauf in verschiedenen Lungenbezirken.  Pflugers Arch  1915; 162:225.

Rooney, 1985. Rooney SA: The surfactant system and lung phospholipid biochemistry.  Am Rev Respir Dis  1985; 131:439.

Rooney et al., 1974. Rooney SA, Canavan PM, Motoyama EK: The identification of phosphatidyl glycerol in the rat, rabbit, monkey and human lung.  Biochem Biophys Acta  1974; 360:56-67.

Rossaint et al., 1993. Rossaint R, Falke KJ, Lopez F, et al: Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med  1993; 328:399.

Rudolph, 1970. Rudolph AM: The changes in the circulation after birth; their importance in congenital heart disease.  Circulation  1970; 41:343.

Sampson and Vidruk, 1977. Sampson SR, Vidruk EH: Chemical stimulation of rapidly adapting receptors in the airways.   In: Fitzgerald RS, Gautier H, Lahiri S, ed. Thermoregulation of respiration during sleep and anesthesia,  New York: Plenum Press; 1977.

Sampson and Vidruk, 1975. Sampson SR, Vidruk EH: Properties of “irritant” receptors in canine lung.  Respir Physiol  1975; 25:9.

Sant'Ambrogio et al., 1993. Sant'Ambrogio FB, Anderson JW, Nishino T, Sant'Ambrogio G: Effects of halothane and isoflurane in the upper airway of dogs during development.  Respir Physiol  1993; 91:237.

Sant'Ambrogio, 1982. Sant'Ambrogio G: Information arising from the tracheobronchial tree of mammals.  Physiol Rev  1982; 62:531.

Sant'Ambrogio et al., 1983. Sant'Ambrogio G, Mathew OP, Fisher JT, Sant'Ambrogio FB: Laryngeal receptors responding to transmural pressure, airflow and local muscle activity.  Respir Physiol  1983; 54:317.

Sant'Ambrogio et al., 1985. Sant'Ambrogio G, Mathew OP, Sant'Ambrogio FB, Fisher JT: Laryngeal cold receptors.  Respir Physiol  1985; 59:35.

Sant'Ambrogio et al., 1995. Sant'Ambrogio G, Tsubone H, Sant'Ambrogio FB: Sensory information from the upper airway: Role in the control of breathing.  Respir Physiol  1995; 102:1-16.

Sasaki, 1979. Sasaki CT: Development of laryngeal function: Etiologic significance in the sudden infant death syndrome.  Laryngoscope  1979; 89:1964.

Sasaki et al., 1977. Sasaki CT, Levine PA, Laitman JT, Crelin Jr ES: Postnatal descent of the epiglottis in man.  Arch Otolaryngol  1977; 103:169.

Sauerland and Harper, 1976. Sauerland EK, Harper RM: The human tongue during sleep: Electromyographic activity of the genioglossus muscle.  Exp Neural  1976; 51:160.

Savoy et al., 1982. Savoy J, Arnup ME, Anthonisen NR: Response to external inspiratory resistive loading and bronchospasm in anesthetized dogs.  J Appl Physiol  1982; 53:355.

Scher et al., 1992. Scher MS, Steppe DA, Dahl RE, et al: Comparison of EEG sleep measures in healthy full-term and preterm infants at matching conceptional ages.  Sleep  1992; 15:442-448.

Sellick and Widdicombe, 1970. Sellick H, Widdicombe JG: Vagal deflation and inflation reflexes mediated by lung irritant receptors.  J Exp Physiol  1970; 55:153.

Serafini et al., 1999. Serafini G, Cornara G, Cavalloro F, et al: Pulmonary atelectasis during paediatric anaesthesia: CT scan evaluation and effects of positive end expiratory pressure (PEEP).  Paediatr Anaesth  1999; 9:225-228.

Severinghaus, 1966. Severinghaus JW: Blood gas calculator.  J Appl Physiol  1966; 21:1108.

Severinghaus, 1972. Severinghaus JW: Hypoxic respiratory drive and its loss during chronic hypoxia.  Clin Physiol  1972; 2:57.

Severinghaus and Mitchell, 1962. Severinghaus JW, Mitchell RA: “Ondine's curse”: Failure of respiratory center automaticity while awake.  Clin Res  1962; 10:122.

Severinghaus et al., 1963. Severinghaus JW, Mitchell RA, Richardson BW, Singer MM: Respiratory control of high altitude suggesting active transport regulation of CSF pH.  J Appl Physiol  1963; 18:1155.

Shah et al., 1994. Shah NS, Jacob TD, Exler R, et al: Inhaled nitric oxide in congenital diaphragmatic hernia.  J Pediatr Surg  1994; 29:1010.

Shannon et al., 1977. Shannon DC, Kelly DH, O'Connor KG: Abnormal regulation of ventilation in infants: A risk for sudden infant death syndrome.  N Engl J Med  1977; 297:747.

Sly and Hayden, 1998. Sly PD, Hayden MJ: Applied clinical respiratory physiology.   In: Taussig LM, Landau LI, ed. Pediatric respiratory medicine,  St. Louis: Mosby; 1998:95.

Smith and Bogues, 1982. Smith BT, Bogues WG: Effects of drugs and hormones on lung maturation in experimental animal and man.  Pharmacol Ther  1982; 9:51.

Smith et al., 1991. Smith JC, Ellenberger HH, Ballanyi K, et al: Pre-Boetzinger complex: A brain stem region that may generate respiratory rhythm in mammals.  Science  1991; 254:726-729.

Smith et al., 1970. Smith TC, Colton ET, Behar MG: Does anesthesia alter hemoglobin dissociation?.  Anesthesiology  1970; 32:5.

Sorensen and Severinghaus, 1968. Sorensen SC, Severinghaus JW: Irreversible respiratory insensitivity to acute hypoxia in man born at high altitude.  J Appl Physiol  1968; 25:217.

Spear et al., 1969. Spear GS, Vaeusorn O, Avery ME, et al: Inclusions in terminal air spaces of fetal and neonatal human lung.  Biol Neonate  1969; 14:344.

Spitzer and Fox, 1984. Spitzer AR, Fox WW: Infant apnea.  Clin Pediatr  1984; 23:374.

Stamler et al., 1994. Stamler JS, Loh E, Roddy MA, et al: Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.  Circulation  1994; 89:2035.

Stark and Thach, 1976. Stark AR, Thach BT: Mechanisms of airway obstruction leading to apnea in newborn infants.  J Pediatr  1976; 89:982.

Stern et al., 1969. Stern E, Parmelee AH, Akiyama Y, et al: Sleep cycle characteristics in infants.  Pediatrics  1969; 43:65.

Steward, 1982. Steward DJ: Preterm infants are more prone to complications following minor surgery than are term infants.  Anesthesiology  1982; 56:304.

Stocks, 1980. Stocks J: Effect of nasogastric tubes on nasal resistance during infancy.  Arch Dis Child  1980; 55:17.

Stocks and Godfrey, 1978. Stocks J, Godfrey S: Nasal resistance during infancy.  Respir Physiol  1978; 34:233.

Stocks and Godfrey, 1977. Stocks J, Godfrey S: Specific airway conductance in relation to postconceptional age during infancy.  J Appl Physiol  1977; 43:144.

Stocks et al., 1977. Stocks J, Levy NM, Godfrey S: A new apparatus for the accurate measurement of airway resistance in infancy.  J Appl Physiol  1977; 43:155.

Strang and MacLeish, 1961. Strang LB, MacLeish MH: Ventilatory failure and right-to-left shunt in newborn infants with respiratory distress.  Pediatrics  1961; 28:17.

Suzuki and Sasaki, 1977. Suzuki M, Sasaki CT: Laryngeal spasm: A neurophysiologic redefinition.  Ann Otol Rhinol Laryngol  1977; 86:150.

Swift and Emery, 1973. Swift PGF, Emery JL: Clinical observations in response to nasal occlusion in infancy.  Arch Dis Child  1973; 48:947.

Sykes et al., 1972. Sykes MK, Loh L, Seed RF, et al: The effect of inhalational anaesthetics on hypoxic pulmonary vasoconstriction and pulmonary vascular resistance in the perfused lungs of the dog and cat.  Br J Anaesth  1972; 44:776.

Tabatabai and Behnia, 1995. Tabatabai M, Behnia R: Neurochemical regulation of respiration.   In: Collins VJ, ed. Physiological and pharmacological basis of anesthesia,  Philadelphia: Williams & Wilkins; 1995.

Tauesch et al., 1973. Tauesch Jr HW, Carson SH, Wang NS, Avery ME: Heroin induction of lung maturation and growth retardation in fetal rabbits.  J Pediatr  1973; 82:869.

Taussig et al., 1982. Taussig LM, Landau LI, Godfrey S, Arad I: Determinants of forced expiratory flows in newborn infants.  J Appl Physiol  1982; 53:1220.

Temp et al., 1992. Temp JA, Henson LC, Ward DS: Does a subanesthetic concentration of isoflurane blunt the ventilatory response to hypoxia?.  Anesthesiology  1992; 77:1116.

Temp et al., 1994. Temp JA, Henson LC, Ward DS: Effect of subanesthetic minimum alveolar concentration of isoflurane on two tests of the hypoxic ventilatory response.  Anesthesiology  1994; 80:739.

Thach, 1985. Thach BT: Sleep apnea in infancy and childhood.  Med Clin North Am  1985; 69:1289.

Thach, 1988. Thach BT: Potential role of airway obstruction in SIDS.   In: Krous H, Culbertson H, ed. Sudden infant death syndrome,  Baltimore: Johns Hopkins Press; 1988.

Thach, 1992. Thach BT: Neuromuscular control of the upper airway.   In: Beckerman RC, Brouillette RT, Hunt CE, ed. Respiratory control disorders in infants and children,  Baltimore: Williams & Wilkins; 1992.

Thach et al., 1989. Thach BT, Menon PA, Schefft G: Effects of negative upper airway pressure on the pattern of breathing in sleeping infants.  J Appl Physiol  1989; 66:1599.

Thorling and Erslev, 1968. Thorling EG, Erslev AJ: The “tissue” tension of oxygen and its relation to hematocrit and erythropoiesis.  Blood  1968; 31:332.

Thorsteinsson et al., 1994. Thorsteinsson A, Larsson A, Jonmarker C, Werner O: Pressure-volume relations of the respiratory system in healthy children.  Am J Respir Crit Care Med  1994; 150:421.

Thurlbeck, 1975. Thurlbeck WM: Postnatal growth and development of the lung.  Am Rev Respir Dis  1975; 111:803.

Toda et al., 1992. Toda H, Nakamura K, Hatano Y, et al: Halothane and isoflurane inhibit endothelium-dependent relaxation elicited by acetylcholine.  Anesth Analg  1992; 75:198.

van Iwaarden et al., 1990. van Iwaarden F, Welmers B, Verhoef J, et al: Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages.  Am J Respir Cell Mol Biol  1990; 2:91.

Vidruk et al., 1977. Vidruk EH, Hahn HL, Nadel JA, Sampson SR: Mechanisms by which histamine stimulates rapidly adapting receptors in dog lungs.  J Appl Physiol  1977; 43:397.

von Euler, 1986. von Euler C: Brain stem mechanisms for generation and control of breathing pattern.   In: Cherniack NS, Widdicombe JG, ed. Handbook of physiology. Section 3. The respiratory system. Vol 2. Control of breathing, part 1,  Bethesda, MD: American Physiology Society; 1986.

von Euler, 1983. von Euler C: On the central pattern generator for the basic breathing rhythmicity.  J Appl Physiol  1983; 55:1647.

von Euler, 1991. von Euler C: Neural organization and rhythm generation.   In: Crystal RG, West JB, ed. The lung: Scientific foundations,  New York: Raven Press; 1991.

von Euler and Trippenbach, 1975. von Euler C, Trippenbach T: Cyclic excitability changes of the inspiratory “off switch” mechanism.  Acta Physiol Scand  1975; 93:560.

Wade et al., 1970. Wade JG, Larson Jr CP, Hickey RF, et al: Effect of carotid endarterectomy on carotid chemoreceptor and baroreceptor function in man.  N Engl J Med  1970; 282:823.

Wahba, 1980. Wahba WM: Analysis of ventilatory depression by enflurane during clinical anesthesia.  Anesth Analg  1980; 59:103.

Wagner, 1988. Wagner PD: Diffusion, diffusing capacity, and chemical reactions.   In: Fishman AP, ed. Pulmonary diseases and disorders,  New York: McGraw-Hill Book Co.; 1988.

Wagner et al., 1974. Wagner PD, Saltzman HA, West JB: Measurement of continuous distributions of ventilation-perfusion ratios: Theory.  J Appl Physiol  1974; 36:588.

Weaver and Whitsett, 1991. Weaver T, Whitsett JA: Function and regulation of expression of pulmonary surfactant proteins.  Biochem J  1991; 273:249.

Weibel, 1963. Weibel ER: Morphometry of the human lung,  New York, Academic Press, 1963.

Weibel, 1973. Weibel ER: Morphological basis of alveolar-capillary gas exchange.  Physiol Rev  1973; 53:419.

Weiskopf et al., 1974. Weiskopf RB, Raymond LW, Severinghaus JW: Effects of halothane on canine respiratory response to hypoxia with and without hypercarbia.  Anesthesiology  1974; 41:350.

Welborn et al., 1988. Welborn LG, DeSoto H, Hannallah RS, et al: The use of caffeine in the control of post-anesthetic apnea in former premature infants.  Anesthesiology  1988; 68:796.

Welch and Loscalzo, 1994. Welch G, Loscalzo J: Collective review: Nitric oxide and the cardiovascular system.  J Card Surg  1994; 9:361.

Wessel, 1993. Wessel DL: Inhaled nitric oxide for the treatment of pulmonary hypertension before and after cardiopulmonary bypass.  Crit Care Med  1993; 21(suppl):S344.

West, 1974. West JB: Blood flow to the lung and gas exchange.  Anesthesiology  1974; 41:124.

West, 1965. West JB: Topographical distribution of blood flow in the lung.   In: Fenn WO, Rahn H, ed. Handbook of physiology. Vol 2. Section 3. Respiration,  Washington, DC: American Physiological Society; 1965.

West, 1970. West JB: Ventilation/blood flow and gas exchange,  ed 2. Oxford, Blackwell Scientific Publications, Ltd., 1970.

West, 1994. West JB: Ventilation, blood flow, and gas exchange.   In: Murray JF, Nadel JA, ed. Textbook of respiratory medicine,  ed 2. Philadelphia: WB Saunders; 1994.

Westbrook et al., 1973. Westbrook PR, Stubbs SE, Sessler AD, et al: Effects of anesthesia and muscle paralysis on respiratory mechanics in normal man.  J Appl Physiol  1973; 34:81.

Whitelaw et al., 1975. Whitelaw WA, Derenne JP, Milic-Emili J: Occlusion pressure as a measure of respiratory center output in conscious man.  Respir Physiol  1975; 23:181.

Whitsett and Horowitz, 1998. Whitsett JA, Horowitz AD: Surfactant and associated proteins.   In: Fishman AP, ed. Fishman's pulmonary diseases and disorders,  ed 3. New York: McGraw-Hill; 1998:119.

Widdicombe, 1981. Widdicombe JG: Nervous receptors in the respiratory tract and lungs.   In: Hornbein TF, ed. Regulation of breathing, part 1,  New York: Marcel Dekker; 1981.

Widdicombe, 1974. Widdicombe JG: Reflex control of breathing.   In: Widdicombe JG, ed. Respiratory physiology. MTP International Review of Science, series 1, vol 2,  Borough Green, Kent: Butterworth; 1974.

Widdicombe, 1985. Widdicombe JG: Reflexes from the upper respiratory tract.   In: Cherniak NS, Widdicombe JG, ed. Handbook of physiology. Section 3. The respiratory system. Vol II. Control of breathing, Part 1,  Bethesda, MD: American Physiological Society; 1985.

Wohl et al., 1969. Wohl MEB, Stigol LC, Mead J: Resistance of the total respiratory system in healthy infants and infants with bronchiolitis.  Pediatrics  1969; 43:495.

Wolfe et al., 1972. Wolfe WG, Ebert PA, Sabiston DC: Effect of high oxygen tension on mucociliary function.  Surgery  1972; 72:246.

Woolcock et al., 1969. Woolcock AJ, Vincent NJ, Macklem PT: Frequency dependence of compliance as a test for obstruction in small airways.  J Clin Invest  1969; 48:1097.

Wu et al., 1973. Wu B, Kikkawa Y, Orzalesi MM, et al: The effect of thyroxine on the maturation of fetal rabbit lungs.  Biol Neonate  1973; 22:161.

Xue et al., 1996. Xue FS, Huang YG, Tong SY, et al: A comparative study of early postoperative hypoxemia in infants, children, and adults undergoing elective plastic surgery.  Anesth Analg  1996; 83:709-715.

Yoshida and Okabe, 1992. Yoshida K, Okabe E: Selective impairment of endothelium-dependent relaxation by sevoflurane: Oxygen free radicals participation.  Anesthesiology  1992; 76:440.

Zapletal et al., 1971. Zapletal A, Motoyama EK, Gibson LE, Bouhuys A: Pulmonary mechanics in asthma and cystic fibrosis.  Pediatrics  1971; 48:64.

Zapletal et al., 1969. Zapletal A, Motoyama EK, van de Woestijne KP, et al: Maximum expiratory flow-volume curves and airway conductance in children and adolescents.  J Appl Physiol  1969; 26:308.

Zapletal et al., 1976. Zapletal A, Paul T, Samanek M: Pulmonary elasticity in children and adolescents.  J Appl Physiol  1976; 40:953.

Zapletal et al., 1987. Zapletal A, Samanek M, Paul T: Lung function in children and adolescents: Methods, reference values,  New York, Karger, 1987.

Zeltner and Burri, 1987. Zeltner TB, Burri PH: The postnatal development and growth of the human lung. II. Morphology.  Respir Physiol  1987; 67:269.

Zin et al., 1982. Zin WA, Pengelly LD, Milic-Emili J: Single-breath method for measurement of respiratory mechanics in anesthetized animals.  J Appl Physiol  1982; 52:1266.